Assessment at the bedside or in the clinic using the history, examination and laboratory tests to distinguish between different types of dementia

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1 Assessment at the bedside or in the clinic using the history, examination and laboratory tests to distinguish between different types of dementia AP Passmore

2 Content Common dementia syndromes (older people) Clinical features Assessments Proposed diagnostic criteria for AD Use of CSF Case histories

3 Few points At bedside delirium? better to delay clinical assessment for dementia ensure assessment by or follow up at memory service Can assess clinically, check bloods and perform neuroimaging Later presentation very difficult (primary diagnosis) Age factor

4 Common causes of dementia Alzheimer s Disease (AD) Vascular dementia AD + CVD Lewy body dementia Parkinson s disease dementia Fronto-temporal lobar degeneration *

5 Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Longitudinal follow up, first 141 autopsies 50 with dementia AD + Infarcts AD VaD 12 AD + PD/DLB Other 30 80% have AD pathology Schneider, Neurology 2007; 61:

6 Clinical criteria exist for all main dementia subtypes All criteria require a diagnosis of dementia and include the caveats that there should not be a symptom pattern more in keeping with another of the dementias and that cognitive impairments should not be better explained by a psychiatric illness. Neuropsychiatric symptoms should be sought Often features such as hallucinations and delusions will not be volunteered unless specific enquiries are made.

7 Diagnostic Criteria for AD Probable AD: A plus one or more supportive features B, C, D, or E Core diagnostic criteria A. Presence of an early and significant episodic memory impairment that includes the following features: 1. Gradual and progressive change in memory function reported by patients or informants over more than 6 months 2. Objective evidence of significantly impaired episodic memory on testing: this generally consists of recall deficit that does not improve significantly or does not normalise with cueing or recognition testing and after effective encoding of information has been previously controlled 3. The episodic memory impairment can be isolated or associated with other cognitive changes at the onset of AD or as AD advances Dubois et al. Lancet Neurol 2007;6:734 46

8 The diagnosis of dementia due to Alzheimer s disease: Recommendations from the NIA - Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease The diagnosis of probable AD dementia should not be applied when there is evidence of substantial concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter hyperintensity burden McKhann et al. Alzheimer s & Dementia 2011;7:

9 NINDS AIREN Criteria for Vascular Dementia Dementia Cerebrovascular disease: Focal CNS signs Evidence of CVD by brain imaging A relationship between the two manifested by one or more of the following: Dementia onset within 3 months of stroke Abrupt deterioration in cognition or fluctuating stepwise course Neurology 1994;43:250-60

10 Classification and Causes of Sporadic Vascular Cognitive Impairment Post-stroke dementia Vascular dementia multi-infarct dementia (cortical vascular dementia) subcortical ischaemic vascular dementia strategic infarct dementia hypoperfusion dementia haemorrhagic dementia dementia caused by specific arteriopathies Mixed AD and vascular dementia Vascular mild cognitive impairment O Brien et al., Lancet Neurology 2003;2:89-98

11 Hachinski Ischaemic Score Item Score value Correlates of VaD (OR) Abrupt onset 2 Stepwise deterioration Fluctuating course Nocturnal confusion 1 Relative preservation of personality 1 Depression 1 Somatic complaints 1 Emotional incontinence 1 History of hypertension History of strokes Evidence of associated atherosclerosis 1 Focal neurological symptoms Focal neurological signs 2

13 Diagnostic Criteria for Dementia with Lewy Bodies Central: Dementia Core clinical features: fluctuating attention, recurrent visual hallucinations, Parkinsonism Suggestive features: REM sleep behaviour disorder, severe neuroleptic sensitivity, low dopamine transporter uptake in the basal ganglia on functional neuroimaging Additional supportive features: repeated falls and syncope, transient unexplained loss of consciousness, severe autonomic dysfunction, hallucinations in other modalities, systematized delusions, depression, relative preservation of medial temporal lobe structures on structural neuroimaging, reduced occipital activity on functional neuroimaging, prominent slow wave activity on electroencephalogram, and low uptake myocardial scintigraphy McKeith et al. Neurology ;65:

14 CVD + AD

15 Can past history help?

Overlap between AD and VaD AD Female Genetics VaD Male Genetics

Cholinergic deficits Hypercholesterolemia Age Definite AD AF AF

VaD Homocysteine Diabetes Amyloid Plaques Neurofibrillary Tangles

16 Overlap between AD and VaD AD Female Genetics VaD Male Genetics Stroke/TIA Hypertension Hypertension Hypercholesterolemia Cholinergic deficits Hypercholesterolemia Age Definite AD AF AF Definite VaD Age Probable AD Possible AD Mixed Possible VaD Probable VaD Homocysteine Diabetes Amyloid Plaques Neurofibrillary Tangles Diabetes Homocysteine Kalaria RN, Ballard C. Alzheimer Dis Assoc Disord. 1999;13:S

