Neuropsychological Assessment of Dementia*bradd/library/salmon_annur… · ·...

ANRV364-PS60-10 ARI 27 October 2008 16:15

NeuropsychologicalAssessment of Dementia∗

David P. Salmon1 and Mark W. Bondi2,3

1Department of Neurosciences, 2Department of Psychiatry, University of California,San Diego, California 92093; 3Veterans Affairs San Diego Healthcare System, San Diego,California 92161; email: [email protected]

Annu. Rev. Psychol. 2009. 60:257–82

The Annual Review of Psychology is online atpsych.annualreviews.org

This article’s doi:10.1146/annurev.psych.57.102904.190024

Copyright c© 2009 by Annual Reviews.All rights reserved

0066-4308/09/0110-0257$20.00

∗The U.S. Government has the right to retain anonexclusive, royalty-free license in and to anycopyright covering this paper.

Key Words

cognition, memory, Alzheimer’s disease

AbstractNeuropsychological studies show that cognitive deficits associated withAlzheimer’s disease (AD) are distinct from age-associated cognitive de-cline. Quantitative and qualitative differences are apparent across manycognitive domains, but are especially obvious in episodic memory (par-ticularly delayed recall), semantic knowledge, and some aspects of ex-ecutive functions. The qualitatively distinct pattern of deficits is lesssalient in very old AD patients than in younger AD patients. Althoughdecline in episodic memory is usually the earliest cognitive change thatoccurs prior to the development of the AD dementia syndrome, asym-metry in cognitive abilities may also occur in this “preclinical” phase ofthe disease and predict imminent dementia. Discrete patterns of cogni-tive deficits occur in AD and several neuropathologically distinct age-associated neurodegenerative disorders. Knowledge of these differenceshelps to clinically distinguish among various causes of dementia andprovides useful models for understanding brain-behavior relationshipsthat mediate cognitive abilities affected in various neurodegenerativediseases.

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Dementia: syndromeof acquired intellectualimpairment ofsufficient severity tointerfere with social oroccupationalfunctioning caused bybrain dysfunction

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 258NEUROPSYCHOLOGICAL

DETECTION OFALZHEIMER’S DISEASE . . . . . . . . 258The Impact of Aging on the

Neuropsychological Detectionof Alzheimer’s Disease. . . . . . . . . . . 260

Neuropsychological Detection of“Preclinical” Alzheimer’sDisease . . . . . . . . . . . . . . . . . . . . . . . . . 263

ALZHEIMER’S DISEASE AS ADISCONNECTIONSYNDROME . . . . . . . . . . . . . . . . . . . . . 264

DISTINGUISHING ALZHEIMER’SDISEASE FROM OTHERAGE-RELATED CAUSESOF DEMENTIA . . . . . . . . . . . . . . . . . . 266Alzheimer’s Disease versus

Huntington’s Disease . . . . . . . . . . . 266Alzheimer’s Disease versus Dementia

with Lewy Bodies . . . . . . . . . . . . . . . 268Alzheimer’s Disease versus

Frontotemporal Dementia. . . . . . . 271Alzheimer’s Disease versus

Vascular Dementia . . . . . . . . . . . . . . 272CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 274

INTRODUCTION

The detection and characterization of cognitivedeficits associated with age-related neurode-generative diseases such as Alzheimer’s disease(AD) is the focus of growing clinical researchinterest as increasing numbers of peoplesurvive into older age. This interest is fueledby the need to accurately detect the onset ofcognitive changes that signal the beginningof a progressive dementia syndrome and todifferentiate among disorders with distinctetiologies and sites of pathology. This can bea particularly difficult task given the insidiousonset and slow progression of most neurode-generative diseases, but it is critically importantgiven the lack of a reliable biological marker

that can distinguish AD from normal aging orother neurodegenerative disorders that leadto dementia. Accurate clinical diagnosis ofdementia and its underlying cause is crucialfor prognosis and the early and appropriateapplication of disease-specific treatments thatare currently available or in development.

Neuropsychological research on dementiahas focused on AD because it is the most com-mon cause of dementia and is primarily definedby its impact on cognition. This research hasled to increased knowledge about the particu-lar cognitive deficits that occur in the earlieststages of AD, and this has enhanced the abil-ity to clinically diagnosis the disease early in itscourse. The impact of aging on the ability todetect AD has been described, and subtle cog-nitive changes that might foreshadow the de-velopment of dementia in those with “preclin-ical” AD have been identified. The cognitivemanifestations of AD have been compared andcontrasted to those of other age-related neu-rodegenerative disorders in order to improvedifferential diagnosis and provide informationabout the neurological basis of various cognitiveabilities that are affected. The contributions ofthis research to the neuropsychological assess-ment of dementia are reviewed below.

NEUROPSYCHOLOGICALDETECTION OFALZHEIMER’S DISEASE

Alzheimer’s disease is an age-related degener-ative brain disorder characterized by neuronalatrophy, synapse loss, and the abnormal accu-mulation of amyloidogenic plaques and neu-rofibrillary tangles in medial temporal lobelimbic structures (e.g., entorhinal cortex, hip-pocampus) and the association cortices of thefrontal, temporal, and parietal lobes (Braak &Braak 1991). Consistent with these widespreadneuropathological changes, the primary clini-cal manifestation of AD is a progressive globaldementia syndrome that usually begins in laterlife (i.e., ages 60–70). In the usual case, the de-mentia syndrome is characterized by prominentamnesia with additional deficits in language and

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semantic knowledge, abstract reasoning, execu-tive functions, attention, and visuospatial abili-ties (Salmon & Bondi 1999). These cognitivedeficits and the decline in everyday functionthey produce are the core features of the ADdementia syndrome and are the focus of clini-cal assessment of the disease.

Although the pattern of progression of ADpathology is not fully known, evidence suggeststhat the earliest changes occur in medial tempo-ral lobe structures (e.g., hippocampus, entorhi-nal cortex) that are critical for episodic memory(Braak & Braak 1991). This is consistent witha wealth of neuropsychological evidence show-ing that episodic memory impairment (i.e., am-nesia) is usually the earliest and most salientaspect of the AD dementia syndrome (for re-view, see Salmon 2000). Studies of the clini-cal utility of episodic memory measures for theearly detection of AD have identified a numberof characteristics that are quite effective in dif-ferentiating between mildly demented AD pa-tients and normal older adults. First, patientswith very early AD are particularly impairedon measures of delayed recall (i.e., have ab-normally rapid forgetting), with several stud-ies showing that absolute delayed recall scoresor “savings” scores (i.e., amount recalled afterthe delay divided by the amount recalled onthe immediate learning trial) can differentiatemildly demented AD patients from healthy el-derly controls with approximately 85% to 90%accuracy (for review, see Salmon 2000). Second,to-be-remembered information is not accessi-ble after a delay even if retrieval demands arereduced by the use of recognition testing (e.g.,Delis et al. 1991). Third, AD patients exhibitan abnormal serial position effect characterizedby an attenuation of the primacy effect (i.e., re-call of words from the beginning of a list), sug-gesting that they cannot effectively transfer in-formation from primary memory to secondarymemory (e.g., Bayley et al. 2000). Fourth, se-mantic encoding is less effective in improvingthe episodic memory performance of patientswith AD than normal elderly individuals (forreview, see Backman & Small 1998). Fifth, pa-tients with AD have an enhanced tendency to

Executive functions:higher-order cognitiveprocesses involved inplanning, conceptformation, problemsolving, cue-directedbehavior, and theconcurrentmanipulation andretention ofinformation

Episodic memory:memory forautobiographicalevents and episodesthat depend upontemporal and/orspatial contextual cuesfor their retrieval

Semantic memory:general fund ofknowledge thatconsists of overlearnedfacts and concepts thatare not dependentupon contextual cuesfor retrieval (e.g.,meanings of words andwell-knowngeographical,historical, andarithmetical facts)

produce intrusion errors (i.e., when previouslylearned information is produced during the at-tempt to recall new material) on both verbaland nonverbal memory tests, presumably due toincreased sensitivity to interference and/or de-creased inhibitory processes (Butters et al. 1987,Jacobs et al. 1990). Evaluation of these charac-teristics of the memory deficit associated withAD is incorporated into several memory teststhat are effective for early detection of the dis-ease (e.g., Buschke 1973, Buschke et al. 1997,Knopman & Ryberg 1989) and in clinical al-gorithms developed to differentiate AD fromother types of dementia (e.g., Delis et al. 1991).

As the neuropathology of AD spreads be-yond medial temporal lobe structures to the as-sociation cortices of the temporal, frontal, andparietal lobes (Braak & Braak 1991), a numberof higher-order cognitive abilities are affected.Patients with AD develop a semantic memorydeficit that manifests itself as a loss of generalknowledge and impairment of language abil-ities (i.e., aphasia). Patients with AD are oftenimpaired on tests of confrontation naming, ver-bal fluency, and semantic categorization, andhave a reduced ability to recall overlearned facts(e.g., the number of days in a year) (for re-views, see Chan et al. 1998, Hodges & Patterson1995, Nebes 1989). Interestingly, patients arehighly consistent in the individual items theymiss across different semantic memory teststhat employ unique modes of access and out-put (e.g., fluency versus confrontation naming;Chertkow & Bub 1990, Hodges et al. 1992) orwithin the same test across unique evaluations(Norton et al. 1997). This suggests that AD re-sults in a true loss of semantic knowledge ratherthan only an impaired ability to retrieve in-formation from intact semantic memory stores(also see Salmon et al. 1999). A similar loss ofknowledge is thought to contribute to the se-vere deficit that patients with AD exhibit in theability to remember past events that were suc-cessfully remembered prior to the onset of thedisease (i.e., retrograde amnesia) (for review, seeSalmon 2000).

Deficits in executive functions responsi-ble for concurrent mental manipulation of

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information, concept formation, problem solv-ing, and cue-directed behavior occur early inthe course of AD (Perry & Hodges 1999). Theability to perform concurrent manipulation ofinformation appears to be particularly vulner-able. Lefleche & Albert (1995) demonstratedthat very mildly demented patients with ADwere significantly impaired relative to elderlynormal control subjects on tests that requiredset shifting, self-monitoring, or sequencing, butnot on tests that required cue-directed attentionor verbal problem solving. Patients with ADhave also been shown to be impaired on (a) dif-ficult problem-solving tests such as the Towerof London puzzle (Lange et al. 1995) and themodified Wisconsin Card Sorting Task (Bondiet al. 1993), (b) tests of relational integration(Waltz et al. 2004), and (c) various other clini-cal neuropsychological tests that assess execu-tive functions such as the Porteus Maze Task,Part B of the Trail-Making Test, and the RavenProgressive Matrices Task (e.g., Grady et al.1988).

Deficits in attention and visuospatial abili-ties develop during the course of AD, but areusually less salient than other cognitive deficitsin the early stages of disease (Butters et al. 1988,Storandt et al. 1984). When attention deficitsdo occur, they are usually evident on dual-processing tasks, tasks that require the disen-gagement and shifting of attention, and work-ing memory tasks that are dependent upon thecontrol of attentional resources (for reviews, seeParasuraman & Haxby 1993, Perry & Hodges1999). Visuospatial deficits associated with ADusually affect visuoconstructional abilities as-sessed by the Block Design Test, the ClockDrawing Test, and complex figure copying (i.e.,apraxia), and visuoperceptual abilities tappedby tests such as Judgment of Line Orienta-tion or the Money Road Map Test (for reviews,see Cronin-Golomb & Amick 2001, Freedmanet al. 1994).

The neuropsychological research reviewedabove suggests that in the usual case, AD isassociated with a specific pattern of cognitivedeficits that can effectively differentiate the dis-ease from normal aging. This was confirmed

in a study by Salmon and colleagues (2002)that compared the performances of 98 patientswith early AD (i.e., scored ≥24 on the Mini-Mental State Exam) and 98 gender-, age-, andeducation-matched normal control subjects onsensitive measures of learning and memory, ex-ecutive abilities, language, and visuospatial abil-ities. The diagnosis of AD was verified in eachof the AD patients by subsequent autopsy orlongitudinal clinical evaluations that showed atypical course for the disease. Receiver Operat-ing Characteristic curve analyses showed excel-lent sensitivity and specificity for the detectionof very mild AD for learning and delayed recallmeasures from the California Verbal LearningTest (sensitivity: 95%–98%, specificity: 88%–89%), the category fluency test (sensitivity:96%, specificity: 88%), and Part B of the Trail-Making Test (sensitivity: 85%, specificity: 83%)(see Figure 1). A diagnostic model obtained us-ing a nonparametric recursive partitioning pro-cedure (classification tree analysis) showed thata combination of performance on the categoryfluency test (a measure of semantic memory andexecutive function) and the delayed recall mea-sure of the Visual Reproduction Test accuratelyclassified 96% of the patients with AD and 93%of the elderly normal control subjects, a levelof accuracy higher than achieved with any in-dividual cognitive measure. These results sup-port the view that deficits in episodic memory(e.g., rapid forgetting), certain executive func-tions (e.g., cognitive set shifting), and seman-tic knowledge are particularly characteristic ofearly AD.

