1. Diagnosis of Dementia and Use of Anti-dementia Medications
Prof Philip Morris
MB BS, BSc(med), PhD, FRANZCP, FAChAM (RACP)
Consultant Psychiatrist/Neuropsychiatrist
Medical Advisor – DBMAS NT
Medical Director
Gold Coast – Tweed Memory Clinic
36 Beryl St, Tweed Heads, NSW, Australia
Ph and
Suite 2, Level 5, 123 Nerang St, Southport, Qld, Australia Ph

2. Presentation Objectives
1. Recognize and assess significant cognitive impairment in older individuals
The 'anatomy' of memory - 'Normal' versus 'Pathological' memory changes with aging - Bedside or office testing of cognitive function
2. Understand the clinical presentation and nature of common dementia syndromes
Common 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 dementia
3. Determine which patients might benefit from anti-dementia drugs and other psychotropics
Target symptoms for medications - Alertness and attention/concentration – Memory – Motivation - Improve speech - Improve mood - Reduce anxiety - Reduce psychotic symptoms - Reduce agitation and aggression
Common nootropics and psychotropics in dementia - Acetyl cholinesterase inhibitors - Memantine (NMDA receptor antagonist) – Benzodiazepines – Antidepressants – Antipsychotics - Anticonvulsants and mood stabilizers
4. Appreciate the safety concerns using anti-dementia and psychotropic drugs in older patients
Cardiac effects - Sedation and falls - Epileptogenic effects - Increased mortality

3. Lateral Brain Motor cortex Somatosensory cortex Pars
opercularis
Sensory associative
cortex
Visual associative
cortex
Visual
cortex
Broca’s
area
Primary
Auditory cortex
Wernicke’s
area

4. Limbic Brain

5. Spatial relations
Numbers
Word understanding
Word production
Vision
Problem solving
Planning
Behavioural control
Emotion
Attention and arousal
Memory Emotion
(Limbic system - not visible)

7. Subjective memory complaints
Disorientation
forget time, place, trace of time
Disorganization
forget appointments, instructions
Omission
leave things behind, losing things, forgetting lights
Repetition
asking same question, telling same story
All can occur in healthy people!
Testing memory – list of words and cues – verbal recall

8. Assessment Memory problems Cortical regions involved
Assessment Memory problems Cortical regions involved Frontal (judgment, reasoning, finances, attention, planning, motivation, impulsivity) Temporal (memory, word finding, remembering names, irritability, misinterpretations) Parietal (disorientation, spatial misjudgment, left- right confusion, dressing apraxias)

9. 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)

10. Neuroanatomy of Memory Episodic memory – limbic system and hippocampus Semantic memory – widely distributed in cortex Implicit memory – basal ganglia, cerebellum, spinal cord
Disorders of Memory
Disorders of working memory - problems with attention and ‘central executive function’ - the ‘scratchpad’ or RAM
Disorders of episodic memory - inability to retain new information/material (amnesia) - hippocampus based
Disorders of semantic memory (knowledge) - more difficult to erode, less affected by disease
Disorders of ‘metamemory’ - inability to judge own memory function - insight

11. 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 years
MCI 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

12. 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 diagnostic
criteria 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 multiple
non-memory domains.
• Individuals with MCI affecting multiple domains may be more severely
cognitively impaired and represent a more advanced prodromal stage.

13. Dementia ‘epidemic’ explodes. Main types of dementia
Dementia ‘epidemic’ explodes Main 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)

14. Dementia Conditions Most Common Dementias
Less than 1% of the under age 65 population compared with 20% of over 80s individuals
Most Common Dementias
Alzheimer’s disease
Vascular dementia
Dementia with Lewy bodies
Frontotemporal dementia
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)

15. 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

16. Differentiating Alzheimer’s disease and vascular dementia
The most important differential diagnosis is between AD and VD, although in some cases AD and VD will overlap. Some key differences between the two diseases are listed on the slide.

17. Frontotemporal dementia
Previously known as Pick’s disease
Second 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 memory
Pathology 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 dementia
Behavioural variant
Personality 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 aphasia
Slow 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 movements
Both types of aphasia can progress to behavioural disturbance

18. Parkinsonian disorders associated with dementia
Parkinson’s disease
Pathology of Lewy bodies (clumps of alpha-synuclein protien) in substantia nigra region of brain stem
20% 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 tangles
A ‘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 affected
Sensitive to antipsychotic medication, may respond to ACEIs
Progressive supranuclear palsy
Rigid Parkinson’s disease, gaze palsy, swallowing problems and frontal dementia
Corticobasal degeneration (CBD)
Rigidity, bradykinesia, apraxia (‘alien limb’ syndrome), and behavioural variant of frontotemporal dementia

19. Less Common Early Onset Dementias
Motor Neurone Disease with dementia
Huntington’s disease
Alcohol related dementia and Korsakoff’s syndrome
Multiple sclerosis
HIV-related dementia

20. Rare Causes of Younger Onset Dementia
Creutzfeldt-Jacob disease (CJD)
Dementia after head injury
Dementia in Down syndrome
Homocystinuria
Vasculitis
Wilson’s disease
Porphyria
Adrenoleukodystrophy
Lipid storage diseases
Mitochondrial disorders
Dentatorubralpallidoluysian atrophy (DRPLA)
Neuroacanthocytosis

21. 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

22. The Clinical Problem
Age Related Changes or Subjective Cognitive Complaints (SCC) Vs
Mild Cognitive Impairment (MCI) or Cognitive Impairment Not Dementia (CIND)
Early Dementia?