17 Diagnosis The common mistake is to label what is AD w/ CVD as VaD

18 Parkinson s disease dementia Early symptoms Sensitivity to dopaminergic treatment Hallucinations

19 Proforma essential History patient and informant Cognitive checklist Neuropsychiatric symptoms Depression Activities of daily living (Bristol ADL) PMH Family history Medication (cholinergic burden) Head injury

20 Cognitive assessment Proforma MMSE (orientation, registration and recall, attention, language, visual construction) ACE III (attention, memory, verbal fluency, language, visuospatial) General examination important CVS CNS

21 Investigations Full blood picture ESR/CRP Clinical chemistry profile (U&E, calcium, glucose) Thyroid function B 12 and folate Neuroimaging (next talk)

22 Diagnostic Criteria for AD Supportive features B. Presence of medial temporal lobe atrophy Volume loss of hippocampi, entorhinal cortex, amygdala evidenced on MRI with qualitative ratings using visual scoring (referenced to well characterised population with age norms) or quantitative volumetry of regions of interest (referenced to well characterised population with age norms) C. Abnormal cerebrospinal fluid biomarker Low amyloid β1 42 concentrations, increased total tau concentrations, or increased phospho-tau concentrations, or combinations of the three Other well validated markers to be discovered in the future Dubois et al. Lancet Neurol 2007;6:734 46

23 Diagnostic Criteria for AD Supportive Features D. Specific pattern on functional neuroimaging with PET Reduced glucose metabolism in bilateral temporal parietal regions Other well validated ligands, including those that foreseeably will emerge such as Pittsburg compound B or FDDNP E. Proven AD autosomal dominant mutation within the immediate family Dubois et al. Lancet Neurol 2007;6:734 46

24 CSF Studies

25 AD Diagnosis Low CSF Aβ42 and high t-tau or p-tau proteins have shown high accuracy for AD diagnosis (Galasko et al 1998; Andreasen et al 2001; Schoonenboom et al 2004) Studies that compared AD patients with normal control subjects have demonstrated that low Aβ42 had % sensitivity and 47 81% specificity for AD diagnosis High CSF t-tau levels had 70% sensitivity and 92% specificity and p-tau showed 77% sensitivity and 87% specificity However, p-tau appears to be better than t-tau in the diagnosis of AD, and it has shown a positive predictive value of 90%, especially p-tau phosphorylated at threonine 181 (ptau181; Hampel et al 2004a; Mitchell 2009).

26 Differential Diagnosis

27 Differential Diagnosis

28 Assessment of CSF Aβ42 as an aid to discriminating AD from other dementias and mild cognitive impairment: meta-analysis of 50 studies. CSF Aβ42 concentrations were significantly lower in AD compared to: MCI (SMD: -0.68, 95% CI: [-0.80, -0.56], P<0.001) FTD (SMD: -1.09, 95% CI: [-1.41, -0.76], P<0.001) PDD (SMD: -0.75, 95% CI: [-1.39, -0.10], P=0.023) VaD (SMD: -0.95, 95% CI: [-1.30, -0.61], P<0.001) Compared to DLB, Aβ42 concentrations are moderately lower in AD (SMD: -0.27, 95% CI: -0.51, -0.03, P=0.028) Results from this meta-analysis hinted that CSF Aβ42 is a good biomarker for discriminating Alzheimer's disease from other dementias and MCI. Tang et al. J Neurol Sci. 2014;345(1-2):26-36

29 Lumbar puncture is a routine procedure, but may not be readily acceptable to all patients. Despite being associated with side effects such as headache, it is generally well tolerated. CSF studies perhaps afford the most promising use of biomarkers for prediction, diagnosis and disease progression CSF studies probably do not add significantly to diagnostic certainty when the patient meets current clinical criteria for probable AD CSF studies may provide confirmation whether the underlying cause of MCI is likely due to AD

30 Case 1 73 year old man with 2 year history of short term memory problems. Gradual onset and more noticeable to self and family Needs persuaded to go out and play bowls. Memory loss causes some frustration/agitation, no other behavioural issues Reluctant to make telephone calls, some difficulty with finances and simple household maintenance tasks. Driving is fine, can manage his medication PMH: hypertension and ischaemic heart disease. No head injury Medication: aspirin 75mg, amlodipine 5mg, perindopril 5mg No family history of cognitive problems Cognition: ACE III 73/100. deficits in memory, attention and visuospatial testing Physical examination nothing of note Bloods normal

31 Diagnosis? 1. Mild cognitive impairment 2. Depression 3. Alzheimer s disease dementia 4. Vascular dementia 5. Alzheimer s disease + cerebrovascular disease dementia 6. Lewy body dementia

32 Case 2 76 year old lady. 18 month history of problems with short term memory. Noticeable to herself and family. Family notice a difficulty with organisational ability. Symptoms can vary. Mood can be a bit down at times but denies depression. No other cognitive or behavioural symptoms. Difficulties with finances and use of TV controls. PMH: hypertension, diabetes mellitus, ischaemic heart disease, CKD Medications: metformin 1g bd, clopidogrel 75mg, bisoprolol 5mg, perindopril 5mg No family history of cognitive problems Cognition: ACE III 76/100. Deficits in attention mostly and in language Physical examination: gait a little unsteady, symmetrical brisk reflexes Bloods: haemoglobin 110, egfr 45, BS 8.6,