The Impact of Aging on theNeuropsychological Detectionof Alzheimer’s Disease

Although much progress has been made inidentifying the typical pattern of cognitivedeficits associated with early AD, the bound-aries between normal age-related cognitivechange and early signs of AD remain especiallydifficult to delineate in very elderly individuals(i.e., over the age of 80). This is because manyof the early structural and functional brain

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CVLT Long-Delay Free Recall (Z-Score)

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Figure 1Receiver Operating Characteristic curves comparing sensitivity and specificity for the accurate diagnosis of early Alzheimer’s disease(AD) achieved with the Trial 1–5 Learning measure from the California Verbal Learning Test (CVLT), the Long-Delay Free Recallmeasure from the CVLT, the Category Fluency Test (a semantic memory and executive function measure), and Part B of theTrail-Making Test (an executive function measure). The maximally effective cut-point for memory and executive function measuresshowed excellent sensitivity and specificity in distinguishing between very mild AD and normal aging. (Adapted from Salmon et al.2002.)


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MRI: magneticresonance imaging

changes of AD overlap with changes observed innormal aging. Normal aging is associated withmild brain atrophy and increased white matterabnormality seen on magnetic resonance imag-ing (MRI) scans (e.g., Jack et al. 1998, Jerniganet al. 2001, Pfefferbaum et al. 1994), decreasedhemodynamic response seen on functional MRIscans (D’Esposito et al. 1999), and reducedsynaptic density evident upon histopathologi-cal examination of brain tissue (Masliah et al.1993). These brain changes are thought to me-diate age-related decline in information pro-cessing speed, executive function, learning ef-ficiency, and effortful retrieval (for review, seeHedden & Gabrieli 2004). Because normal ag-ing can detrimentally affect many of the samecognitive abilities affected by AD, the promi-nence of specific deficits related to AD may bemuch less evident in the Very-Old (over theage of 80) than in the Young-Old (below theage of 70), especially after performance is stan-dardized to that of the age-appropriate normalcohort. As a result, a less distinct and some-what atypical cognitive deficit profile is associ-ated with AD in the Very-Old compared to theYoung-Old.

This difference in profiles was illustratedin a study that directly compared the neu-ropsychological test performance of AD pa-tients who were Very-Old or Young-Old (Bondiet al. 2003). Despite achieving similar rawscores on all neuropsychological measures, theYoung-Old and Very-Old AD patients dif-fered in the severity and pattern of the cog-nitive deficits they exhibited in relation totheir age-appropriate controls (see Figure 2).The Young-Old AD patients were generallymore impaired than the Very-Old patients andshowed a typical AD profile. That is, they ex-hibited worse deficits in episodic memory (i.e.,savings scores) and executive functions than inother cognitive domains. The Very-Old ADpatients, in contrast, exhibited a similar levelof impairment across all cognitive domains sothat their deficit profile lacked the dispropor-tionate saliency of memory and executive func-tion deficits typical of the disease. Because theraw scores of the Young-Old and Very-Old ADpatients were similar, the driving force behindtheir unique deficit profiles was the age-relateddifferences in the performance of the nor-mal control cohorts. Thus, normal aging can

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Figure 2The average composite impairment score achieved by Alzheimer’s disease (AD) patients older than age 80 oryounger than age 70 in the cognitive domains of language, visuospatial abilities, executive functions, andmemory (savings scores). The presented scores are z-scores referenced to the patient groups’ respectiveage-appropriate healthy elderly control cohort. (Adapted from Bondi et al. 2003.)

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significantly affect the severity and patternof neuropsychological deficits associated withearly AD and reduce the saliency of the deficitprofile as a diagnostic marker of the disease.This finding has important clinical implicationsbecause it identifies the significant risk of falsenegative diagnostic errors in very elderly ADpatients if the clinician expects to see the typi-cal deficit pattern characteristic of younger ADpatients. Accurate detection of AD in the veryelderly patient may require a multifaceted ap-proach to diagnosis that integrates neuropsy-chological assessment, neuroimaging, and ge-netic factors.

Neuropsychological Detection of“Preclinical” Alzheimer’s Disease

It is commonly accepted that the neurodegen-erative changes of AD begin well before clin-ical manifestations of the disease become ap-parent (e.g., Katzman 1994). As the pathologicchanges of AD gradually accumulate, a thresh-old for the initiation of the clinical symptomsof the disease is eventually reached. Once thisthreshold is crossed, cognitive deficits becomeevident and gradually worsen in parallel withcontinued neurodegeneration. When the cog-nitive deficits become global and severe enoughto interfere with normal social and occupationalfunctioning, established criteria for dementiaand a clinical diagnosis of AD are met. It isclear from this sequence of events that subtlecognitive decline is likely to occur in a patientwith AD well before the clinical diagnosis canbe made with any certainty. Identification ofthe cognitive changes that occur during this“preclinical” phase of the disease might pro-vide a reliable way to detect AD in its earlieststages, when potential disease-modifying treat-ments might be most effective (Thal 1999). Be-cause of the importance of this goal, the attemptto identify preclinical cognitive changes of ADis one of the most active areas of neuropsycho-logical research.

In light of neuropathological evidence thatthe earliest changes of AD usually occur in themedial temporal lobe structures that are known

to be critical for episodic memory (Braak &Braak 1991), it is not surprising that the searchfor preclinical cognitive markers of the diseasehas focused largely on this aspect of cognition.Indeed, a number of prospective longitudinalstudies of cognitive function in nondementedolder adults have shown that a subtle declinein episodic memory often occurs prior to theemergence of the obvious cognitive and behav-ioral changes required for a clinical diagnosis ofAD (for review, see Twamley et al. 2006). Thesefindings led to the development of formal crite-ria for mild cognitive impairment (MCI), a pre-dementia condition in elderly individuals thatis characterized by both subjective and objec-tive memory impairment that occurs in the faceof relatively preserved general cognition andfunctional abilities (for reviews, see Albert &Blacker 2006, Collie & Maruff 2000, Petersenet al. 2001).

The course of episodic memory change dur-ing the preclinical phase of AD has been thefocus of a number of studies (Backman et al.2001, Chen et al. 2001, Rubin et al. 1998, Smallet al. 2000, Storandt et al. 2002). These studiessuggest that memory performance may be poorbut stable a number of years prior to the de-velopment of the dementia syndrome in thosewith AD, and then decline rapidly in the pe-riod immediately preceding the dementia diag-nosis. Small et al. (2000) and Backman et al.(2001), for example, found that episodic mem-ory was mildly impaired six years prior to de-mentia onset, but changed little over the nextthree years. In contrast, Chen et al. (2001) andLange et al. (2002) showed a significant andsteady decline in episodic memory beginningabout three years prior to the dementia diag-nosis in individuals with preclinical AD. Theseresults indicate that an abrupt decline in mem-ory in an elderly individual might better predictthe imminent onset of dementia than poor butstable memory ability.

Although the search for cognitive changes inpreclinical AD has largely focused on episodicmemory, several recent reviews and meta-analyses suggest that largely nonspecific cog-nitive decline occurs in the two to three years


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Corticocorticaldisconnection: theloss of effectiveinteraction betweenfunctionally relatedcortical associationareas

preceding a dementia diagnosis (Backman et al.2004, 2005; Twamley et al. 2006). Althoughthese studies consistently find a decline inepisodic memory, they also often reveal addi-tional deficits in executive functions, perceptualspeed, verbal ability, visuospatial skill, and at-tention during the preclinical phase of AD. Thiswidespread decline in cognitive abilities mirrorsevidence that multiple brain regions (e.g., me-dial temporal lobes, frontal lobes, anterior cin-gulate cortex) are impaired in preclinical AD(Albert et al. 2001, Small et al. 2003).

Consistent with this broader view, Jacobsonand colleagues (2002) found that asymmetry incognitive performance can be a marker of pre-clinical AD. Based upon prior research doc-umenting lateralized cognitive deficits (e.g.,greater verbal than visuospatial deficits, or viceversa) in subgroups of mildly demented AD pa-tients, these investigators compared cognitivelynormal elderly adults with preclinical AD (i.e.,they were diagnosed with AD approximatelyone year later) and age- and education-matchednormal control subjects on a derived neuropsy-chological test measure that reflected the abso-lute difference between verbal and visuospatialability (i.e., a measure of cognitive asymmetry).Although the groups performed similarly on in-dividual cognitive tests of memory, language,and visuospatial ability, a greater proportion ofthe preclinical AD patients than the controlshad asymmetric cognitive changes in either theverbal or visuospatial direction that were ob-scured when cognitive scores are averaged overthe entire group. Thus, the consideration ofboth cognitive asymmetry and subtle declinesin memory may improve the ability to detectAD in its earliest, preclinical stages.

ALZHEIMER’S DISEASE AS ADISCONNECTION SYNDROME

A growing body of evidence indicates that animportant early consequence of AD is the lossof effective interaction between various regionsof the cortex (e.g., De Lacoste & White 1993).From an anatomical perspective, neurofibril-lary tangles have been shown to have a strong

predilection for cortical layers (e.g., layer-IIIand layer-V) and cell types (e.g., midsize pyra-midal neurons) that support connections be-tween functionally related cortical associationareas. This is most clearly seen in the limbicsystem, where neurofibrillary tangle pathologyin midsize pyramidal neurons of the entorhinalcortex disconnects the hippocampus from neo-cortex (e.g., Hyman et al. 1984). Although lessobvious, this disconnection also occurs in theneocortex, where AD pathology in layer-III andlayer-V pyramidal neurons selectively disruptscorticocortical pathways that connect function-ally related cortical association areas (for reviewof the corticocortical disconnection, see Hof &Morrison 1999).

Neurophysiologically, cortical disconnec-tion appears to lead to marked abnormalitiesin the interregional pattern of blood-flow acti-vation elicited during the performance of cog-nitive tasks (for review, see Delbeuck et al.2003). It also appears to underlie reduced co-herence (i.e., synchronization) between elec-troencephalography signals measured at differ-ent scalp surface electrode sites that correspondto neocortical association areas that must workin concert during integrative cognitive tasks(e.g., cross-modal stimulus processing) (e.g.,Dunkin et al. 1995, Hogan et al. 2003, Jelic et al.1996, Knott et al. 2000, Stevens et al. 2001).Evoked potential refractory effects related topresentation of intermodal stimuli (i.e., audi-tory and visual) are also abnormally reduced inpatients with AD, consistent with impaired in-teraction between visual and auditory corticalsystems (Golob et al. 2001).

Few studies have directly examined the be-havioral consequences of functional discon-nectivity in patients with AD, but those thathave tend to find a selective impairment in in-formation integration (Della Sala et al. 2000,Freedman & Oscar-Berman 1997, Kurylo et al.1996, Lakmache et al. 1998, Tippett et al.2003). This was illustrated in a study by Fosterand colleagues (1999) that examined the im-pact of AD on “feature binding” (Treisman1996), the moment-by-moment ability to com-bine discrete sensory inputs analyzed in distinct

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cortical regions (e.g., color, shape, location) intoa coherent representation of a single object.Feature binding was hypothesized to be par-ticularly sensitive to cortical disconnection inAD because defective interaction among neo-cortical areas should produce a specific deficitin effectively integrating distinct stimulus fea-tures despite an intact ability to process eachfeature separately. Consistent with this notion,Foster and colleagues (1999) found that patientswith AD exhibited disproportionately greaterresponse times (compared to normal controls)when required to identify targets on the basisof a conjunction of two or more features (i.e.,a conjunction search) than when required toidentify targets solely on the basis of a singlefeature (i.e., a feature search). Tales et al. (2002)recently extended this finding by demonstratingthat the selective impairment of patients withAD on conjunction search tasks could not be at-tributed to different attentional demands inher-ent in conjunction versus single-feature tasks.

