Diagnosis of Dementia and Use of Anti-dementia

MedicationsProf Philip Morris

MB BS, BSc(med), PhD, FRANZCP, FAChAM (RACP)Consultant Psychiatrist/Neuropsychiatrist

Medical Advisor – DBMAS NTMedical Director

Gold Coast – Tweed Memory Clinic36 Beryl St, Tweed Heads, NSW, Australia

Ph 07 55992220 andSuite 2, Level 5, 123 Nerang St, Southport, Qld, Australia

Ph 07 55327655www.memoryclinic.com.au

Presentation Objectives1. Recognize and assess significant cognitive impairment in older individualsThe 'anatomy' of memory - 'Normal' versus 'Pathological' memory changes with aging - Bedside or office testing of cognitive function2. Understand the clinical presentation and nature of common dementia syndromesCommon dementia clinical syndromes - Alzheimer's disease - Vascular cognitive impairment - Frontotemporal dementia - behavioural, semantic and progressive aphasia types - Dementia with Lewy bodies - Subcortical dementias - Parkinson's disease dementia - Alcohol, traumatic brain injury, multiple sclerosis, motor neuron disease, Huntington'sdisease, AIDS and other dementias - Routine investigations in dementia3. Determine which patients might benefit from anti-dementia drugs and other psychotropicsTarget symptoms for medications - Alertness and attention/concentration – Memory – Motivation - Improve speech - Improve mood - Reduce anxiety - Reduce psychotic symptoms - Reduce agitation and aggressionCommon nootropics and psychotropics in dementia - Acetyl cholinesterase inhibitors - Memantine (NMDA receptor antagonist) – Benzodiazepines – Antidepressants – Antipsychotics - Anticonvulsants and mood stabilizers4. Appreciate the safety concerns using anti-dementia and psychotropic drugs in older patientsCardiac effects - Sedation and falls - Epileptogenic effects - Increased mortality

Broca’sarea

Parsopercularis

Motor cortex Somatosensory cortexSensory associativecortex

PrimaryAuditory cortex

Wernicke’sarea

Visual associativecortex

Visualcortex

Lateral Brain

Limbic Brain

Word understanding

Memory Emotion(Limbic system - not visible)

Vision

Spatial relationsNumbers Word production

Problem solvingPlanning

Behavioural controlEmotion

Attention and arousal

Subjective memory complaints

Disorientationforget time, place, trace of time

Disorganizationforget appointments, instructions

Omissionleave things behind, losing things, forgetting

lightsRepetition

asking same question, telling same story

All can occur in healthy people!

Testing memory – list of words and cues – verbal recall

AssessmentAssessment

Memory problemsMemory problems

Cortical regions involvedCortical regions involved

Frontal (judgment, reasoning, finances, attention, Frontal (judgment, reasoning, finances, attention, planning, motivation, impulsivity)planning, motivation, impulsivity)

Temporal (memory, word finding, remembering Temporal (memory, word finding, remembering names, irritability, misinterpretations)names, irritability, misinterpretations)

Parietal (disorientation, spatial misjudgment, left-Parietal (disorientation, spatial misjudgment, left-right confusion, dressing apraxias)right confusion, dressing apraxias)

Structure of Memory

Memory – 3 Rs: registration (encode - needs attention and arousal), retain (store), and recall (retrieve)

Implicit/procedural Declarative/explicit (unconscious) (conscious)(learning of skills and (learning of information)automatic behaviours) Motor/conditioning/priming Working/short term memory

(over seconds) (over seconds to minutes) Phonological loop Visuo-spatial sketch pad

Long term memory (over days)Semantic memory (knowledge and memory about things) Episodic memory (narrative memories)

Neuroanatomy of Memory

Episodic memory – limbic system and hippocampusSemantic memory – widely distributed in cortexImplicit memory – basal ganglia, cerebellum, spinal cord

Disorders of Memory

Disorders of working memory - problems with attention and ‘central executive function’ - the ‘scratchpad’ or RAMDisorders of episodic memory - inability to retain new information/material (amnesia) - hippocampus basedDisorders of semantic memory (knowledge) - more difficult to erode, less affected by diseaseDisorders of ‘metamemory’ - inability to judge own memory function - insight