33 Diagnosis? 1. Mild cognitive impairment 2. Depression 3. Alzheimer s disease dementia 4. Vascular dementia 5. Alzheimer s disease + CVD 6. Lewy body dementia

34 Case 3 78 year old man with complaints of short term memory loss for 8 months. Some restless legs, symptoms can vary. No apathy Some difficulty with managing medicines. Not keen on driving. Needs some help with finances Some frustration with memory problems. Daughter mentions he sets an extra place for dinner as he has seen his wife (she died 16 months before) in the house at times. Mood variable PMH: has fallen 3 or 4 times over past 6 months, no syncope. Hypertension, peripheral vascular disease No family history of cognitive problems Medication: amlodipine 5mg, clopidogrel 75mg, quinine sulphate 300mg, zopiclone 7.5mg Cognition: ACE III 75/100. Deficits in attention and memory mostly and a little in language Physical examination: a little slow to respond to questions, gait a little unsteady, no postural BP drop Bloods: normal

35 Diagnosis? 1. Mild cognitive impairment 2. Depression 3. Alzheimer s disease dementia 4. Vascular dementia 5. Alzheimer s disease + CVD 6. Lewy body dementia

36 Thank you for your attention

38 Global Function Cognitive Function Caregiver Burden Activities of Daily Living Behavioural Disturbances

39 Suggested Diagnostic Work-up for Dementia Diagnostic interview both patient and a reliable informant Office-based clinical assessment comprehensive physical examination brief neurologic and mental status evaluation brief quantified cognitive function evaluation (MMSE) Office-based clinical assessment (cont d) laboratory evaluation (CBC, chemistries, thyroid, vitamin B 12 ) optional imaging studies (CT head scan, MRI) Neuropsychological testing if diagnosis is unclear AAGP, AA, AGS consensus statement, 1997

41 Ideal Biomarker for AD Should detect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases Should have a diagnostic sensitivity of more than 80% for detecting AD and a specificity of more than 80% for distinguishing other dementias Should be reliable, reproducible, noninvasive, simple to perform, and inexpensive It would be especially useful if the biomarker could capture the beneficial effect of disease-modifying therapy predict conversion from MCI to AD correspond closely to available clinical detection methods and thus provide an opportunity for early intervention or prevention. Neurobiol Aging. 1998; 19:

42 AD diagnosis and progression Aβ42/tau ratio is used to improve the diagnosis of AD Meta-analysis showed that Aβ42/tau ratio had a sensitivity of 71% and specificity of 83% for AD (Hampel et al 2004) A recent study showed that the signature of AD, based on the CSF Aβ42/p-tau181 ratio cut offs, was present in 90% of the AD patients compared to 36% in the normal control group (De Meyer et al 2010) Although these CSF biomarkers seem to be useful to diagnose AD, they are not sensitive enough to assess disease progression

43 The diagnosis of dementia due to Alzheimer s disease: Recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia McKhann et al. Alzheimer s & Dementia 2011;7:

44 World Alzheimer Report 2011

45 Neuropsychiatric Inventory (Cummings et al., Neurology 1994;44: ) Behavioural Apathy Aberrant motor behaviour Appetite disturbance Irritability Agitation / aggression Sleep disturbance Psychological Depression Anxiety Delusions Disinhibition Hallucinations Elation

46 History Cognitive impairments central to the diagnosis of dementia can be categorised into five main domains: memory; executive function; language; visuospatial abilities; personality and behaviour As dementia, of any cause progresses, cognitive impairments broaden, involving more domains, and deepen, causing increased functional impairment It can thus be difficult to distinguish dementias of different aetiologies in the later stages In the early stages however the pattern of prominent symptoms can help identify the most likely underlying disease process

47 CSF Little doubt that CSF AB and tau are markers of AD No cut offs defined Global studies to standardize assays

48 Cochrane Database Syst Rev Jun 10;(6):CD doi: / CD pub4. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Ritchie C1, Smailagic N, Noel-Storr AH, Takwoingi Y, Flicker L, Mason SE, McShane R. The proposed diagnostic criteria for prodromal dementia and MCI due to Alzheimer's disease, although still being debated, would be fulfilled where there is both core clinical and cognitive criteria and a single biomarker abnormality. From our review, the measure of abnormally low CSF Aß levels has very little diagnostic benefit with likelihood ratios suggesting only marginal clinical utility. The quality of reports was also poor, and thresholds and length of follow-up were inconsistent. We conclude that when applied to a population of patients with MCI, CSF Aß levels cannot be recommended as an accurate test for Alzheimer's disease

Introduction, use of imaging and current guidelines. John O Brien Professor of Old Age Psychiatry University of Cambridge

Introduction, use of imaging and current guidelines John O Brien Professor of Old Age Psychiatry University of Cambridge Why do we undertake brain imaging in AD and other dementias? Exclude other causes