Building upon these previous findings, Festaand colleagues (2005) examined the impact ofcorticocortical disconnectivity in AD on theability to integrate motion and color informa-tion that is processed in distinct visual pro-cessing “streams.” These streams are function-ally segregated parallel cortical circuits thatanalyze different aspects of the visual scene(e.g., Ungerleider & Mishkin 1982). The dorsalstream projecting from striate cortex to pari-etal cortex selectively analyzes motion and lu-minance contrast information, while the ventralstream projecting from striate cortex to tempo-ral cortex selectively analyzes form and colorinformation. Previous research has shown thatneurologically intact individuals can integrate(i.e., bind) either type of surface feature (coloror luminance) with motion information in or-der to substantially reduce thresholds for mo-tion detection (e.g., Croner & Albright 1997).Color or luminance information is equally ef-fective in this regard even though enhancementof motion detection from color cues places rel-atively greater demand on cross-cortical inter-action since it requires the integration of in-formation across ventral (motion) and dorsal

(color) cortical streams (Dobkins & Albright1998). Enhancement of motion detection fromluminance cues only requires the integration ofinformation within the ventral stream.

Festa and colleagues (2005) showed that ADpatients had normal enhancement of motiondetection with luminance cues, but enhance-ment was significantly less than normal withcolor cues (see Figure 3). That is, patientscould effectively bind information processedwithin one visual stream, but could not cross-cortically bind information processed in sepa-rate cortical streams. This deficit could not beeasily attributed to general cognitive dysfunc-tion because both luminance-motion and color-motion integration were normal in dementedpatients with Huntington’s disease who do nothave prominent cortical dysfunction. Rather,these results provide psychophysical evidencefor cortical disconnectivity in AD and suggestthat AD might serve as a model system forinvestigating the neurocognitive substrates ofsensory integration. The specificity of cortical

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Figure 3The mean color-motion integration index scores achieved by normal control(NC) subjects, Alzheimer’s disease (AD) patients, and Huntington’s disease(HD) patients on a visual sensory integration task. The color-motionintegration index reflects the gain in motion direction detection derived fromusing color information that segments coherently moving targets fromdistracters. Patients with AD, but not those with HD, were significantly (∗)impaired in integrating motion and color information. (Adapted from Festaet al. 2005.)


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HD: Huntington’sdisease

DLB: dementia withLewy bodies

FTD: frontotemporaldementia

disconnectivity in AD suggests that it may havepotential as a cognitive marker for detecting andtracking progression of the disease.

DISTINGUISHING ALZHEIMER’SDISEASE FROM OTHERAGE-RELATED CAUSESOF DEMENTIA

Although AD is the leading cause of demen-tia in the elderly, it has been known for sometime that dementia can arise from a wide va-riety of etiologically and neuropathologicallydistinct disorders that give rise to different pat-terns of relatively spared and impaired cognitiveabilities. Knowledge of these differences maylead to better understanding of the neurobio-logical basis of specific cognitive deficits (andnormal cognition) and improve differential di-agnosis of various neurodegenerative disorders.The remaining sections review similarities anddifferences in the cognitive deficits of AD andthose of other age-related causes of dementiaincluding Huntington’s disease (HD), dementiawith Lewy bodies (DLB), frontotemporal de-mentia (FTD), and vascular dementia.

Alzheimer’s Disease versusHuntington’s Disease

HD is an inherited, autosomal dominant dis-ease that results in the midlife (i.e., ages 30–40) development of movement disorder (e.g.,chorea, dysarthria, gait disturbance, oculomo-tor dysfunction), behavioral changes (e.g., de-pression, irritability, anxiety) and dementia.These deficits arise primarily from a progres-sive deterioration of the neostriatum (caudatenucleus and putamen) (Vonsattel & Di Figlia1998) that disrupts frontostriatal loops thatconsist of projections from the frontal neo-cortex to the striatum, striatum to the globuspallidus, globus pallidus to thalamus, and tha-lamus back to specific regions of frontal cor-tex (e.g., dorsolateral prefrontal, orbitofrontal,and anterior cingulate cortex) (Alexander et al.1986). These circuits are believed to providea subcortical influence on both motor control

and higher cognitive functions (Alexander et al.1986). The cognitive and behavioral deficits as-sociated with HD have been described as a “sub-cortical dementia” syndrome that is broadlycharacterized by slowness of thought, impairedattention, executive dysfunction, poor learn-ing, visuoperceptual and constructional deficits,and personality changes such as apathy and de-pression (McHugh & Folstein 1975). This syn-drome differs from the “cortical dementia” syn-drome of AD (described above), and the twodisorders are often used as a model to study thecortical-subcortical dementia distinction.

Qualitative differences between AD andHD exist in many aspects of cognition, andthey may aid in differentiating between sub-cortical and cortical dementia syndromes. Asmentioned above, a severe deficit in episodicmemory is characteristic of AD and has beenattributed to ineffective consolidation (i.e.,storage) of new information (Salmon 2000).Patients with HD, in contrast, exhibit a mild-to-moderate memory impairment that appearsto result from a general deficit in the ability toinitiate and carry out systematic retrieval ofsuccessfully stored information (Butters et al.1985, 1986). This distinction was illustratedin a study by Delis and colleagues (1991) thatdirectly compared AD and HD patients on arigorous test of verbal learning and memory,the California Verbal Learning Test. Althoughthe HD and AD patients had comparable im-mediate and delayed free-recall deficits (basedon age-corrected normative data), they differedin several important ways. First, patients withAD exhibited equivalent deficits when memorywas assessed using free recall or recognitionprocedures, whereas patients with HD were lessimpaired with recognition testing than free re-call testing. The significant improvement withrecognition testing suggests that HD patients’memory impairment is attenuated when theneed for effortful, strategic retrieval is reduced(Butters et al. 1985, 1986). A similar improve-ment with recognition testing is observed in theremote memory test performance of patientswith HD (but not AD patients), presumablya reflection of ineffective retrieval during free

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recall (Sadek et al. 2004). Second, patients withAD exhibited significantly faster forgettingover a delay interval than did patients with HD.Whereas HD patients retained approximately70% of the initially acquired information overa 20-minute delay, AD patients retained lessthan 20%. The qualitative difference in theperformances of AD and HD patients is con-sistent with the notion that information is noteffectively consolidated and rapidly dissipatesin patients with AD, whereas informationcan be successfully stored but not effectivelyretrieved by patients with HD. This is not tosay, however, that impaired retrieval is the onlycause of the episodic memory deficit in HD.Some residual memory deficit is apparent evenwhen retrieval demands are reduced (Brandtet al. 1992; for review, see Montoya et al. 2006).

Qualitative differences in the language andsemantic knowledge deficits exhibited by pa-tients with AD and HD are evident on testsof naming, verbal fluency, and semantic cate-gorization. Patients with AD exhibit a signifi-cant confrontation naming deficit (e.g., Bayles& Tomoeda 1983) that is not shared by patientswith HD (Hodges et al. 1991), and the twogroups produce distinct patterns of naming er-rors wherein a greater proportion of AD errorsare semantically based (e.g., superordinate er-rors such as calling a “camel” an “animal”) anda greater proportion of HD errors are percep-tually based (e.g., calling a “pretzel” a “snake”)(Hodges et al. 1991). On tests of verbal fluency,patients with HD are severely and equivalentlyimpaired on both letter-fluency (i.e., generatewords that begin with the letters F, A, or S) andcategory-fluency (i.e., generate exemplars ofanimals, fruits, or vegetables) tasks, whereas pa-tients with AD are more impaired on category-fluency than on letter-fluency tasks (for reviews,see Henry et al. 2004, 2005). In addition, thetemporal dynamics of retrieval from seman-tic memory during the letter- and category-fluency tasks indicate that patients with ADhave a lower-than-normal mean latency consis-tent with the notion that they effectively drawexemplars from a semantic set that is abnor-mally small due to a loss of semantic knowledge,

whereas patients with HD have a higher-than-normal mean response latency, consistent withthe view that they have a normal-size semanticset but draw exemplars abnormally slowly dueto a disruption of retrieval processes (Rohreret al. 1999). Studies using multidimensionalmodeling techniques indicate that the networkof semantic associations for patients with HDis virtually identical to that of control subjects,whereas that of patients with AD is character-ized by weaker and more conceptually concreteassociations (for review, see Chan et al. 1998).Thus, AD appears to be characterized by a de-cline in the structure and organization of se-mantic knowledge that does not occur in HD.

Deficits in attention, working memory, andexecutive functions occur in both AD and HD,but specific aspects of these cognitive processesare differentially affected in the two disorders.A general deficit in attention is usually moresalient in patients with HD than in those withAD (e.g., Butters et al. 1988). A deficit in shift-ing or allocating attention is often quite appar-ent in HD (Hanes et al. 1995, Lange et al. 1995,Lawrence et al. 1996) and appears to be par-ticularly evident when attentional shifts mustbe internally regulated (Sprengelmeyer et al.1995). The ability to effectively shift attentionbetween stimulus dimensions in a visual dis-crimination task in which first one stimulus di-mension (e.g., color) and then another (e.g.,shape) was reinforced as correct was impaired inmoderately to severely demented patients withHD, but not in patients with AD or in mildlydemented patients with HD (Lange et al. 1995,Lawrence et al. 1996). All aspects of workingmemory are affected relatively early in HD, in-cluding the maintenance of information in thetemporary memory buffers (e.g., as evidencedby poor digit-span performance), inhibition ofirrelevant information, and the use of strate-gic aspects of memory (e.g., planning, organi-zation) to enhance free recall (for review, seeSalmon et al. 2001). In contrast, AD is ini-tially characterized by relatively mild working-memory deficits that primarily involve disrup-tion of the central executive with sparing of thephonological loop and visuospatial scratchpad


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(Baddeley et al. 1991, Collette et al. 1999). Itis not until later stages of AD that all aspectsof the working memory system become com-promised (Baddeley et al. 1991, Collette et al.1999).

The prominent deficits in attention andworking memory that occur in HD are accom-panied by impairment of various executive func-tions involved in planning and problem solv-ing such as goal-directed behavior, the abilityto generate multiple response alternatives, thecapacity to resist distraction and maintain re-sponse set, and the cognitive flexibility to evalu-ate and modify behavior (for review, see Brandt& Bylsma 1993). Deficits in these abilities areapparent on a variety of tests that require ex-ecutive functions such as the Wisconsin CardSorting Test (Paulsen et al. 1995, Peinemannet al. 2005, Pillon et al. 1991, Ward et al. 2006),the Stroop Test (Peinemann et al. 2005, Wardet al. 2006), the Tower of London Test (Langeet al. 1995), the Gambling Decision Makingtask (Stout et al. 2001), and tests of verbalconcept formation (Hanes et al. 1995). Thesedeficits progress throughout the course of dis-ease (Ho et al. 2003, Ward et al. 2006) but arenot unique to HD. A number of studies haveshown that extensive executive dysfunction alsooccurs in AD (for review, see Perry & Hodges1999). Specific aspects of executive dysfunctionmay be more common in one dementia syn-drome than in another, but few studies have di-rectly compared this aspect of cognition in thetwo disorders.

Although visuospatial deficits are charac-teristic of both AD (for review, see Cronin-Golomb & Amick 2001) and HD (Ward et al.2006; for review, see Brandt & Butters 1986),relatively little is known about the specific com-ponents of visuospatial processing that might bedifferentially affected in the two disorders. Inone of the few studies to directly address thisissue, Brouwers and colleagues (1984) foundthat patients with AD, but not those with HD,were impaired on tests of visuoconstructionalability that required extrapersonal orientation(e.g., copying a complex figure), whereas pa-tients with HD, but not those with AD, were

impaired on visuospatial tasks that required per-sonal orientation (e.g., the Money Road MapTest). This dissociation was supported by theresults of another study that examined the abil-ity to mentally rotate representations of ob-jects (Lineweaver et al. 2005). Patients with HDwere significantly slower than normal controlsubjects in performing mental rotation (perhapsdue to general bradyphrenia) but were as accu-rate as controls in making the rotation and re-porting the correct side of the target. Patientswith AD, in contrast, performed the mental ro-tation as quickly as controls but were signifi-cantly impaired in making an accurate rotationand reporting the correct side of the target. Thismay reflect a deficit in extrapersonal visual ori-entation in AD secondary to neocortical dam-age in brain regions thought to be involved inprocessing visual motion (e.g., the middle tem-poral gyrus).