Subjective cognitive complaints (SCC) Benign course, forgets names, misplaces

things, needs more reminders, reduced concentration and increased distraction, anxiety and depression, excess demand

Cognitive impairment not dementia (CIND) also known as mild cognitive impairment (MCI)

1/3 better, 1/3 same, 1/3 worse over two yearsMCI single domain – amnesic MCI multiple domain – memory, concentration,

complex activities (cooking, finances), new learning

Early dementia Multi domain impairment plus functional

effects and impairments on instrumental ADLs

Mild Cognitive Impairment – Sub-types

• Mild Cognitive Impairment (MCI) is considered a transitional state between ‘normal’ cognitive changes of ageing and the earliest clinical presentation of dementia. The original definition of amnestic MCI has empirical support as a prodrome to Alzheimer’s disease with conversion rates of 10-15% per year.

• MCI is now recognised as a heterogeneous syndrome and diagnosticcriteria have been broadened to include 4 clinical subtypes* Amnestic MCI single domain (aMCI) – memory impairment only* Amnestic MCI multiple domain (maMCI) – impairment in memory + other cognitive domain(s)* Non-amnestic MCI single domain (nMCI) – impairment in a single nonmemory domain* Non-amnestic MCI multiple domain (mnMCI) – impairment in multiplenon-memory domains.

• Individuals with MCI affecting multiple domains may be more severelycognitively impaired and represent a more advanced prodromal stage.

Dementia ‘epidemic’ explodesMain types of dementia

Alzheimer’s disease (35%)Vascular dementia (20%)Mixed Alzheimer’s/vascular (20%)Dementia with Lewy bodies (10%)Focal lobar atrophies (frontal variant FTD, semantic dementia,

progressive non-fluent aphasia, and motor neuron dementia) (5%)Sub cortical dementias (Parkinson’s disease, progressive

supranuclear palsy, multiple system atrophy, Huntington’s disease) (5%)

Alcohol related (3%)Head injury (2%)

Memory loss a cardinal feature of dementia along with either aphasia, apraxia, agnosia or a disturbance of executive functioning (planning, organizing, sequencing, abstracting)

Dementia Conditions

Less than 1% of the under age 65 population compared with 20% of over 80s individuals

Most Common Dementias

Alzheimer’s diseaseVascular dementiaDementia with Lewy bodiesFrontotemporal dementia

Alzheimer’s disease

Most common. Inflammatory plaques of amyloid outside neurones, and deposition of tau tangles inside neurones. Initially concentrated in hippocampus and acetylcholine producing neurones. First causes learning and recent memory problems, and attention difficulties. Early onset Alzheimer’s disease more often inherited (chromosomes 14, 1, and 21 including Down’s syndrome)

Vascular dementia

Multi-infarct dementia and Binswanger’s disease (deep white matter ischemia or subcortical vascular dementia) Vascular risk factors prominent (smoking, high blood pressure, diabetes, high lipids/cholesterol) Early onset may indicate an inherited Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Causes migranes, recurrent strokes and dementia. Chromosome 19 NOTCH3 gene mutation.

Some early onset vascular dementias are autoimmune conditions affecting blood vessels in brain and may be treatable Memory less affected compared with Alzheimer’s disease. Frontal lobe executive functions, language, emotion and apathy, walking problems and incontinence more prominent.

Stepwise deterioration

Differentiating Alzheimer’s disease and vascular dementiaDifferentiating Alzheimer’s disease and vascular dementia

Frontotemporal dementiaPreviously known as Pick’s diseaseSecond most common degenerative disease causing dementia in younger adults (after Alzheimer’s disease)More localised damage in frontal or temporal lobes causing changes in personality, language skills, and later memoryPathology includes severe loss of neurones (causing focal atrophy), as well as deposition of tau protein as ‘Pick bodies’ in neurones and accumulation of ubiquitin protein. A small number (20%) of cases are due to chromosome 17 mutations (tau and progranulin genes).Three clinical presentations of frontotemporal dementiaBehavioural variantPersonality change most distinctive – loss of empathy and warmth, apathy, and disinhibition. Poor judgment, reasoning, planning and organisation. Reduction in conversation, eating changes, decline in self-care and loss of independent ADLs.Progressive aphasia – semantic dementia (fluent)Loss of memory for words, impaired comprehension of word meaning, reading and spelling affected, numerical abilities preserved.Progressive nonfluent aphasiaSlow and tortuous production of words causing distortion of speech, wrong words and grammatical errors. Problems with using telephone or talking in groups. Apraxia of hand movementsBoth types of aphasia can progress to behavioural disturbance

