Memory and treatment of Memory and treatment of cognitive impairmentscognitive impairments

MUDr. Tomáš KašpárekMUDr. Tomáš Kašpárek

Dep. of PsychiatryDep. of Psychiatry

Masaryk University, BrnoMasaryk University, Brno

ContentsContents

IntroductionIntroduction

Physiology and classificationPhysiology and classification

Memory assessmentMemory assessment

Disturbances in memoryDisturbances in memory

Treatment of cognitive impairmentTreatment of cognitive impairment

IntroductionIntroduction

Definition:Definition: ability to register, store, and ability to register, store, and recall information recall information (three stages of memory)(three stages of memory)

Memory: part of Memory: part of cognitive functions cognitive functions (involved in information processing;(involved in information processing; such as perception, such as perception, thinking, attention)thinking, attention)

Dimensions of behaviorDimensions of behavior– cognition (reasoning) and emotionalitycognition (reasoning) and emotionality

Stages of memory I: RegistrationStages of memory I: Registration

capacity to capacity to add new material add new material (sensory, (sensory,

conceptual, perceptual)conceptual, perceptual) to memory to memory

new information need to be new information need to be properly properly processedprocessed (percepted)(percepted) – – disturbing factorsdisturbing factors– consciousnessconsciousness– attentionattention– emotionsemotions– repetitionrepetition

„„Life cycle“ of a memory traceLife cycle“ of a memory trace

Immediate memoryImmediate memory– information stored for 15-20sinformation stored for 15-20s

Short-term memoryShort-term memory– consolidation of the memory trace – several consolidation of the memory trace – several

minutes to 2 daysminutes to 2 days– medial temporal structuresmedial temporal structures

Long-term memoryLong-term memory– formed traceformed trace– large cortical areaslarge cortical areas

Stages of memory II: RetentionStages of memory II: Retention

ability to hold memories in a storageability to hold memories in a storage

large # of neurons large # of neurons (changes in connectivity)(changes in connectivity) involved in the storage of specific memoryinvolved in the storage of specific memory– sensory specific fractions of complex sensory specific fractions of complex

perceptions in corresponding cortical areasperceptions in corresponding cortical areas

Stages of memory III: RecallStages of memory III: Recall

ability to return stored informationability to return stored informationactive reconstructionsactive reconstructions– adding together fractions of the exact adding together fractions of the exact

recollectionrecollection– in a specific situation (=influence) – possibility in a specific situation (=influence) – possibility

of the failure to represent of past events of the failure to represent of past events properlyproperly

– awareness of the recollection, sureness, awareness of the recollection, sureness, proper addressing of time and situation of proper addressing of time and situation of recollection acquirementrecollection acquirement

Types of memory: Types of memory: Memory Memory modules modules (Willingham 1997)(Willingham 1997)

Explicit (declarative) memoryExplicit (declarative) memory – medial – medial temporal cortextemporal cortexProcedural memoryProcedural memory – sensory-motor functional – sensory-motor functional systemssystemsWorking memoryWorking memory – prefrontal cortex – prefrontal cortexClassical conditioningClassical conditioning – cerebellum; relation – cerebellum; relation between motor function and perceptionbetween motor function and perceptionEmotional conditioningEmotional conditioning – amygdala; relation – amygdala; relation between perception and emotionbetween perception and emotionPrimingPriming - parietal, temporal and frontal cortex - parietal, temporal and frontal cortex

Memory assessmentMemory assessment

Immediate recallImmediate recall– series of numbers (most adult recall 6 # forward and 3 series of numbers (most adult recall 6 # forward and 3

in reverse)in reverse)

Short-term memoryShort-term memory– names names of of 3 inrelated objects after 5 min3 inrelated objects after 5 min

Long-term memoryLong-term memory– personal history (independent confirmation), general personal history (independent confirmation), general

information (names of presidents...)information (names of presidents...)