23. Beyond the Mini Mental State Exam
Beyond the Mini Mental State Exam? The Addenbrooke’s Cognitive Examination

24. Int J Geriatr Psychiatry 2006; 21: 1078–1085.
The Addenbrooke’s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening
Eneida Mioshi1,2, Kate Dawson2, Joanna Mitchell2, Robert Arnold1 and John R. Hodges1,2*
1MRC Cognition and Brain Sciences Unit, Cambridge, UK
2University of Cambridge Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, UK
SUMMARY
There 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 Scale
was 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 cognitive
dysfunction.

25. ADDENBROOKE'S COGNITIVE EXAMINATION - ACE-R
Prof 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)

32. 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

34. Memory Clinic Program
Initial Consultation
The initial consultation involves a medical review, a mental health assessment, and a memory and cognitive screening evaluation.
Investigations
Further 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 Consultation
At 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 Program
A 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-up
Assessment of clinical and cognitive status. At further consultations the plan is monitored and reviewed in collaboration with the GP/local doctor.

35. MRI brain saggital view

36. MRI brain trans-axial or cross-sectional view

37. Brain atrophy – general and hippocampus – coronal view

38. MRI trans-axial view – deep white matter ischemia

41. Providing a rationale for treatment: Dementia
The diagram on the slide, or a similar diagram, could be used as a tool when providing a treatment rationale for dementia.

42. Effects of treatment on target symptoms
Antidepressant agents are helpful in managing depressive symptoms in patients with dementia. Antipsychotic agents are useful in managing psychotic symptoms and associated behavioural disturbance. Atypical antipsychotic agents are preferred due to reduced risk of adverse side effects. Care should be taken to exclude patients with DLB.

43. Cognitive Enhancing Drugs - Nootropics
Acetyl cholinesterase inhibitors
Donepezil
Glamtamine
Rivastigmine
NMDA receptor agonist
Memantine

44. Acetylcholinsterase Inhibitors (AChEIs)
Evidence from studies indicate:
AChEIs are effective in the treatment of mild to moderate AD
40-50% of patients show improvement in cognitive symptoms and delay in progression of illness
Improvement in non-cognitive symptoms (apathy, hallucinations, behaviour disturbance) are reported
Benefits last between 6 months to 2 years
eg. Donepezil 5mg nocte to start, 10mg after one month
N-methyl-D-aspartate (NMDA)-receptor antagonist - Memantine
Block glutamate toxicity
Effective in moderate - severe AD
Combination therapy – AChEIs plus Memantine

45. Acetylcholinsterase Inhibitors (AChEIs)
Evidence from studies indicate:
AChEIs are effective in the treatment of mild to moderate AD
40-50% of patients show improvement in cognitive symptoms and delay in progression of illness
Improvement in non-cognitive symptoms (apathy, hallucinations, behaviour disturbance) are reported
Benefits last between 6 months to 2 years

46. Management of Dementia with Lewy Bodies
Patients demonstrate neuroleptic sensitivity
AChEIs have been shown to improve cognition, psychotic symptoms and neuropsychiatric symptoms in some patients with DLB
Evidence is accumulating for the use of AChEIs as first-line pharmacological treatment of cognitive dysfunction, apathy, psychosis and agitation in some patients (McKeith, 2002, p. 146)
If DLB is suspected, patients should be referred for specialist assessment.
Patients demonstrate neuroleptic sensitivity, so specialist advice should be sought before prescribing antipsychotic agents to patients who present with features of dementia, depression and fluctuating cognition.
AChEIs have been shown to improve cognition, psychotic symptoms and neuropsychiatric symptoms in some patients with DLB.
Evidence is also accumulating for the use of AChEIs as first-line pharmacological treatment of cognitive dysfunction, apathy, psychosis and agitation in some patients. (McKeith, 2002, p. 146)

47. Frontotemporal dementia – associated features
Patients with FTD may present with slowness and apathy or restlessness, overactivity, distractibility and disinhibition
Neurological signs of Parkinsonism, rigidity, dyspraxia, dysarthria, tremor or ocular problems occur with disease progression
Pharmacological treatments are limited; there have been reports of some symptomatic response to SSRIs, possibly AChEIs
Patients with FTD may present with slowness and apathy or restlessness, overactivity, distractibility and disinhibition. Neurological signs of Parkinsonism, rigidity, dyspraxia, dysarthria, tremor or ocular problems occur with disease progression. Pharmacological treatments are limited; although there have been reports of some symptomatic response to SSRIs.

48. Acetyl cholinesterase inhibitors Memantine Atypical antipsychotics
Safety Concerns
Acetyl cholinesterase inhibitors
Memantine
Atypical antipsychotics

49. Memory Rehabilitation Program
Lifestyle 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 head
Nutrient 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 programs
Stress Management**
[ ] Stress reduction, increase resilience, and manage depression and anxiety
Community Organizations
[ ] Alzheimer’s Australia (Living with Memory Loss courses) Ph
Medical 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
[ ] Others
Accommodation and home care support
[ ] ACAT assessment
** Included in the Memory Rehabilitation Program