Mild Cognitive ImpairmentMild Cognitive Impairment

Susan K. Schultz MDSusan K. Schultz MDProfessor of PsychiatryProfessor of Psychiatry

University of Iowa Carver College of University of Iowa Carver College of MedicineMedicine

DisclosuresDisclosures• Research support from the NIA-funded

Alzheimer’s Disease Cooperative Study in partnership with Baxter Healthcare

• Research support from NIA (ADNI), NCI, NIMH• Professional support from the American

Psychiatric Association• Acknowledgement for Presentation

– Constantine G. Lyketsos, MD, MHS– Elizabeth Plank Althouse Professor, Johns Hopkins

University– Chair of Psychiatry, Johns Hopkins Bayview

Diagnosis of Mild Cognitive Diagnosis of Mild Cognitive Impairment (MCI)Impairment (MCI)

Petersen RC, Smith GE, Waring SC et al. (1999), Arch Neurol 56(3):303-308.

Importance of Managing MCIImportance of Managing MCI

• Record numbers of patients presenting with MCI– Media brings in patients with milder symptoms

• Clinical Assessment – Addresses patient and family concerns– An opportunity to delay or prevent onset of dementia

• Future trials may benefit patients without dementia who have AD pathology– Senile plaques and neurofibrillary tangles– Volume loss in hippocampus and entorhinal cortex

reflecting loss of neuron number– Predate neurocognitive deficits

MCI: Significant Risk for MCI: Significant Risk for Alzheimer’s Dementia (AD)Alzheimer’s Dementia (AD)

• Highest conversion rates in referral populations– Amnestic MCI dementia: 5-15% annually– Up to 80% AD within 5 years in some

reports.

• Population samples: 25-40% do not dementia

• MCI is a risk group, not a diagnosis

Predicting Incident AD in Predicting Incident AD in MCIMCI

• Biomarkers

• Neuropsychiatric symptoms

Biomarkers of Preclinical AD Predictive of MCI Dementia

• Loss of brain volume (structural MRI)– Hippocampus– Entorhinal cortex

• Decreased glucose uptake (FDG-PET)– Temporal, parietal

cortex, posterior cingulate

• Functional biomarkers– CSF changes

• Decreased amyloid-b

• Increased tau– Amyloid imaging

• 11C-PIB• 18F-AV-45

Vemuri P, Neurology 2009

MCI and DepressionMCI and Depression

• Is depression a risk factor?

• Is it is the earliest sign of MCI?

Modrego, P. J. et al. Arch Neurol 2004;61:1290-1293.

Major Depressive Disorder in MCI Dementia

•Followed 114 patients with amnestic MCI for 3 years

• 41 with MDD• 73 without MDD

•85% with (+) MDD developed incident AD •vs. 32% with (-) MDD

• RR 2.6 • (95% CI 1.8-3.6)

(-) MDD

(+) MDD

Depression in MCI0.

000.

250.

500.

751.

00T

MT

-B <

224

sec

0 1000 2000 3000Days

GDS <9 GDS >=9

HR 2.5 (95% CI 1.6-3.8)p<.001

Kaplan-Meier curveBaseline Depression vs. TMT-B • 436 older women with

normal cognition

• Examined risk of dropping below 10th percentile on cognitive tests

• Baseline depression (GDS-30 > 9) doubled risk of incident impairment in immediate recall, TMT-A, TMT-B

Rosenberg P et. al. Am J Geriatric Psychiatry 2010 Mar;18(3):204-11.

Treatment of Depression and MCI

• N=109 subjects >65 years in an outpatient geriatric mental health clinic

• 38% were diagnosed with MCI • Despite adequate depression treatment

response, nearly half of remitted depressed subjects still had a cognitive disorder

• Bhalla RK Am J. Geriatr Psychiatry. 2009 Apr;17(4):308-16.

Management of MCIManagement of MCI

• Evaluate

• Diagnose

• Treat

Evaluation for MCIEvaluation for MCI

• Patients/families frequently extremely anxious– Among the most “worried well” patients– Often the patient had parent with dementia

• Meet patient and family separately if possible– Patient alone for history and exam– Family alone for history

• Often need to discuss highly charged issues

Elements of the EvaluationElements of the Evaluation

• History from patient and family• Examination• Diagnostic tests

– Screening cognitive assessment • Montreal Cognitive Assessment• http://www.mocatest.org/• MOCA < 26

– Full neuropsychological testing – Brain Imaging (CT, MRI, PET)– Laboratory evaluation

History of Present IllnessHistory of Present Illness

• Identify highest level of functioning, SES

• Anchor around when “last well”

• Earliest signs and symptoms

• Temporal course of symptoms– Relationship to one another

• Systematic ROS– Cognitive, functional, neuropsychiatric

Brain ImagingBrain Imaging

Con

• Low yield• Nonspecific findings• Doesn’t influence

treatment• Expensive• Academic value • Useful for research

Pro• Diagnostic potential• Radiologic markers• Early detection• Evaluate progression• Prognostic indicators• Brain-behavior

relationships

Role of ImagingRole of Imaging

• Identify treatable/reversible conditions• Mass lesions—tumors, subdural hematoma• Normal pressure hydrocephalus

• Establish other diagnoses• Identify infarcts—multi-infarct dementia, vascular

dementia + AD• Identify microvascular disease

• Better disease characterization • Atypical Presentations• Early onset cases

Office Treatment: Office Treatment: What does the evidence say?What does the evidence say?