Parkinsonian disorders associated with dementia

Parkinson’s disease

Pathology of Lewy bodies (clumps of alpha-synuclein protien) in substantia nigra region of brain stem20% to 40% later develop dementia characterised by difficulties with abstract thought, memory, behavioural regulation and visual hallucinations.

Dementia with Lewy bodies

Similar pathology to Parkinson’s disease, but in addition plaques and tanglesA ‘cross’ between Parkinson’s disease and Alzheimer’s disease – cognitive features of Alzheimer’s disease with movement disorder of Parkinson’s disease (‘Parkinson’s plus’). Vivid visual hallucinations (faces, animals), rapid fluctuations of alertness, and falls are common Attention is impaired more than memory Copying shapes and understanding visual material is affectedSensitive to antipsychotic medication, may respond to ACEIs

Progressive supranuclear palsyRigid Parkinson’s disease, gaze palsy, swallowing problems and frontal dementiaCorticobasal degeneration (CBD)Rigidity, bradykinesia, apraxia (‘alien limb’ syndrome), and behavioural variant of frontotemporal dementia

Less Common Early Onset Dementias

Motor Neurone Disease with dementiaHuntington’s diseaseAlcohol related dementia and Korsakoff’s syndromeMultiple sclerosisHIV-related dementia

Rare Causes of Younger Onset Dementia

Creutzfeldt-Jacob disease (CJD)Dementia after head injuryDementia in Down syndromeHomocystinuriaVasculitisWilson’s diseasePorphyriaAdrenoleukodystrophyLipid storage diseasesMitochondrial disordersDentatorubralpallidoluysian atrophy (DRPLA)Neuroacanthocytosis

History taking questions

Recent narrative memory, past narrative memory, people's names, names items, learning problems, forgetting things and appointments, word finding problems, comprehension and expression problems, semantic difficulties, topographical disorientation, R/L disorientation, dressing and other apraxias, gait problems, posture, EPS, involuntary movements, incontinence, confusion episodes, mood and affect, psychotic symptoms, motivation and passivity, personality changes, agitation, aggression, planning and sequencing problems, sleep, appetite, weight, ADLs, cooking, shopping, driving

The Clinical Problem

Age Related Changes or Subjective Cognitive Complaints (SCC)

Vs

Mild Cognitive Impairment (MCI) or Cognitive Impairment Not Dementia (CIND)

Vs

Early Dementia?

Beyond the Mini Mental State Exam?

The Addenbrooke’s Cognitive Examination

Int J Geriatr Psychiatry 2006; 21: 1078–1085.The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screeningEneida Mioshi1,2, Kate Dawson2, Joanna Mitchell2, Robert Arnold1 and John R. Hodges1,2*1MRC Cognition and Brain Sciences Unit, Cambridge, UK2University of Cambridge Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, UKSUMMARYThere is a clear need for brief, but sensitive and specific, cognitive screening instruments as evidenced by the popularity of the Addenbrooke’s Cognitive Examination (ACE).Objectives We aimed to validate an improved revision (the ACE-R) which incorporates five sub-domain scores(orientation/attention, memory, verbal fluency, language and visuo-spatial).Methods Standard tests for evaluating dementia screening tests were applied. A total of 241 subjects participated in this study (Alzheimer’s disease=67, frontotemporal dementia=55, dementia of Lewy Bodies=20; mild cognitive impairment–MCI=36; controls=63).Results Reliability of the ACE-R was very good (alpha coefficient=0.8). Correlation with the Clinical Dementia Scalewas significant (r=0.321, p <0.001). Two cut-offs were defined (88: sensitivity=0.94, specificity=0.89; 82:Sensitivity=0.84, specificity=1.0). Likelihood ratios of dementia were generated for scores between 88 and 82: at a cut-off of 82 the likelihood of dementia is 100:1. A comparison of individual age and education matched groups of MCI, AD and controls placed the MCI group performance between controls and AD and revealed MCI patients to be impaired in areas other than memory (attention/orientation, verbal fluency and language).Conclusions The ACE-R accomplishes standards of a valid dementia screening test, sensitive to early cognitivedysfunction.

ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-RProf John Hodges (Prince of Wales Hospital Randwick, NSW)Revised Version A (May 2004) - Australian Version

Orientation (time and place)*Registration (three words)*Attention and concentration (“world” backwards, serial 7s)*Memory - recall (three words)*Memory - anterograde memory (learning name and address)Memory - retrograde memory (recent and past historical figures)Verbal fluency - letter P [phonemic fluency] and animals [semantic fluency]Language - comprehension (follow written instruction and three stage command)*Language – writing (sentence)*Language – repetition (words and phrases)*Language - naming (pictures)Language - comprehension (pictures)Language - reading (words)Visuo-spatial abilities (copying figures* and clock drawing)Visuo-spatial perceptual abilities (count dots and identify letters)Memory - recall (name and address)Memory - recognition (name and address)

Overall score (max 100; below mid 80s suggests dementia)*Includes MMSE score (max 30; below mid 20s suggests dementia)

Neuropsychological Testing

Refer to Neuropsychologist

Pen and paper testing, up to 4 hours, but can be reduced to 2 hours

Can be expensive

Or

Touch-screen, computer-based neuropsychological testing

Brain Resource Company (BRC) Integneuro program

No keyboard skills required

Takes about 1.5 hours

Best for patients with MMSE score 25 and above

Some patients need assistance

Memory Clinic Program

Initial ConsultationThe initial consultation involves a medical review, a mental health assessment, and a memory and cognitive screening evaluation.

InvestigationsFurther comprehensive assessment procedures include a touch screen, computer-based diagnostic and baseline neuropsychological assessment of memory and cognitive function, laboratory blood tests, EEG/QEEG, ECG, structural & functional brain imaging tests (CT/MRI, SPECT, Doppler carotid ultrasound), and interviews with family or carer.

Second ConsultationAt a second consultation the results of all tests are reviewed with the patient (and family/carer) and a diagnosis determined. A personalized management plan is then developed.

Memory Rehabilitation ProgramA unique 12-session (24 hours total) Memory Rehabilitation Program is offered to reduce risk factors for memory loss and to enhance protective factors for preserving memory function.

Follow-upAssessment of clinical and cognitive status. At further consultations the plan is monitored and reviewed in collaboration with the GP/local doctor.

MRI brain saggital view

MRI brain trans-axial or cross-sectional view

Brain atrophy – general and hippocampus – coronal view

MRI trans-axial view – deep white matter ischemia

Providing a rationale for treatment: Providing a rationale for treatment: DementiaDementia

Effects of treatment on target Effects of treatment on target symptomssymptoms

Cognitive Enhancing Drugs - Nootropics

Acetyl cholinesterase inhibitors

Donepezil

Glamtamine

Rivastigmine

NMDA receptor agonist

Memantine

Acetylcholinsterase Inhibitors (AChEIs)Acetylcholinsterase Inhibitors (AChEIs) Evidence from studies indicate:Evidence from studies indicate:

AChEIs are effective in the treatment of mild to moderate ADAChEIs are effective in the treatment of mild to moderate AD40-50% of patients show improvement in cognitive symptoms 40-50% of patients show improvement in cognitive symptoms

and delay in progression of illnessand delay in progression of illnessImprovement in non-cognitive symptoms (apathy, Improvement in non-cognitive symptoms (apathy,

hallucinations, behaviour disturbance) are reportedhallucinations, behaviour disturbance) are reportedBenefits last between 6 months to 2 yearsBenefits last between 6 months to 2 years

eg. Donepezil 5mg nocte to start, 10mg after one montheg. Donepezil 5mg nocte to start, 10mg after one month

N-methyl-D-aspartate (NMDA)-receptor N-methyl-D-aspartate (NMDA)-receptor antagonist - Memantineantagonist - Memantine