Alzheimer’s Disease versus Dementiawith Lewy Bodies

DLB is a clinico-pathologic condition char-acterized by a dementia syndrome that occursin the presence of cell loss and the depositionof Lewy bodies (abnormal intracytoplasmiceosinophilic neuronal inclusion bodies) in asubcortical pattern similar to that of Parkinson’sdisease (e.g., in brain stem nuclei including thesubstantia nigra, locus ceruleus, dorsal motornucleus of the vagus, and substantia innom-inata), the presence of Lewy bodies diffuselydistributed throughout the limbic system (e.g.,cingulate, insula, amygdala, hippocampus,entorhinal cortex, and transentorhinal cortex)and neocortex (e.g., temporal, parietal, andfrontal lobes), and in many cases AD pathology(i.e., neuritic plaques, neurofibrillary tangles)that occurs in the same general distributionthroughout the brain as in “pure” AD (forreview, see Ince & Perry 2005). There iswidespread depletion of cortical cholineacetyltransferase in the neocortex and striatumin DLB (e.g., Tiraboschi et al. 2002) and a dis-ruption of dopaminergic input to the striatumdue to the loss of pigmented substantia nigra

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neurons (Ince & Perry 2005). DLB is not rareand may occur in approximately 20% of all el-derly demented patients (McKeith et al. 1996).

The distribution of neuropathologicchanges in DLB and AD is quite similar, so itis not surprising that the two disorders resultin similar dementia syndromes. Both disordersare initially characterized by the insidious onsetof cognitive decline with no other prominentneurological abnormalities (Hansen et al. 1990,McKeith et al. 1996). Memory impairmentis often the earliest feature of both disorders,but with time, cognitive deficits becomewidespread and inexorably progress to severedementia. Because of these similarities, patientswith DLB are often clinically diagnosed ashaving probable or possible AD during life(e.g., Merdes et al. 2003). However, severalclinical features occur with a higher prevalencein patients with DLB than in those with pureAD. These features include mild spontaneousmotor features of Parkinsonism (e.g., bradyki-nesia, rigidity, and masked facies, but withouta resting tremor), recurrent and well-formedvisual hallucinations, and fluctuating cognitionwith pronounced variations in attention oralertness (for review, see McKeith et al. 2005).These clinical distinctions form the basis forconsensus criteria adopted by the InternationalConsortium on DLB to clinically diagnoseDLB and distinguish it from AD (McKeithet al. 1996, 2005).

Given the difficulty in clinically differenti-ating DLB from AD, a number of studies ofautopsy-confirmed or clinically diagnosed pa-tients have attempted to delineate the two disor-ders further based on patterns of neuropsycho-logical deficits. These studies have consistentlyshown that the most salient neuropsychologicaldifference between the two disorders is a dis-proportionately severe visuospatial and visuo-constructive deficit in patients with DLB. Thishas been shown using tests of visual percep-tion (e.g., segregation of overlapping figures),tests of visual search (e.g., parallel search tasksthat usually elicit the pop-out phenomenon),and tests that require drawing simple and com-plex two-dimensional figures or the construc-

PET: positronemission tomography

tion of three-dimensional objects (for review,see Salmon & Hamilton 2006). These particu-larly severe deficits in visuospatial and visuop-erceptual abilities are often apparent even whenDLB patients perform better than do AD pa-tients on tests of verbal memory (e.g., LambonRalph et al. 2001).

The prominence of visuoperceptual, visu-ospatial, and visuoconstructional deficits in pa-tients with DLB may be related to occipital cor-tex dysfunction that does not usually occur inpatients with AD. Studies using positron emis-sion tomography (PET) or single-photon emis-sion computerized tomography (SPECT) neu-roimaging have shown that relatively early DLBis characterized by hypometabolism and de-creased blood flow in primary visual and visual-association cortex that is not evident in AD(e.g., Minoshima et al. 2001). These metabolicchanges are paralleled by pathologic changesin occipital cortex of patients with DLB thatinclude white matter spongiform change withcoexisting gliosis (Higuchi et al. 2000) and, insome cases, deposition of Lewy bodies (e.g.,Gomez-Tortosa et al. 1999). Because occipitalcortex pathology is rare in pure AD, it is not sur-prising that the visuoperceptual and visuospa-tial abilities that may be dependent upon thesecortices are disproportionately impaired in pa-tients with DLB.

Patients with DLB often also have dispro-portionately severe deficits in executive func-tions and attention in comparison to equally de-mented patients with pure AD. This differenceis evident on tests of attention such as the Wech-sler Adult Intelligence Scale-Revised DigitSpan subtest or the Cancellation Test, tests ofinitiation and systematic retrieval from seman-tic memory such as the Initiation/Perseverationsubscale of the Mattis Dementia Rating Scaleor the phonemic verbal fluency test, andtests of abstract reasoning such as the RavenColored Progressive Matrices or the WechslerAdult Intelligence Scale-Revised Similaritiessubtest (for review, see Salmon & Hamilton2006). A series of studies using a computer-based testing paradigm (i.e., the CambridgeNeuropsychological Test Automated Battery)


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demonstrated that patients with DLB weremore impaired than patients with AD on aconditional pattern-location paired-associateslearning task (Galloway et al. 1992), a delayedmatching-to-sample task (Sahgal et al. 1992a), avisual search task that assessed the ability to fo-

CVLT Savings Scores Logical Memory Savings Scores

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Figure 4The average scores achieved by normal control (NC) subjects, patients withAlzheimer’s disease (AD), and patients with dementia with Lewy bodies (DLB)on various learning and memory measures from the California Verbal LearningTest (CVLT) and the Wechsler Adult Intelligence Scale-Revised LogicalMemory Test. Despite similar levels of global cognitive impairment, the DLBpatients were less impaired than the AD patients on measures of retention(memory savings score) and recognition memory (recognition discriminabilityand recognition accuracy index). PR, percent retained. (Adapted fromHamilton et al. 2004.)

cus attention (Sahgal et al. 1992b), and a spatialworking-memory task that assessed both spatialmemory and the ability to use an efficient searchstrategy (Sahgal et al. 1995). These prominentattention and executive function deficits aresimilar to those that occur in patients with basalganglia dysfunction that interrupts fronto-striatal circuits (e.g., HD). These circuits maybe affected in two ways in patients with DLB:by direct neocortical Lewy body pathology inthe association areas of the frontal lobes andby substantia nigra pathology that interruptsdopaminergic projections to the striatum.When superimposed upon the AD pathologythat is also often present in the frontal cortex ofpatients with DLB, these pathological changesmay result in disproportionately severe deficitsin executive function and attention.

In contrast to DLB patients’ disproportion-ately severe deficits in visuospatial abilities, ex-ecutive functions, and attention, their memorydeficit is generally less severe than that of ADpatients and may reflect a qualitative differ-ence in the processes affected. This was illus-trated in a study that directly compared the per-formances of patients with autopsy-confirmedDLB (all with concomitant AD pathology) orpure AD on the California Verbal Learning Testand the Wechsler Memory Scale-Revised Log-ical Memory Test (Hamilton et al. 2004). Al-though the two groups were equally impairedin their ability to learn new verbal informationon these tests, DLB patients exhibited better re-tention and better recognition memory than didpatients with pure AD. These results suggestthat a deficit in retrieval plays a greater role inthe memory impairment of patients with DLBthan in that of patients with AD. Although thepattern of deficits does not rule out the possi-bility that poor encoding contributes to mem-ory impairment in both disorders, it appearsthat DLB patients have better retention thando patients with AD when retrieval demandsare reduced through the use of the recogni-tion format (see Figure 4). The observed dif-ferences are consistent with neuropathologic(Lippa et al. 1998) and MRI (Barber et al. 2001,Hashimoto et al. 1998) evidence that medial

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temporal lobe structures important for memory(e.g., hippocampus, entorhinal cortex, parahip-pocampal gyrus) are less severely affected inDLB than in AD. A combination of only mod-erate medial temporal lobe damage and fronto-striatal dysfunction might explain the less severeretention deficit and greater impact of deficientretrieval processes in DLB than in AD.

The general pattern of greater visuospatial,attention, and executive function impairmentin DLB than AD, and greater memory impair-ment in AD than DLB, has been confirmed ina number of recent studies that compared clin-ically diagnosed or autopsy-diagnosed patientgroups on batteries of neuropsychological tests(Ferman et al. 2006, Guidi et al. 2006, Johnsonet al. 2005, Kraybill et al. 2005, Stavitskyet al. 2006). Consideration of these patternsof deficits (particularly those of visuospatialabilities) may have important clinical utility indistinguishing between AD and DLB in mildlydemented patients (Tiraboschi et al. 2006).

Alzheimer’s Disease versusFrontotemporal Dementia

Frontotemporal dementia (FTD) is a clinico-pathologic condition characterized by deteri-oration of personality and cognition associatedwith prominent frontal and temporal lobaratrophy. A number of conditions fall under therubric of FTD including Pick’s disease, familialchromosome 17-linked frontal lobe dementia,dementia lacking distinctive histopathology,semantic dementia, and primary progressiveaphasia (for review, see Kertesz 2006). Al-though each of these variants has a uniqueclinical presentation, the most common variantof FTD typically begins with the insidiousonset of personality and behavioral changes(e.g., inappropriate social conduct, apathy,disinhibition, perseverative behavior, loss ofinsight, hyperorality, decreased speech output)that are accompanied or soon followed bycognitive deficits that include alterations in ex-ecutive functions, attention, and/or language,often with relative sparing of visuospatialabilities and memory (for reviews, see Boxer

& Miller 2006, Grossman 2002, Neary 2005).FTD accounts for approximately 6%–12% ofall cases of dementia (Kertesz 2006).

Recent attempts to differentiate FTD andAD based on the nature and severity of be-havioral symptoms have met with some success(see Kertesz 2006). However, the disorders areclinically similar and remain difficult to distin-guish during life (Mendez et al. 1993, Varmaet al. 1999). This has led some investigatorsto propose that consideration of the patternsof cognitive deficits associated with FTD andAD might aid in clinically distinguishing be-tween the two disorders. A number of studiessuggest that patients with FTD are more im-paired than those with AD on tests of verbalfluency (Frisoni et al. 1995, Lindau et al. 1998,Mathuranath et al. 2000) or less impaired ontests of memory (Binetti et al. 2000, Frisoniet al. 1995, Lindau et al. 1998, Pachana et al.1996, Thomas-Anterion et al. 2000) and visu-ospatial abilities (Elfgren et al. 1994, Mendezet al. 1996). Unfortunately, these findings areoften based on relatively small, clinically de-fined (not autopsy-confirmed) patient samplesthat are susceptible to cross-contamination, andon studies that compared FTD and AD pa-tients who were at different stages of illness.In addition, the ability to detect differenceswas attenuated by the choice of neuropsycho-logical test in some studies, such as those thatmay have failed to find a significant differencein the visuospatial-constructional abilities ofFTD and AD patients because they used a Rey-Osterrieth Complex Figure task that is knownto require attention and organizational abilitiesdependent on the frontal lobes (Frisoni et al.1995, Lindau et al. 1998, Pachana et al. 1996,Varma et al. 1999).

Several studies that examined profiles ofcognitive deficits associated with FTD and ADsuggest that FTD patients have a greater deficitin executive functions than in other cogni-tive abilities, whereas AD patients have exec-utive dysfunction that is proportional to theirdeficits in language and visuospatial abilitiesand less prominent than their episodic memorydeficit (Forstl et al. 1996, Rascovsky et al.


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VaD: vasculardementia

2002, Starkstein et al. 1994). In a study thatretrospectively compared the cognitive profilesof patients with autopsy-confirmed FTD or ADwho were matched for education and level ofdementia at the time of testing, Rascovsky andcolleagues (2002) found that FTD patients per-formed significantly worse than AD patientson word-generation tasks that are sensitive tofrontal lobe dysfunction (i.e., letter and cate-gory fluency tests), but significantly better ontests of memory (i.e., Mattis Dementia Rat-ing Scale Memory subscale) and visuospatialabilities (i.e., Block Design and Clock Draw-ing tests) that are sensitive to dysfunction ofmedial temporal and parietal association cor-tices. A logistic regression model using letterfluency, memory subscale, and Block Designtest scores provided good discriminability be-tween the groups, correctly classifying 91% ofAD patients and 77% of FTD patients. Similarlevels of diagnostic accuracy were observed instudies comparing clinically diagnosed patientson executive function, visuospatial, and mem-ory tests (Elfgren et al. 1994, Gregory et al.1997, Libon et al. 2007, Lipton et al. 2005).