Scales – MiniMental State ExaminationScales – MiniMental State ExaminationSpecific tests – Wechsler Memory Scale IIISpecific tests – Wechsler Memory Scale III

Disturbances in memoryDisturbances in memory

General notesGeneral notes

memory = set of functions based on memory = set of functions based on different neuronal processes = various different neuronal processes = various dysfunctions according to the pathological dysfunctions according to the pathological processprocess

Disturbances in registrationDisturbances in registration

pathological processpathological process– disturbed vigilance, attentiondisturbed vigilance, attention

head trauma, seizures, delirium, intoxication (BZD, head trauma, seizures, delirium, intoxication (BZD, sedatives), psychosis, depression, anxietysedatives), psychosis, depression, anxiety

– disturbed structures involved in memory disturbed structures involved in memory consolidationconsolidation

hippocampus, mammillary bodies, fornix – i.e. hippocampus, mammillary bodies, fornix – i.e. mediotemporal structuresmediotemporal structures

short-term memoryshort-term memory dysfunction, dysfunction, immediate recall may be sparedimmediate recall may be spared

Disturbances in retentionDisturbances in retention

pathological processpathological process– impairment of large cortical areasimpairment of large cortical areas– posttraumatic amnesiaposttraumatic amnesia– cognitive disorderscognitive disorders

Disturbances in recallDisturbances in recall

may reflect damaged storagemay reflect damaged storage

may occur separately may occur separately – failure to recall with later proper recollectionfailure to recall with later proper recollection– personality, situationpersonality, situation– attention, fatigue...attention, fatigue...

„„Quantitative“ dysfunctionsQuantitative“ dysfunctions

Amnesia: Amnesia: short/long-term memory impairment in a state of short/long-term memory impairment in a state of normal consciousnessnormal consciousness

– anterograde: failure to form new informationanterograde: failure to form new informationhead trauma, state of CNS dysbalance, drug effecthead trauma, state of CNS dysbalance, drug effect

– retrograde: failure to recall old informationretrograde: failure to recall old informationhead traumahead trauma

dissociative amnesia: patchy or selectivedissociative amnesia: patchy or selective

Hypermnesia: Hypermnesia: unusually vivid memoryunusually vivid memory

– mania, posttraumatic stress disorder (intrusive mania, posttraumatic stress disorder (intrusive memories), obsessive or paranoid personality traitsmemories), obsessive or paranoid personality traits

„„Qualitative“ dysfunctionsQualitative“ dysfunctions

paramnesias – retrospective falsification of paramnesias – retrospective falsification of memories during its recollection memories during its recollection (awareness of recalled (awareness of recalled memory, failure to proper class time and situation of memory memory, failure to proper class time and situation of memory acquirement)acquirement)

confabulation – filling memory gaps with confabulation – filling memory gaps with inaccurate information; inaccurate information; frontal lobe and self-monitoring?frontal lobe and self-monitoring?

deja vu – sensation of previously experienced deja vu – sensation of previously experienced situation when experiencing the first timesituation when experiencing the first time– false awareness of memoryfalse awareness of memory– common in normality, increased in fatigue, common in normality, increased in fatigue,

intoxication, complex partial seizuresintoxication, complex partial seizures

Treatment of cognitive Treatment of cognitive impairmentimpairment

General notesGeneral notes

no specific way to treat memory deficitno specific way to treat memory deficit

treatment modalities focused on the whole treatment modalities focused on the whole spectrum of impairments in cognitive spectrum of impairments in cognitive disordersdisorders

the most data available for Alzheimer's the most data available for Alzheimer's diseasedisease

PsychopharmacotherapyPsychopharmacotherapy

Reinforcement of cholinergic mechanismReinforcement of cholinergic mechanism– Cholinesterase inhibitors (ChEIs)Cholinesterase inhibitors (ChEIs)

Prevention of excitotoxicityPrevention of excitotoxicity– Memantine - NMDA antagonistsMemantine - NMDA antagonists

Cholinesterase inhibitors ICholinesterase inhibitors I

cholinesterasescholinesterases: acetylcholinesterase : acetylcholinesterase (AChE), butyrylcholinexterase (BChe)– (AChE), butyrylcholinexterase (BChe)– hydrolysis hydrolysis of acetylcholin, thus of acetylcholin, thus decreasedecrease its amount in synapsesits amount in synapsesmolecular forms of AChemolecular forms of AChe– G4 (tetramer) – presynaptic membrane – both G4 (tetramer) – presynaptic membrane – both

hydrolysis and feedback inhibition; decrease hydrolysis and feedback inhibition; decrease in AD and agingin AD and aging

– G1 (monomer) – postsynaptic membrane; no G1 (monomer) – postsynaptic membrane; no significant decreasesignificant decrease

Cholinesterase inhibitors IICholinesterase inhibitors II

donepezildonepezil– long-acting, selective, reversible AChEIlong-acting, selective, reversible AChEI– metabolized by the liver microsome syst.metabolized by the liver microsome syst.