Block glutamate toxicityBlock glutamate toxicityEffective in moderate - severe ADEffective in moderate - severe AD

Combination therapy – AChEIs plus Combination therapy – AChEIs plus MemantineMemantine

Acetylcholinsterase Inhibitors Acetylcholinsterase Inhibitors (AChEIs)(AChEIs)

Evidence from studies indicate:Evidence from studies indicate:• AChEIs are effective in the treatment of mild to AChEIs are effective in the treatment of mild to

moderate ADmoderate AD• 40-50% of patients show improvement in cognitive 40-50% of patients show improvement in cognitive

symptoms and delay in progression of illnesssymptoms and delay in progression of illness• Improvement in non-cognitive symptoms (apathy, Improvement in non-cognitive symptoms (apathy,

hallucinations, behaviour disturbance) are reportedhallucinations, behaviour disturbance) are reported• Benefits last between 6 months to 2 yearsBenefits last between 6 months to 2 years

Management of Dementia with Lewy BodiesManagement of Dementia with Lewy Bodies

Patients demonstrate neuroleptic sensitivityPatients demonstrate neuroleptic sensitivity

AChEIs have been shown to improve cognition, AChEIs have been shown to improve cognition, psychotic symptoms and neuropsychiatric psychotic symptoms and neuropsychiatric symptoms in some patients with DLBsymptoms in some patients with DLB

Evidence is accumulating for the use of AChEIs as Evidence is accumulating for the use of AChEIs as first-line pharmacological treatment of cognitive first-line pharmacological treatment of cognitive dysfunction, apathy, psychosis and agitation in dysfunction, apathy, psychosis and agitation in some patients some patients (McKeith, 2002, p. 146)(McKeith, 2002, p. 146)

Frontotemporal dementia – Frontotemporal dementia – associated featuresassociated features

Patients with FTD may present with slowness Patients with FTD may present with slowness and apathy or restlessness, overactivity, and apathy or restlessness, overactivity, distractibility and disinhibitiondistractibility and disinhibition

Neurological signs of Parkinsonism, rigidity, Neurological signs of Parkinsonism, rigidity, dyspraxia, dysarthria, tremor or ocular problems dyspraxia, dysarthria, tremor or ocular problems occur with disease progressionoccur with disease progression

Pharmacological treatments are limited; there Pharmacological treatments are limited; there have been reports of some symptomatic have been reports of some symptomatic response to SSRIs, possibly AChEIsresponse to SSRIs, possibly AChEIs

Safety Concerns

Acetyl cholinesterase inhibitors

Memantine

Atypical antipsychotics

Memory Rehabilitation ProgramLifestyle Interventions**[ ] Exercise - 30 min walking (or equivalent) per day five days a week[ ] Resistance strength exercises three times a week for 20 min[ ] Reduce weight, BMI and abdominal girth[ ] Diet – low saturated fat Mediterranean style diet (colored vegetables, monounsaturated oils, lots of fish, garlic)[ ] Reduce alcohol (max. 2 standard drinks per day), no tobacco, no drugs[ ] Social interaction[ ] Intellectual stimulation[ ] Active leisure pursuits[ ] Protect the headNutrient Supplements[ ] Mega-folate (5 mg per day)[ ] Multivitamins (antioxidants [vitamins A, D, C, E], B-group vitamins [B1, B2, B3, B6, B12], and trace elements [copper, iodine, manganese, phosphate, selenium])[ ] Omega 3 fish oil capsules (DHA long chain type)Memory and Cognition Training**[ ] Memory aids and techniques (books, guides)[ ] Computer-based and counselor-guided memory training programsStress Management**[ ] Stress reduction, increase resilience, and manage depression and anxietyCommunity Organizations[ ] Alzheimer’s Australia (Living with Memory Loss courses) Ph 1800 100 500Medical Interventions[ ] Low dose aspirin (or other blood thinner)[ ] Blood pressure control[ ] Anti-cholesterol and anti-triglyceride medications (satins)Memory enhancing medications (nootropics)[ ] Acetyl-cholinesterase inhibitor drugs[ ] Memantine[ ] OthersAccommodation and home care support[ ] ACAT assessment** Included in the Memory Rehabilitation Program