AD FTD

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Figure 5Mean z-scores achieved by patients with Alzheimer’s disease (AD) and patientswith frontotemporal dementia (FTD; excluding semantic dementia) on theletter fluency and semantic category fluency tests. FTD patients were moreimpaired on the letter fluency than semantic fluency task, whereas AD patientswere more impaired on the semantic fluency than letter fluency task. ∗p < 0.05,∗∗p < 0.01. (Adapted from Rascovsky et al. 2007.)

In a related study, Rascovsky and colleagues(2007) compared the performances of autopsy-confirmed FTD and AD patients on letter andsemantic category fluency tests to determine ifdistinct patterns of deficits might be evident onthese relatively simple tasks. Although both ver-bal fluency tasks utilize frontal lobe–mediatedexecutive processes, distinct patterns were hy-pothesized because semantic category fluencyrequires a search through semantic or concep-tual memory and is critically dependent uponknowledge of the physical and/or functional at-tributes that define a particular semantic cate-gory, whereas letter fluency requires the use ofphonemic cues to guide retrieval and may thusrequire greater effort and more active strate-gic search than semantic category fluency. Re-sults showed that despite similar age, education,and dementia severity, FTD patients performedworse than AD did patients overall, and letterfluency was worse than semantic fluency for theFTD patients, whereas semantic fluency wasworse than letter fluency for the AD patients(see Figure 5). A derived measure of the dis-parity between letter and semantic fluency (theSemantic Index) correctly classified 92% of ADpatients and 85% of FTD patients for an overallcorrect classification of nearly 90%. The uniquepatterns of fluency deficits in FTD and ADmay be indicative of differences in the relativecontribution of frontal lobe–mediated retrievaldeficits (most prominent in FTD) and temporallobe–mediated semantic deficits (most promi-nent in AD) in the two disorders.

Alzheimer’s Disease versusVascular Dementia

Vascular dementia (VaD) refers to a cumula-tive decline in cognitive functioning secondaryto multiple or strategically placed infarctions,ischemic injury, or hemorrhagic lesions. Theclinical and neuropathologic presentation ofVaD is quite heterogeneous, and a variety ofconditions fall under the general rubric of VaD.As Hodges & Graham (2001) pointed out, theseconditions generally fall into three large cate-gories: multi-infarct dementia associated with

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multiple large cortical infarctions (usually af-fecting 10cc or more of brain tissue), demen-tia due to strategically placed infarction (e.g.,left angular gyrus damage related to infarc-tion of the posterior branch of the medial cere-bral artery), and subcortical ischemic vasculardementia due to subcortical small vessel dis-ease that results in multiple lacunar strokes,leukoaraiosis (Binswanger’s disease), or diffusewhite matter pathology.

Specific research criteria for the broadly de-fined diagnosis of VaD have been proposed(e.g., Chui et al. 1992, Roman et al. 1993).In general, these guidelines require that mul-tiple cognitive deficits (i.e., dementia) occur inthe presence of focal neurological signs andsymptoms and/or laboratory (e.g., computer-ized tomography or MRI scan) evidence ofcerebrovascular disease that is thought to beetiologically related to the cognitive impair-ment. A relationship between dementia andcerebrovascular disease is often indicated if theonset of dementia occurs within several monthsof a recognized stroke, cognitive functioningabruptly deteriorates, or the course of cognitivedeterioration is fluctuating or stepwise. In oneset of diagnostic criteria (Roman et al. 1993),VaD can be subcategorized on the basis of thesuspected type of vascular pathology (as deter-mined by clinical, radiologic, and neuropatho-logic features), and possible or probable VaDmay be assigned depending on the certainty ofthe contribution of cerebrovascular disease tothe dementia syndrome. Definite VaD is diag-nosed only on the basis of histopathologic evi-dence of cerebrovascular disease that occurs inthe absence of neurofibrillary tangles and neu-ritic plaques exceeding those expected for age(i.e., AD) and without clinical evidence of anyother disorder capable of producing dementia(e.g., Pick’s disease, diffuse Lewy body disease).

Recent studies of the neuropsychologicaldeficits associated with VaD have primarilyfocused on differentiating between subcorti-cal VaD and AD. These studies largely showthat patients with subcortical VaD are moreimpaired than those with AD on tests of ex-ecutive functions, whereas patients with AD

are more impaired than those with subcorti-cal VaD on tests of episodic memory (partic-ularly delayed recall) (Desmond 2004, Grahamet al. 2004, Kertesz & Clydesdale 1994, Lafosseet al. 1997, Lamar et al. 1997). In addition,these studies suggest that the executive dys-function associated with subcortical VaD is itsmost prominent deficit, perhaps because sub-cortical pathology interrupts frontosubcorti-cal circuits that mediate this aspect of cogni-tion. Indeed, a study by Price and colleagues(2005) showed that VaD patients with a signif-icant volume of white matter abnormality onimaging exhibited a profile of greater execu-tive/visuoconstructional impairment than im-pairment of memory and language abilities.

Although neuropsychological studies pro-vide consistent evidence for distinct cognitiveprofiles in subcortical VaD and AD, most ofthese studies employed clinically diagnosedpatients without autopsy confirmation ofdiagnosis. This may have led to some degreeof misclassification of patients across groupsbecause AD and VaD are quite heterogeneousand can overlap in their clinical presentations.To avoid this potential confound, Reed andcolleagues (2007) recently compared the pro-files of neuropsychological deficits exhibitedby patients with autopsy-confirmed subcorticalVaD or AD. Consistent with previous studiesof clinically diagnosed patients, patients withAD had a deficit in episodic memory (bothverbal and nonverbal) that was significantlygreater than their executive function deficit. Incontrast, patients with subcortical VaD had adeficit in executive functions that was greaterthan their deficit in verbal (but not nonverbal)episodic memory, but this difference was notsignificant. An analysis of individual patientprofiles was carried out to explore these differ-ences further. This analysis showed that 71%of AD patients exhibited a profile with memoryimpairment more prominent than executivedysfunction, whereas only 45% of patientswith subcortical VaD exhibited a profile withmore prominent executive dysfunction thanmemory impairment. Interestingly, relativelysevere cerebrovascular disease at autopsy was


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often not associated with clinically significantcognitive decline. When the profile analysiswas restricted to those patients who exhibitedsignificant cognitive impairment at theirclinical assessment, the distinction betweensubcortical VaD and AD patients was morepronounced, with 79% of AD patients ex-hibiting a low memory profile (5% with a lowexecutive profile) and 67% of subcortical VaDpatients exhibiting a low executive profile (0%with a low memory profile). The results of thisstudy suggest that relatively distinct cognitivedeficit profiles might be clinically useful in dif-ferentiating between subcortical VaD and AD,but additional research with autopsy-diagnosedpatients is needed to further define the deficitprofile that will be most useful in this regard.

CONCLUSIONS

Considerable progress has been made in differ-entiating between the cognitive changes that

occur as a normal consequence of aging andthose that signal the onset of a dementia syn-drome caused by AD or another neurodegen-erative disease. Clinical and experimental neu-ropsychological research has identified many ofthe basic cognitive processes that are adverselyaffected by AD and is beginning to uncoverthe earliest preclinical cognitive changes thatmight predict the subsequent development ofdementia and AD in nondemented individuals.Neuropsychological research has also madeconsiderable progress in delineating differentpatterns of relatively preserved and impairedcognitive abilities that distinguish between ADand other age-associated neurodegenerativedisorders. Greater understanding of the cog-nitive distinctions between these disorders canaid in the development of better differentialdiagnosis and has important implications forthe nature of brain-behavior relationshipsunderlying memory, language, executivefunctions, and other cognitive abilities.

SUMMARY POINTS

1. Cognitive deficits associated with AD can be differentiated from age-associated cognitivedecline by quantitative and qualitative differences in episodic memory, semantic knowl-edge, and some aspects of executive functions. However, the qualitatively distinct patternof deficits is less salient in very old AD patients than in younger AD patients.

2. Decline in episodic memory (particularly delayed recall) is usually the earliest cognitivechange that occurs prior to the development of the AD dementia syndrome and may pre-dict imminent dementia. Recent evidence suggests that asymmetry in cognitive abilitiesmay also occur in this preclinical phase of AD.

3. The cortical neuropathology of AD appears to result in a loss of functional connec-tivity that allows effective interaction between distinct and relatively intact corticalinformation-processing systems. This loss has been demonstrated in AD patients’ im-paired ability to bind distinct visual stimulus features that are effectively processed in dif-ferent cortical streams (i.e., motion and color). This behavioral manifestation of corticaldisconnectivity has potential as a cognitive marker for detecting and tracking progressionof AD.

4. Distinct patterns of cognitive deficits occur in AD and other age-associated neurodegen-erative disorders such as Huntington’s disease, dementia with Lewy bodies, frontotempo-ral dementia, and vascular dementia. Differences in the cognitive profiles associated withthese various disorders can aid in differential diagnosis and provide a useful model forunderstanding brain-behavior relationships that mediate the affected cognitive abilities.

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FUTURE ISSUES

1. The early diagnosis of AD in a preclinical stage that might be most amenable to treatmentsthat halt or slow disease progression remains an extremely important goal. It is essentialto recognize and verify the accuracy of subtle cognitive abnormalities (e.g., poor delayedrecall performance, cognitive asymmetry) that might identify those nondemented elderlyindividuals who are destined to develop dementia.

2. The role of cortical disconnectivity in producing the specific pattern of cognitive deficitsthat occurs in early AD needs to be determined. Furthermore, the identification of cog-nitive processes that are particularly vulnerable to the effects of cortical disconnectivityin early AD might provide a cognitive marker that could be used to assess the effectsof medications that specifically target cortical function (e.g., the N-methyl-D-aspartatereceptor antagonist memantine).

3. It remains difficult to estimate rate of cognitive decline in AD and other age-related neu-rodegenerative diseases, but emerging evidence suggests that certain aspects of currentcognitive performance can predict subsequent rate of global cognitive decline in patientswith AD (e.g., Chan et al. 1995). Further research is needed to confirm this possibilityand to generalize it to other neurodegenerative disorders such as DLB and FTD.

4. There is a continuing need to identify differences in the profiles of cognitive deficitsassociated with AD and other age-related neurodegenerative diseases (e.g., DLB, FTD)and to determine how these profiles can be incorporated with other clinical features toimprove the accuracy of differential diagnosis in very mildly demented individuals. Accu-rate early diagnosis is a particularly important goal since the various neurodegenerativedisorders are likely to respond differently to the potential treatments for dementia thatare in development.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of thisreview.

ACKNOWLEDGMENTS

The preparation of this review was supported by funds from NIA grants AG-05131, AG-12963,and AG-12674 to the University of California, San Diego.

LITERATURE CITED

Albert MS, Blacker D. 2006. Mild cognitive impairment and dementia. Annu. Rev. Clin. Psychol. 2:379–88

Measures of episodicmemory and executivefunction predicted thedevelopment ofdementia within threeyears in patients withmild memory difficulty.

Albert MS, Moss MB, Tanzi R, Jones K. 2001. Preclinical prediction of AD using neuropsychologicaltests. J. Int. Neuropsychol. Soc. 7:631–39

Alexander GE, DeLong MR, Strick PL. 1986. Parallel organization of functionally segregated circuits linkingbasal ganglia and cortex. Annu. Rev. Neurosci. 9:357–81

A review showing thatmultiple cognitivedomains (i.e., episodicmemory, executivefunction, and perceptualspeed) are adverselyaffected several yearsbefore a clinicaldiagnosis of AD.