rivastigminrivastigmin– pseudo-irreversible, both AChEI (G1) and BChEIpseudo-irreversible, both AChEI (G1) and BChEI– no liver microsome metabolismno liver microsome metabolism

galantamingalantamin– reversibilie, competitive reversibilie, competitive (increases AC only in areas with low AC (increases AC only in areas with low AC

concentration – lower central cholinergic side effects than concentration – lower central cholinergic side effects than

noncompetitive inhibitors)noncompetitive inhibitors) AChEI + allosteric modulation of AChEI + allosteric modulation of nACRnACR

Cholinesterase inhibitors III – Cholinesterase inhibitors III – adverse effectsadverse effects

significant significant cholinergic cholinergic side effects in 15% of side effects in 15% of patients receiving higher dosespatients receiving higher dosesmost common:most common:– GIT: nausea, vomiting, diarrhea, anorexia, weight lossGIT: nausea, vomiting, diarrhea, anorexia, weight loss– CNS: headache, dizziness, insomnia, drowsiness, CNS: headache, dizziness, insomnia, drowsiness,

fatigue, agitationfatigue, agitation– CVS: bradycardia, syncopeCVS: bradycardia, syncope

generally mild in severity, short-lived, related to generally mild in severity, short-lived, related to titration (slowly!)titration (slowly!)caution in patients with asthma, CHOPD, cardiac caution in patients with asthma, CHOPD, cardiac conduction defects/clinically significant conduction defects/clinically significant bradycardiabradycardia

Memantine I - RationaleMemantine I - Rationale

excessive glutamate release in excessive glutamate release in Alzheimer's Alzheimer's disease disease ((as well as vascular dementiaas well as vascular dementia - - ischemic damage)ischemic damage)

excitotoxic degradation of neuronsexcitotoxic degradation of neurons– progression of cognitive decline, severity of progression of cognitive decline, severity of

other symptomsother symptoms

neuronal degradation is linked with neuronal degradation is linked with amyloid accumulationamyloid accumulation

Memantine II – Mechanism of Memantine II – Mechanism of actionaction

non-competitive NMDA antagonistnon-competitive NMDA antagonist– voltage dependent, fast receptor kinetics – enable voltage dependent, fast receptor kinetics – enable

physiologic function (LTP, memory)physiologic function (LTP, memory)decreased activity of glutamate systemdecreased activity of glutamate system

hippocampus, neocortexhippocampus, neocortex

decreased excitotoxicity - neuronal damage – amyloid decreased excitotoxicity - neuronal damage – amyloid accumulationaccumulationi.e. i.e. slow down slow down progression of the diseaseprogression of the disease

5HT5HT33 blockade blockade– facilitation of LTPfacilitation of LTP– antiemetic effect and regulation of GIT motility antiemetic effect and regulation of GIT motility

(combination with ACEI)(combination with ACEI)

Memantine III – Clinical efficacyMemantine III – Clinical efficacy

slower progression of vascular and slower progression of vascular and Alzheimer dementiaAlzheimer dementiafast onset of action – 2 weeksfast onset of action – 2 weeksimprovement of cognitive functions, vigility, improvement of cognitive functions, vigility, daily activitiesdaily activitiesreduction of the need for the help of reduction of the need for the help of caregiverscaregiversefficacy even in the moderate to severe efficacy even in the moderate to severe disease stages x ACEIdisease stages x ACEI

Memantine IV Memantine IV

Adverse events Adverse events – generally well toleratedgenerally well tolerated– higher than placebo: insomnia, dizziness, headache, higher than placebo: insomnia, dizziness, headache,

hallucinations (NMDA antagonist – PCP)hallucinations (NMDA antagonist – PCP)

PharmacokineticsPharmacokinetics– renal excretionrenal excretion– no extensive metabolizationno extensive metabolization– no cytochrome P 450 inhibitionno cytochrome P 450 inhibition– dosagedosage

20 mg pro die in 2 doses20 mg pro die in 2 dosesstart: 5 mg, titration: 5 mg per weekstart: 5 mg, titration: 5 mg per week

References :References :

Waldinger R.J.: Psychiatry for medical Waldinger R.J.: Psychiatry for medical students, Washington, DC : American students, Washington, DC : American Psychiatric Press, 1997Psychiatric Press, 1997

Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Sadock´s synopsis of psychiatry, Baltimore: Sadock´s synopsis of psychiatry, Baltimore: Williams and Wilkins, 1997Williams and Wilkins, 1997