• No clearly positive trials of AD medications

• Interventions with positive-leaning results

– Treatment of depression

– Exercise

– Cognitive stimulation

– Variety in leisure activities

• Nutriceuticals are an open question

Cholinesterase InhibitorsCholinesterase InhibitorsRecommendationsRecommendations

• Not routinely indicated in MCI• Three published and five unpublished randomized trials met

the inclusion criteria (donepezil -3, rivastigmine-2, galantamine -3).

• Rate of conversion ranged 13% (over 2 yr) to 25% (over 3 yr) among treated patients

– 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups

• Use in MCI was not associated with delay in the onset of AD / dementia

– Raschetti R, et a;PLoS Med. 2007 Nov 27;4(11):e338.

Cholinesterase InhibitorsCholinesterase Inhibitors

• Patients with MCI and mild AD who were treated with cholinesterase inhibitors and memantine were assessed across ADNI sites.– 177 (44.0%) of 402 MCI patients and – 159 (84.6%) of 188 mild-AD were treated with ChEIs

• Those with MCI receiving ChEIs (with or without memantine) were more impaired, showed greater decline in scores, and progressed to dementia sooner than patients who did not receive ChEIs.

• Schneider LS Arch Neurol. 2011 Jan;68(1):58-66.

Cholinesterase inhibitorsCholinesterase inhibitors

• Older adults treated for depression: N=135; >65 yrs• Compared donepezil with antidepressant therapy to

placebo with antidepressant therapy• In cognitively intact patients, donepezil appeared to

have no benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression.– The mild cognitive impairment subgroup (n=57) had

recurrence rates of major depression of 44% with donepezil vs 12% with placebo

• Reynolds CF, Arch Gen Psychiatry. 2011 Jan;68(1):51-60

NutriceuticalsNutriceuticals• Vitamin E

– There was no significant difference in the probability of progression from MCI to AD between the Vitamin E group and the placebo group.

– No significant difference between the placebo group and the Vitamin E group in death, adverse events.

• Issac MG: Cochrane Database Syst Rev. 2008 Jul 16;(3):CD002854

• Antioxidants, polyphenols under study:– Folate, Curry (curcumin), Blueberries, Resveratrol

• Reviews: Ray B. et al Curr Opin Pharmacol. 2009 Aug;9(4):434-44.

• Darvesh A, Expert Rev Neurother. 2010 May;10(5):729-45

• Evidence base is evolving….

Lifestyle Changes: Better Lifestyle Changes: Better Evidence than MedicationsEvidence than Medications

• Manage co-morbidities and “vascular” factors

• Exercise, especially• Cognitive stimulation• Increase variety of leisure activities• Optimize nutrition

– Favor dietary choices with omega-3 fatty acids, antioxidants, polyphenols.

ExerciseExercise• Physical exercise, aging, and mild cognitive

impairment: a population-based study.• N=1324 without dementia who completed a

Physical Exercise Questionnaire.• 198 with MCI, 1126 without MCI• Odds ratio:• Any frequency of moderate exercise:

– 0.61 for midlife (age range, 50-65 years) – 0.68 for late life >65 years.

• Conclusion: Any frequency of moderate exercise performed in midlife or late life was associated with a reduced odds of having MCI.

– Geda YE, Arch Neurol. 2010 Jan;67(1):80-6.

How Much to Exercise?How Much to Exercise?• Light exercise: e.g., bowling, leisurely walking,

stretching, slow dancing, golfing with golf cart.

• Moderate exercise: e.g., brisk walking, hiking, aerobics, strength training, swimming, tennis doubles, yoga, martial arts, weight lifting, golfing without a golf cart, and moderate use of exercise machines (e.g., an exercise bike).

• Vigorous exercise: e.g., jogging, backpacking, bicycling uphill, tennis singles, racquetball, skiing, and intense use of exercise machines.

–Geda YE, Arch Neurol. 2010 Jan;67(1):80-6.

Meta-analysis of ExerciseMeta-analysis of Exercise

• 15 studies; N= 33,816 non-demented subjects followed for 1-12 years

• 3210 had cognitive decline– High level of physical activity

• HR 0.62 p<.00001– Low to moderate physical activity

• HR 0.65 p<.00001

• Conclude: A significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline.

• Sofi F, et al J Intern Med. 2011 Jan;269(1):107-17

ConclusionsConclusions

• Diagnosis of MCI is well understood

• Prevention and treatment options are less well-defined– Use of medications depends on style of

practice– Treatment of depression– Supportive care and management– Lifestyle changes