Backman L, Jones S, Berger AK, Laukka EJ, Small BJ. 2004. Multiple cognitive deficits during thetransition to Alzheimer’s disease. J. Intern. Med. 256:195–204

Backman L, Jones S, Berger AK, Laukka EJ, Small BJ. 2005. Cognitive impairment in preclinical Alzheimer’sdisease: a meta-analysis. Neuropsychology 19:520–31


Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Backman L, Small BJ. 1998. Influences of cognitive support on episodic remembering: tracing the process ofloss from normal aging to Alzheimer’s disease. Psychol. Aging 13:267–76

Backman L, Small BJ, Fratiglioni L. 2001. Stability of the preclinical episodic memory deficit in Alzheimer’sdisease. Brain 124:96–102

Baddeley AD, Bressi S, Della Sala S, Logie R, Spinnler H. 1991. The decline of working memory in Alzheimer’sdisease: a longitudinal study. Brain 114:2521–42

Barber R, McKeith IG, Ballard C, Gholkar A, O’Brien JT. 2001. A comparison of medial and lateral tem-poral lobe atrophy in dementia with Lewy bodies and Alzheimer’s disease: magnetic resonance imagingvolumetric study. Dement. Geriatr. Cogn. Disord. 12:198–205

Bayles KA, Tomoeda CK. 1983. Confrontation naming impairment in dementia. Brain Lang. 19:98–114Bayley PJ, Salmon DP, Bondi MW, Bui BK, Olichney J, et al. 2000. Comparison of the serial position effect

in very mild Alzheimer’s disease, mild Alzheimer’s disease, and amnesia associated with electroconvulsivetherapy. J. Int. Neuropsychol. Soc. 6:290–98

Binetti G, Locascio JJ, Corkin S, Vonsattel JP, Growdon JH. 2000. Differences between Pick disease andAlzheimer disease in the clinical appearance and rate of cognitive decline. Arch. Neurol. 57:225–32

Bondi MW, Houston WS, Salmon DP, Corey-Bloom J, Katzman R, et al. 2003. Neuropsychological deficitsassociated with Alzheimer’s disease in the very old: discrepancies in raw vs standardized scores. J. Int.Neuropsychol. Soc. 9:783–95

Bondi MW, Monsch AU, Butters N, Salmon DP, Paulsen JS. 1993. Utility of a modified version of theWisconsin Card Sorting Test in the detection of dementia of the Alzheimer type. Clin. Neuropsychol.7:161–70

Boxer AL, Miller BL. 2006. Clinical features of frontotemporal dementia. Alzheimer Dis. Assoc. Disord. 19:S3–6Braak H, Braak E. 1991. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82:239–59Brandt J, Butters N. 1986. The neuropsychology of Huntington’s disease. Trends Neurosci. 9:118–20Brandt J, Bylsma FW. 1993. The dementia of Huntington’s disease. In Neuropsychology of Alzheimer’s Disease

and Other Dementias, ed. RW Parks, RF Zec, RS Wilson, pp. 265–82. New York: Oxford Univ. PressBrandt J, Corwin J, Krafft L. 1992. Is verbal recognition memory really different in

Huntington’s and Alzheimer’s disease? J. Clin. Exp. Neuropsychol. 14:773–84Brouwers P, Cox C, Martin A, Chase T, Fedio P. 1984. Differential perceptual-spatial impairment in

Huntington’s and Alzheimer’s dementias. Arch. Neurol. 41:1073–76Buschke H. 1973. Selective reminding for analysis of memory and learning. J. Verb. Learn. Verb. Behav. 12:543–

50Buschke H, Sliwinski MJ, Kuslansky G, Lipton RB. 1997. Diagnosis of early dementia by the double memory

test. Neurology 48:989–97Butters N, Granholm E, Salmon DP, Grant I, Wolfe J. 1987. Episodic and semantic memory: a comparison

of amnesic and demented patients. J. Clin. Exp. Neuropsychol. 9:479–97Butters N, Salmon DP, Cullum CM, Cairns P, Troster AI, et al. 1988. Differentiation of amnesic and demented

patients with the Wechsler Memory Scale-Revised. Clin. Neuropsychol. 2:133–48Butters N, Wolfe J, Granholm E, Martone M. 1986. An assessment of verbal recall, recognition and fluency

abilities in patients with Huntington’s disease. Cortex 22:11–32Butters N, Wolfe J, Martone M, Granholm E, Cermak LS. 1985. Memory disorders associated with Hunt-

ington’s disease: verbal recall, verbal recognition and procedural memory. Neuropsychologia 23:729–43Chan AS, Salmon DP, Butters N. 1998. Semantic network abnormalities in patients with Alzheimer’s disease.

In Fundamentals of Neural Network Modeling, ed. RW Parks, DS Levine, DL Long, pp. 381–93. Cambridge,MA: MIT Press

Chan AS, Salmon DP, Butters N, Johnson S. 1995. Semantic network abnormality predicts rate of cognitivedecline in patients with Alzheimer’s disease. J. Int. Neuropsychol. Soc. 1:297–303

Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M. 2001. Patterns of cognitive decline inpresymptomatic Alzheimer disease: a prospective community study. Arch. Gen. Psychiatry 58:853–58

Chertkow H, Bub D. 1990. Semantic memory loss in dementia of Alzheimer’s type. Brain 113:397–417Chui H, Victoroff J, Margolin D, Jagust W, Shankle R, Katzman R. 1992. Criteria for the diagnosis of ischemic

vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic Treatment Centers.Neurology 42:473–80

276 Salmon · Bondi

Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Collette F, Van Der Linden M, Bechet S, Salmon E. 1999. Phonological loop and central executive functioningin Alzheimer’s disease. Neuropsychologia 37:905–18

Collie A, Maruff P. 2000. The neuropsychology of preclinical Alzheimer’s disease and mild cognitive impair-ment. Neurosci. Biobehav. Rev. 24:365–74

Croner LJ, Albright TD. 1997. Image segmentation enhances discrimination of motion in visual noise. VisionRes. 37:1415–27

Cronin-Golomb A, Amick M. 2001. Spatial abilities in aging, Alzheimer’s disease, and Parkinson’s disease. InHandbook of Neuropsychology, Vol. 6: Aging and Dementia, ed. F Boller, SF Cappa, pp. 119–43. Amsterdam:Elsevier. 2nd ed.

De Lacoste M, White CL. 1993. The role of cortical connectivity in Alzheimer’s disease pathogenesis: a reviewand model system. Neurobiol. Aging 14:1–16

Delbeuck X, Van Der Linden M, Collette F. 2003. Alzheimer’s disease as a disconnection syndrome? Neu-ropsychol. Rev. 13:79–92

Delis DC, Massman PJ, Butters N, Salmon DP, Cermak LS, Kramer JH. 1991. Profiles of demented andamnesic patients on the California Verbal Learning Test: implications for the assessment of memorydisorders. Psychol. Assess. 3:19–26

Della Sala S, Kinnear P, Spinnler H, Stangalino C. 2000. Color-to-figure matching in Alzheimer’s disease.Arch. Clin. Neuropsychol. 15:571–85

Desmond DW. 2004. The neuropsychology of vascular cognitive impairment: Is there a specific cognitiveimpairment? J. Neurol. Sci. 226:3–7

D’Esposito M, Zarahn E, Aguirre GK, Rypma B. 1999. The effect of normal aging on the coupling of neuralactivity to the BOLD hemodynamic response. NeuroImage 10:6–14

Dobkins KR, Albright TD. 1998. The influence of chromatic information on visual motion processing in theprimate visual system. In High-Level Motion Processing—Computational, Neurobiological and PsychophysicalPerspectives, ed. T Watanabe, pp. 53–94. Cambridge, MA: MIT Press

Dunkin JJ, Osato S, Leuchter AF. 1995. Relationships between EEG coherence and neuropsychological testsin dementia. Clin. Electroencephal. 26:47–59

Elfgren C, Brun A, Gustafson L, Johanson A, Minton L, et al. 1994. Neuropsychological tests as discriminatorsbetween dementia of Alzheimer’s type and frontotemporal dementia. Int. Geriatr. Psychiatry 9:635–42

Ferman TJ, Smith GE, Boeve BF, Graff-Radford NR, Lucas JA, et al. 2006. Neuropsychological differentiationof dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin. Neuropsychol. 20:623–36

AD patients exhibitedspecific deficits inbinding visual featureswhen cross-corticalintegration wasrequired (e.g., motion-color versusmotion-luminance).

Festa E, Insler RZ, Salmon DP, Paxton J, Hamilton JM, Heindel WC. 2005. Neocortical disconnec-tivity disrupts sensory integration in Alzheimer’s disease. Neuropsychology 19:728–38

Forstl H, Besthorn C, Geiger-Kabisch C, Sattel H, Schreitter-Gasser U. 1996. Frontal lobe degeneration andAlzheimer’s disease: a controlled study on clinical findings, volumetric brain changes and quantitativeelectroencephalography data. Dementia 7:27–34

AD patients hadabnormal increase inreaction time withincreasing array sizeduring conjoinedfeature searchsuggesting impairedperceptual integration.

Foster JK, Behrmann M, Stuss DT. 1999. Visual attention deficits in Alzheimer’s disease: simpleversus conjoined feature search. Neuropsychology 13:223–45

Freedman M, Leach L, Kaplan E, Winocur G, Shulman KI, Delis DC. 1994. Clock Drawing: A NeuropsychologicalAnalysis. New York: Oxford Univ. Press

Freedman M, Oscar-Berman M. 1997. Breakdown of cross-modal function in dementia. Neuropsychiatry Neu-ropsychol. Behav. Neurol. 10:102–6

Frisoni GB, Pizzolato G, Geroldi C, Rossato A, Bianchetti A, Trabucchi M. 1995. Dementia of the frontaltype: neuropsychological and 99[TC-HMPAO] SPECT features. J. Geriatr. Psychiatry Neurol. 8:42–48

Galloway PH, Sahgal A, McKeith IG, Lloyd S, Cook JH, et al. 1992. Visual pattern recognition memory andlearning deficits in senile dementias of Alzheimer and Lewy body types. Dementia 3:101–7

Golob EJ, Miranda GG, Johnson JK, Starr A. 2001. Sensory cortical interactions in aging, mild cognitiveimpairment, and Alzheimer’s disease. Neurobiol. Aging 22:755–63

Gomez-Tortosa E, Newell K, Irizarry MC, Albert M, Growdon JH, Hyman BT. 1999. Clinical and quantitativepathologic correlates of dementia with Lewy bodies. Neurology 53:1284–91

Grady CL, Haxby JV, Horwitz B, Sundaram M, Berg G, et al. 1988. Longitudinal study of the early neuropsy-chological and cerebral metabolic changes in dementia of the Alzheimer type. J. Clin. Exp. Neuropsychol.10:576–96


Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Graham NL, Emery T, Hodges JR. 2004. Distinct cognitive profiles in Alzheimer’s disease and subcorticalvascular dementia. J. Neurol. Neurosurg. Psychiatry 75:61–71

Gregory CA, Orrell M, Sahkian B, Hodges J. 1997. Can frontotemporal dementia and Alzheimer’s disease bedifferentiated using a brief battery of tests? Int. Geriatr. Psychiatry 12:357–83

Grossman M. 2002. Frontotemporal dementia: a review. J. Int. Neuropsychol. Soc. 8:566–83Guidi M, Paciaroni L, Paolini S, DePadova S, Scarpino O. 2006. Differences and similarities in the neuropsy-

chological profile of dementia with Lewy bodies and Alzheimer’s disease in the early stage. J. Neurol. Sci.248:120–23

Hamilton JM, Salmon DP, Galasko D, Delis DC, Hansen LA, et al. 2004. A comparison of episodic memorydeficits in neuropathologically-confirmed dementia with Lewy bodies and Alzheimer’s disease. J. Int.Neuropsychol. Soc. 10:689–97

Hanes KR, Andrewes DG, Pantelis C. 1995. Cognitive flexibility and complex integration in Parkinson’sdisease, Huntington’s disease, and schizophrenia. J. Int. Neuropsychol. Soc. 1:545–53

Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, et al. 1990. The Lewy body variant of Alzheimer’sdisease: a clinical and pathologic entity. Neurology 40:1–8

Hashimoto M, Kitagaki H, Imamura T, Hirono N, Shimomura T, et al. 1998. Medial temporal and whole-brain atrophy in dementia with Lewy bodies. Neurology 51:357–62

Hedden T, Gabrieli JDE. 2004. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev.5:87–97

Henry JD, Crawford JR, Phillips LH. 2004. Verbal fluency performance in dementia of the Alzheimer’s type:a meta-analysis. Neuropsychologia 42:1212–22

Henry JD, Crawford JR, Phillips LH. 2005. A meta-analytic review of verbal fluency deficits in Huntington’sdisease. Neuropsychology 19:243–52

Higuchi M, Tashiro M, Arai H, Okamura N, Hara S, et al. 2000. Glucose hypometabolism and neuropatho-logical correlates in brains of dementia with Lewy bodies. Exp. Neurol. 162:247–56

Ho AK, Sahakian BJ, Brown RG, Barker RA, Hodges JR, et al. 2003. Profile of cognitive progression in earlyHuntington’s disease. Neurology 61:1702–6

Hodges JR, Graham NL. 2001. Vascular dementias. In Early Onset Dementia: A Multidisciplinary Approach, ed.JR Hodges, pp. 319–37. Oxford: Oxford Univ. Press

Hodges JR, Patterson K. 1995. Is semantic memory consistently impaired early in the course of Alzheimer’sdisease? Neuroanatomical and diagnostic implications. Neuropsychologia 33:441–59

Hodges JR, Salmon DP, Butters N. 1991. The nature of the naming deficit in Alzheimer’s and Huntington’sdisease. Brain 114:1547–58

Hodges JR, Salmon DP, Butters N. 1992. Semantic memory impairment in Alzheimer’s disease: failure ofaccess or degraded knowledge? Neuropsychologia 30:301–14

Hof PR, Morrison JH. 1999. The cellular basis of cortical disconnection in Alzheimer’s disease and relateddementing conditions. In Alzheimer Disease, ed. RD Terry, R Katzman, KL Bick, SS Sisodia, pp. 207–32.New York: Raven

Hogan MJ, Swanwick GRJ, Kaiser J, Rowan M, Lawlor S. 2003. Memory-related EEG power and coherencereductions in mild Alzheimer’s disease. Int. J. Psychophysiol. 49:147–63

Hyman BT, Damasio AR, Van Hoesen GW, Barnes CL. 1984. Alzheimer’s disease: cell specific pathologyisolates the hippocampal formation. Science 225:1168–70

Ince PG, Perry EK. 2005. Pathology of dementia with Lewy bodies. In Dementia, ed. A Burns, J O’Brien, DAmes, pp. 615–33. London: Hodder Arnold. 3rd ed.

Jacobs D, Salmon DP, Troster AI, Butters N. 1990. Intrusion errors in the figural memory of patients withAlzheimer’s and Huntington’s disease. Arch. Clin. Neuropsychol. 5:49–57

Jacobson MW, Delis DC, Bondi MW, Salmon DP. 2002. Do neuropsychological tests detect preclinicalAlzheimer’s disease? Individual-test versus cognitive discrepancy analyses. Neuropsychology 16:132–39

Jack CR, Petersen RC, Xu YC, Waring SC, O’Brien PC, et al. 1998. Medial temporal atrophy on MRI innormal aging and very mild Alzheimer’s disease. Neurology 49:786–94

Jelic V, Shigeta M, Julin P, Almkvist O, Winblad B, Wahlund LO. 1996. Quantitative electroencephalographypower and coherence in Alzheimer’s disease and mild cognitive impairment. Dementia 7:314–23

278 Salmon · Bondi

Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Jernigan TJ, Archibald SL, Fennema-Notestine C, Gamst AC, Stout JC, et al. 2001. Effects of age on tissuesand regions of the cerebrum and cerebellum. Neurobiol. Aging 22:581–94

Johnson DK, Morris JC, Galvin JE. 2005. Verbal and visuospatial deficits in dementia with Lewy bodies.Neurology 65:1232–38

Katzman R. 1994. Apolipoprotein E and Alzheimer’s disease. Curr. Opin. Neurobiol. 4:703–7Kertesz A. 2006. Progress in clinical neurosciences: frontotemporal dementia–Pick’s disease. Can. J. Neurol.

Sci. 33:141–48Kertesz A, Clydesdale S. 1994. Neuropsychological deficits in vascular dementia vs Alzheimer’s disease: frontal

lobe deficits prominent in vascular dementia. Arch. Neurol. 51:1226–31Knopman DS, Ryberg S. 1989. A verbal memory test with high predictive accuracy for dementia of the

Alzheimer type. Arch. Neurol. 46:141–45Knott V, Mohr E, Mahoney C, Ilivitsky V. 2000. Electroencephalographic coherence in Alzheimer’s disease:

comparisons with a control group and population norms. J. Geriatr. Psychiatry Neurol. 13:1–8Kraybill ML, Larson EB, Tsuang DW, Teri L, McCormick WC, et al. 2005. Cognitive differences in dementia

patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64:2069–73Kurylo DD, Corkin S, Rizzo JF, Growdon JH. 1996. Greater relative impairment of object recognition than

of visuospatial abilities in Alzheimer’s disease. Neuropsychology 10:74–81Lafosse JM, Reed BR, Mungas D, Sterling SB, Wahbeh H, Jagust WJ. 1997. Fluency and memory differences

between ischemic vascular dementia and Alzheimer’s disease. Neuropsychology 11:514–22Lakmache Y, Lassonde M, Gauthier S, Frigon J-Y, Lepore F. 1998. Interhemispheric disconnection syndrome

in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 95:9042–46Lamar M, Podell K, Carew TG, Cloud BS, Resh R, et al. 1997. Perseverative behavior in Alzheimer’s disease

and subcortical ischemic vascular dementia. Neuropsychology 11:523–34Lambon Ralph MA, Powell J, Howard D, Whitworth AB, Garrard P, Hodges JR. 2001. Semantic mem-

ory is impaired in both dementia with Lewy bodies and dementia of Alzheimer’s type: a comparativeneuropsychological study and literature review. J. Neurol. Neurosurg. Psychiatry 70:149–56

Lange KL, Bondi MW, Salmon DP, Galasko D, Delis DC, et al. 2002. Decline in verbal memory duringpreclinical Alzheimer’s disease: examination of the effect of APOE genotype. J. Int. Neuropsychol. Soc.8:943–55

Lange KW, Sahakian BJ, Quinn NP, Marsden CD, Robbins TW. 1995. Comparison of executive and visu-ospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degreeof dementia. J. Neurol. Neurosurg. Psychiatry 58:598–606

Lawrence AD, Sahakian BJ, Hodges JR, Rosser AE, Lange KW, Robbins TW. 1996. Executive and mnemonicfunctions in early Huntington’s disease. Brain 119:1633–45

Executive functiondeficits in early ADinvolve concurrentmanipulation ofinformation (e.g., set-shifting, sequencing)rather thancued-directed attentionor problem solving.

Lefleche G, Albert MS. 1995. Executive function deficits in mild Alzheimer’s disease. Neuropsychology9:313–20

Libon DJ, Xie SX, Moore P, Farmer J, Antani S, et al. 2007. Patterns of neuropsychological impairment infrontotemporal dementia. Neurology 68:369–75

Lindau M, Almkvist O, Johansson SE, Wahlund LO. 1998. Cognitive and behavioral differentiation of frontallobe degeneration of the non-Alzheimer’s type and Alzheimer’s disease. Dementia Geriatr. Cogn. Disord.9:205–13

Lineweaver TT, Salmon DP, Bondi MW, Corey-Bloom J. 2005. Distinct effects of Alzheimer’s disease andHuntington’s disease on performance of mental rotation. J. Int. Neuropsychol. Soc. 11:30–39

Lippa CF, Johnson R, Smith TW. 1998. The medial temporal lobe in dementia with Lewy bodies: a compar-ative study with Alzheimer’s disease. Ann. Neurol. 43:102–6

Lipton AM, Ohman KA, Womack KB, Hynan LS, Ninman ET, Lacritz LH. 2005. Subscores of the FABdifferentiate frontotemporal lobar degeneration from AD. Neurology 65:726–31

Masliah E, Mallory M, Hansen LA, DeTeresa R, Terry RD. 1993. Quantitative synaptic alterations in thehuman neocortex during normal aging. Neurology 43:192–97

Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Hodges JR. 2000. A brief cognitive test battery todifferentiate Alzheimer’s disease and frontotemporal dementia. Neurology 55:1613–20

McHugh PR, Folstein MF. 1975. Psychiatric symptoms of Huntington’s chorea: a clinical and phenomenologicstudy. In Psychiatric Aspects of Neurological Disease, ed. DF Benson, D Blumer, pp. 267–85. New York: Raven


Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, et al. 2005. Diagnosis and management of dementiawith Lewy bodies: third report of the DLB consortium. Neurology 65:1863–72

McKeith IG, Galasko D, Kosaka K, Perry E, Dickson D, et al. 1996. Clinical and pathological diagnosis ofdementia with Lewy bodies (DLB): Report of the Consortium on Dementia with Lewy Bodies (CDLB)International Workgroup. Neurology 47:1113–24

Mendez MF, Cherrier M, Perryman K, Pachana N, Miller B, Cummings JL. 1996. Frontotemporal dementiasversus Alzheimer’s disease: differential cognitive features. Neurology 47:1189–94

Mendez MF, Selwood A, Mastri AR, Frey WH. 1993. Pick’s disease versus Alzheimer’s disease: a comparisonof clinical characteristics. Neurology 43:289–92

Merdes AR, Hansen LA, Jeste DV, Galasko D, Hofstetter CR, et al. 2003. Influence of Alzheimer pathologyon clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 60:1586–90

DLB patients hadsignificant metabolicreductions in theoccipital cortex thatdistinguished themfrom AD patients (90%sensitivity, 80%specificity).

Minoshima S, Foster NL, Sima A, Frey KA, Albin RL, Kuhl DE. 2001. Alzheimer’s disease versus de-mentia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann. Neurol.50:358–65

Montoya A, Pelletier M, Menear M, Duplessis, Richer F, Lepage M. 2006. Episodic memory impairment inHuntington’s disease: a meta-analysis. Neuropsychologia 44:1984–94

Neary D. 2005. Frontotemporal dementia. In Dementia, ed. A Burns, J O’Brien, D Ames, pp. 667–77. London:Hodder Arnold. 3rd ed.

Nebes R. 1989. Semantic memory in Alzheimer’s disease. Psychol. Bull. 106:377–94Norton LE, Bondi MW, Salmon DP, Goodglass H. 1997. Deterioration of generic knowledge in patients with

Alzheimer’s disease: evidence from the Number Information Test. J. Clin. Exp. Neuropsychol. 19:857–66Pachana NA, Boone KB, Miller BL, Cummings JL, Berman N. 1996. Comparison of neuropsychological

functioning in Alzheimer’s disease and frontotemporal dementia. J. Int. Neuropsychol. Soc. 2:505–10Parasuraman R, Haxby JV. 1993. Attention and brain function in Alzheimer’s disease. Neuropsychology 7:242–72Paulsen JS, Salmon DP, Monsch AU, Butters N, Swenson M, Bondi MW. 1995. Discrimination of cortical

from subcortical dementias on the basis of memory and problem-solving tests. J. Clin. Psychol. 51:48–58Peinemann A, Schuller S, Pohl C, Jahn T, Weindl A, Kassubek J. 2005. Executive dysfunction in early stages of

Huntington’s disease is associated with striatal and insular atrophy: a neuropsychological and voxel-basedmorphometric study. J. Neurol. Sci. 239:11–19

Perry RJ, Hodges JR. 1999. Attention and executive deficits in Alzheimer’s disease: a critical review. Brain122:383–404

Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, et al. 2001. Current concepts in mild cognitiveimpairment. Arch. Neurol. 58:1985–92

Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO. 1994. A quantitative magneticresonance imaging study of changes in brain morphology from infancy to late adulthood. Arch. Neurol.51:874–87

Pillon B, Dubois B, Ploska A, Agid Y. 1991. Severity and specificity of cognitive impairment in Alzheimer’s,Huntington’s, and Parkinson’s diseases and progressive supranuclear palsy. Neurology 41:634–43

Price CC, Jefferson AL, Merino JG, Heilman KM, Libon DJ. 2005. Subcortical vascular dementia: integratingneuropsychological and neuroradiologic data. Neurology 65:376–82

Rascovsky K, Salmon DP, Hansen LA, Thal LJ, Galasko D. 2007. Disparate phonemic and semantic fluencydeficits in autopsy-confirmed frontotemporal dementia and Alzheimer’s disease. Neuropsychology 21:20–30

Neuropsychologicaldeficit patternsdifferentiated betweenpatients withautopsy-confirmedFTD (prominentword-generationdeficits) and AD(prominent memory andvisuospatial deficits).

Rascovsky K, Salmon DP, Ho GJ, Galasko D, Peavy GM, et al. 2002. Cognitive profiles differ inautopsy-confirmed fronto-temporal dementia and Alzheimer’s disease. Neurology 58:1801–8Neuropsychological

deficit profilesdistinguished betweenAD (memory worsethan executivedysfunction) and smallvessel cerebrovasculardisease (memory equalto executivedysfunction).

Reed BR, Mungas DM, Kramer JH, Ellis W, Vinters HV, et al. 2007. Profiles of neuropsychologicalimpairment in autopsy-defined Alzheimer’s disease and cerebrovascular disease. Brain 130:731–39

Rohrer D, Salmon DP, Wixted JT, Paulsen JS. 1999. The disparate effects of Alzheimer’s disease andHuntington’s disease on semantic memory. Neuropsychology 13:381–88

Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, et al. 1993. Vascular dementia: diagnosticcriteria for research studies. Neurology 43:250–60

Rubin EH, Storandt M, Miller JP, Kinscherf DA, Grant EA, et al. 1998. A prospective study of cognitivefunction and onset of dementia in cognitively healthy elders. Arch. Neurol. 55:395–401

280 Salmon · Bondi

Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Sadek JR, Johnson SA, White DA, Salmon DP, Taylor KI, et al. 2004. Retrograde amnesia in dementia:comparison of HIV-associated dementia, Alzheimer’s disease and Huntington’s disease. Neuropsychology18:692–99

Sahgal A, Galloway PH, McKeith IG, Edwardson JA, Lloyd S. 1992b. A comparative study of attentionaldeficits in senile dementias of Alzheimer and Lewy body types. Dementia 3:350–54

Sahgal A, Galloway PH, McKeith IG, Lloyd S, Cook JH, et al. 1992a. Matching-to-sample deficits in patientswith senile dementias of the Alzheimer and Lewy body types. Arch. Neurol. 49:1043–46

Sahgal A, McKeith IG, Galloway PH, Tasker N, Steckler T. 1995. Do differences in visuospatial abilitybetween senile dementias of the Alzheimer and Lewy body types reflect differences solely in mnemonicfunction? J. Clin. Exp. Neuropsychol. 17:35–43

Salmon DP. 2000. Disorders of memory in Alzheimer’s disease. In Handbook of Neuropsychology, Vol. 2: Memoryand Its Disorders, ed. LS Cermak, pp. 155–95. Amsterdam: Elsevier. 2nd ed.

Salmon DP, Bondi MW. 1999. Neuropsychology of Alzheimer’s disease. In Alzheimer Disease, ed. RD Terry,R Katzman, KL Bick, SS Sisodia, pp. 39–56. Philadelphia, PA: Lippincott Williams & Wilkens. 2nd ed.

Salmon DP, Hamilton JM. 2006. Neuropsychological features of dementia with Lewy bodies. In Dementiawith Lewy Bodies, ed. J O’Brien, I McKeith, D Ames, E Chiu, pp. 49–72. London: Taylor & Francis

Salmon DP, Hamilton JM, Peavy GM. 2001. Neuropsychological deficits in Huntington’s disease: implicationsfor striatal function in cognition. In Handbook of Neuropsychology, Vol. 6: Aging and Dementia, ed. F Boller,SF Cappa, pp. 373–402. Amsterdam: Elsevier. 2nd ed.

Salmon DP, Heindel WC, Lange KL. 1999. Differential decline in word generation from phonemic andsemantic categories during the course of Alzheimer’s disease: implications for the integrity of semanticmemory. J. Int. Neuropsychol. Soc. 5:692–703

Delayed recall, categoryfluency, and globalcognitive statusprovided excellentdiscriminabilitybetween very mildlyimpaired AD patientsand NC subjects.

Salmon DP, Thomas RG, Pay MM, Booth A, Hofstetter CR, et al. 2002. Alzheimer’s disease can beaccurately diagnosed in very mildly impaired individuals. Neurology 59:1022–28

Small BJ, Fratiglioni L, Viitanen M, Winblad B, Backman L. 2000. The course of cognitive impairment inpreclinical Alzheimer disease: three- and six-year follow-up of a population-based sample. Arch. Neurol.57:839–44

Small BJ, Mobly JL, Laukka EJ, Jones S, Backman L. 2003. Cognitive deficits in preclinical Alzheimer’s disease.Acta Neurol. Scand. Suppl. 179:29–33

Sprengelmeyer R, Lange H, Homberg V. 1995. The pattern of attentional deficits in Huntington’s disease.Brain 118:145–52

Starkstein SE, Migliorelli R, Teson A, Sabe L, Vazquez S, et al. 1994. Specificity of changes in cerebral bloodflow in patients with frontal lobe dementia. J. Neurol. Neurosurg. Psychiatry 57:790–96

Stavitsky K, Brickman AM, Scarmeas N, Torgan RL, Tang M-X, et al. 2006. The progression of cognition,psychiatric symptoms, and functional abilities in dementia with Lewy bodies and Alzheimer’s disease.Arch. Neurol. 63:1450–56

Stevens A, Kircher T, Nickola M, Bartels M, Rosellen N, Wormstall H. 2001. Dynamic regulation of EEGpower and coherence is lost early and globally in probable DAT. Eur. Arch. Psychiatry Clin. Neurosci.251:199–204

Storandt M, Botwinick J, Danziger WL, Berg L, Hughes CP. 1984. Psychometric differentiation of mildsenile dementia of the Alzheimer type. Arch. Neurol. 41:497–99

Storandt M, Grant EA, Miller JP, Morris JC. 2002. Rates of progression in mild cognitive impairment andearly Alzheimer’s disease. Neurology 59:1034–41

Stout JC, Rodawalt WC, Siemers ER. 2001. Risky decision making in Huntington’s disease. J. Int. Neuropsychol.Soc. 7:92–101

Tales A, Butler SR, Fossey J, Gilchrist ID, Jones RW, Troscianko T. 2002. Visual search in Alzheimer’s disease:a deficiency in processing conjunctions of features. Neuropsychologia 40:1849–57

Thal LJ. 1999. Clinical trials in Alzheimer disease. In Alzheimer Disease, ed. RD Terry, R Katzman, KL Bick,SS Sisodia, pp. 423–39. Philadelphia, PA: William & Wilkens. 2nd ed.

Thomas-Anterion C, Jacquin K, Laurent B. 2000. Differential mechanisms of impairment of remote memoryin Alzheimer’s and frontotemporal dementia. Dement. Geriatr. Cogn. Disord. 11:100–6

Tippett LJ, Blackwood K, Farah MJ. 2003. Visual object and face processing in mild-to-moderate Alzheimer’sdisease: from segmentation to imagination. Neuropsychologia 41:453–68


Ann

u. R

ev. P

sych

ol. 2

009.

60:2

57-2

82. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by H

AR

VA

RD

UN

IVE

RSI

TY

on

03/0

6/09

. For

per

sona

l use

onl

y.


Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, et al. 2002. Early and widespread cholinergic lossesdifferentiate dementia with Lewy bodies from Alzheimer disease. Arch. Gen. Psychiatry 59:946–51

Tiraboschi P, Salmon DP, Hansen LA, Hofstetter CR, Thal LJ, Corey-Bloom J. 2006. What best differentiatesLewy body from Alzheimer’s disease in early-stage dementia? Brain 129:729–35

Treisman A. 1996. The binding problem. Curr. Opin. Neurobiol. 6:171–78Twamley EW, Ropacki SAL, Bondi MW. 2006. Neuropsychological and neuroimaging changes in preclinical

Alzheimer’s disease. J. Int. Neuropsychol. Soc. 12:707–35Ungerleider LG, Mishkin M. 1982. Two cortical visual systems. In The Analysis of Visual Behavior, ed. DJ Ingle,

RJW Mansfield, MS Goodale, pp. 549–86. Cambridge, MA: MIT PressVarma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DMA, Neary D. 1999. Evaluation of the NINCDS-

ADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J. Neurol.Neurosurg. Psychiatry 66:184–88

Vonsattel JP, Di Figlia M. 1998. Huntington disease. J. Neuropathol. Exp. Neurol. 57:369–84Waltz JA, Knowlton BJ, Holyoak KJ, Boone KB, Back-Madruga C, et al. 2004. Relational integration and

executive function in Alzheimer’s disease. Neuropsychology 18:296–305Ward J, Sheppard JM, Shpritz B, Margolis RL, Rosenblatt A, Brandt J. 2006. A four-year study of cognitive

functioning in Huntington’s disease. J. Int. Neuropsychol. Soc. 12:445–54

282 Salmon · Bondi

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revi

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AR364-FM ARI 11 November 2008 15:42

Annual Review ofPsychology

Volume 60, 2009Contents

Prefatory

Emotion Theory and Research: Highlights, Unanswered Questions,and Emerging IssuesCarroll E. Izard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Concepts and Categories

Concepts and Categories: A Cognitive Neuropsychological PerspectiveBradford Z. Mahon and Alfonso Caramazza � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �27

Judgment and Decision Making

Mindful Judgment and Decision MakingElke U. Weber and Eric J. Johnson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �53

Comparative Psychology

Comparative Social CognitionNathan J. Emery and Nicola S. Clayton � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �87

Development: Learning, Cognition, and Perception

Learning from Others: Children’s Construction of ConceptsSusan A. Gelman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 115

Early and Middle Childhood

Social Withdrawal in ChildhoodKenneth H. Rubin, Robert J. Coplan, and Julie C. Bowker � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 141

Adulthood and Aging

The Adaptive Brain: Aging and Neurocognitive ScaffoldingDenise C. Park and Patricia Reuter-Lorenz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 173

Substance Abuse Disorders

A Tale of Two Systems: Co-Occurring Mental Health and SubstanceAbuse Disorders Treatment for AdolescentsElizabeth H. Hawkins � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 197

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Therapy for Specific Problems

Therapy for Specific Problems: Youth Tobacco CessationSusan J. Curry, Robin J. Mermelstein, and Amy K. Sporer � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 229

Adult Clinical Neuropsychology

Neuropsychological Assessment of DementiaDavid P. Salmon and Mark W. Bondi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 257

Child Clinical Neuropsychology

Relations Among Speech, Language, and Reading DisordersBruce F. Pennington and Dorothy V.M. Bishop � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 283

Attitude Structure

Political Ideology: Its Structure, Functions, and Elective AffinitiesJohn T. Jost, Christopher M. Federico, and Jaime L. Napier � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 307

Intergroup relations, stigma, stereotyping, prejudice, discrimination

Prejudice Reduction: What Works? A Review and Assessmentof Research and PracticeElizabeth Levy Paluck and Donald P. Green � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 339

Cultural Influences

Personality: The Universal and the Culturally SpecificSteven J. Heine and Emma E. Buchtel � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 369

Community Psychology

Community Psychology: Individuals and Interventions in CommunityContextEdison J. Trickett � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 395

Leadership

Leadership: Current Theories, Research, and Future DirectionsBruce J. Avolio, Fred O. Walumbwa, and Todd J. Weber � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 421

Training and Development

Benefits of Training and Development for Individuals and Teams,Organizations, and SocietyHerman Aguinis and Kurt Kraiger � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 451

Marketing and Consumer Behavior

Conceptual ConsumptionDan Ariely and Michael I. Norton � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 475

viii Contents

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Psychobiological Mechanisms

Health Psychology: Developing Biologically Plausible Models Linkingthe Social World and Physical HealthGregory E. Miller, Edith Chen, and Steve Cole � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 501

Health and Social Systems

The Case for Cultural Competency in Psychotherapeutic InterventionsStanley Sue, Nolan Zane, Gordon C. Nagayama Hall, and Lauren K. Berger � � � � � � � � � � 525

Research Methodology

Missing Data Analysis: Making It Work in the Real WorldJohn W. Graham � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 549

Psychometrics: Analysis of Latent Variables and Hypothetical Constructs

Latent Variable Modeling of Differences and Changes withLongitudinal DataJohn J. McArdle � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 577

Evaluation

The Renaissance of Field Experimentation in Evaluating InterventionsWilliam R. Shadish and Thomas D. Cook � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 607

Timely Topics

Adolescent Romantic RelationshipsW. Andrew Collins, Deborah P. Welsh, and Wyndol Furman � � � � � � � � � � � � � � � � � � � � � � � � � � � � 631

Imitation, Empathy, and Mirror NeuronsMarco Iacoboni � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 653

Predicting Workplace Aggression and ViolenceJulian Barling, Kathryne E. Dupre, and E. Kevin Kelloway � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 671

The Social Brain: Neural Basis of Social KnowledgeRalph Adolphs � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 693

Workplace Victimization: Aggression from the Target’s PerspectiveKarl Aquino and Stefan Thau � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 717

Indexes

Cumulative Index of Contributing Authors, Volumes 50–60 � � � � � � � � � � � � � � � � � � � � � � � � � � � 743

Cumulative Index of Chapter Titles, Volumes 50–60 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 748

Errata

An online log of corrections to Annual Review of Psychology articles may be found athttp://psych.annualreviews.org/errata.shtml

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