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Investigating dementia

Investigating dementia. Dr Richard Perry Consultant Neurologist Imperial College Healthcare NHS Trust. Overview. Structural imaging – CT and MRI MRI and vascular disease MRI and focal atrophy MRI and microhaemorrhages CSF Biomarkers -Tau and abeta EEG Functional imaging - 18 F FDG PET

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Investigating dementia

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  1. Investigating dementia Dr Richard Perry Consultant Neurologist Imperial College Healthcare NHS Trust

  2. Overview • Structural imaging – CT and MRI • MRI and vascular disease • MRI and focal atrophy • MRI and microhaemorrhages • CSF • Biomarkers -Tau and abeta • EEG • Functional imaging - 18 F FDG PET • Illustrative cases • Amyloid imaging

  3. Structural brain imaging in cognitive impairment • MRI modality of choice • 1.5 T or 3T • CT useful for acute presentations: • Hydrocephalus – acute • Haemorrhage • Mass lesions • If MRI unavailable, CT can give information on • Atrophy • Vascular load

  4. Role of imaging in dementia diagnosis NICE guidance: Structural imaging should be used in the assessment of people with suspected dementia to exclude other cerebral pathologies and to help establish the subtype diagnosis. Magnetic resonance imaging (MRI) is the preferred modality to assist with early diagnosis and detect subcortical vascular changes, although computed tomography (CT) scanning could be used.

  5. MRI and cerebrovascular disease Lacune Leukoaraiosis Small Vessel Disease Large Vessel

  6. White matter hyperintensities Leukoaraiosis T2 hyperintensities Most consistent association is with hypertension Visual rating – Scheltens scale, Fazekas scale

  7. Cheese is yellow, the moon is yellow…. Frisoni et al 2007 Jack et al 2011 Cognitive impairment + WMH on imaging report ≠ vascular dementia WMH responsible for minimal cognitive impairment Often focal atrophy overlooked by radiologists Usually co-existent degenerative disease that is responsible for the cognitive impairment First symptoms and course of disease important e.g. early episodic memory impairment with progressive cognitive impairment and lack of neurological signs Look for gait disorder

  8. MRI and focal atrophy More relevant to new diagnostic criteria for AD and MCI Hippocampal atrophy – biomarker of neuronal degeneration in MCI secondary to AD diagnosis ≈73% sensitivity and ≈81% specificity for predicting whether patients with amnestic MCI will convert to dementia Dependent on skill of radiologist Visual rating scales Quantitative analysis available

  9. MRI and focal atrophy MRI also part of diagnostic criteria for other forms of dementia Temporal variant of Frontotemporal Dementia = Semantic Dementia Behavioural Variant of FTD Always interpret in light of clinical context

  10. MRI and focal atrophy Diagnosis – Posterior Cortical Atrophy 62 yr old man Difficulty in proof reading Difficulty in telling time from clock Digital clock OK Couldn’t see things right in front of him

  11. MRI – specific sequences T2* - Gradient Echo or SWI – susceptibility weighted imaging Good for detecting effects of iron deposition - haemosiderin In effect, is detecting microhaemorrhages Subcortical and basal ganglia microhaemorrhages related to HT Lobar microhaemorrhages related to amyloid angiopathy

  12. EEG • NICE guidelines suggest not a routine investigation • CJD • triphasic waves on EEG • MRI / CSF / Bx • Psychiatric disease or neurological disease? • If abnormal, then either brain disease or drugs • Loss of alpha waves • Asymmetry in accordance with clinical findings • If normal with significant cognitive disturbance then consider psychiatric cause

  13. CSF • LP quick and minimally invasive (?) • Requires bed and operator • Exclude infection and inflammation • Now biomarkers for neurodegenerative disease available • A beta 1-42 • Total tau • Phospho tau • Low abeta levels indicate amyloidopathy • Raised tau levels indicate ongoing neuronal damage • Sensitive and specific tests - require counselling prior to test • Processing of samples important as reliability of assay sub-optimal

  14. AD or FTD, MRI or PET • MRI may be sufficient • tvFTD highly specific MRI appearances • bvFTD MRI may be normal early in course

  15. AD or FTD, MRI or PET • 18F FDG PET adds value with normal MRI or lateralising clincial presentation

  16. Investigations and cascade of events in neurodegenerative disease (AD)

  17. Case 1 - GW 3 yr Hx disorganisation Word finding difficulty Cant follow instructions Not repetitive Multiple episodes of depression over last 10 yrs Performance IQ down to 81 CSF analysis: A-beta 589, Tau 449 Diagnosis – Frontotemporal Lobar Degeneration

  18. Case 2 - SN 2 yr Hx of decreasing verbal output Apathy and passivity EEG showed L frontal slow wave activity Diagnosis – Frontotemporal Dementia

  19. Case 3 - BS • 49 yr old with progressive language impairment 2 yrs • Non-fluent aphasia • Mild apraxia CSF tau level = 1004 CSF abeta level = 379 Genetic testing showed PS-1 mutation Diagnosis – Familial Alzheimer’s Disease

  20. Case 4 - AK • EEG – loss of alpha rhythm and triphasic slow waves • 55 yr old woman • 2 yrHx of loss of confidence, anxiety • Good days and bad days • Unable to perform simple tasks in the workplace • Inconsistencies in neuropsych performance, v tearful • Put down to anxiety disorder • CSF • Tau 955 (high) • Abeta 176 (low) Diagnosis - AD

  21. Amyloid PET imaging • 11C amyloid PET scans used in research – have to scan near cyclotron • 18F compounds now available • 20-30% of asymptomatic 75-80 yr olds have positive scan • Increased risk of conversion from normal to MCI in amyloid positive healthy older controls 8% per year • 86% of aMCI patients with positive amyloid PET develop clinical AD over 3 years

  22. Amyvid • Detection of amyloid plaques • Half hour PET scan • Result positive or negative • Guidelines likely to suggest use by dementia experts in cases of possible AD where previous Ix inconclusive and where diagnostic clarity changes management • Only licensed in patients with cognitive impairment • Negative scan – highly unlikely that cognitive impairment due to AD pathology • Pivotal pathological study, Clarke et al Lancet Neurol 2012 • 59 end of life patients, sensitivity 92% and specificity 96%

  23. Amyloid imaging ligands • Florbetapir – Amyvid • Flutemetamol – Vizamyl • Florbetaben - Neuraceq

  24. Case 5 - RD • 58 yr old district nurse • 18/12 Hx of memory problems and organisational difficulties at work • Local memory clinic MMSE 30/30, ACE-R 97/100 • MRI normal • SPECT reported as showing medial temporal hypoperfusion • Given diagnosis of AD and started on donepezil

  25. Case 5 - RD • Referred for second opinion • Husband felt that memory OK • Daughter reported her as repetitive and more noticeable symptoms over last year • FDG – PET again reported as medial temporal hypometabolism • CSF analysis – tau 108 and abeta 874 • ACE -96, MMSE 28 – one point on orientation and one on memory

  26. Case 6 -VW • 63 yr old woman – Editor for Mensa magazine • 18/12 Hx of memory problems and oranisational difficulties • Collects things, less empathic • Likes eating biscuits • Non-fluent aphasia • Stimulus bound behaviour

  27. Case 6 - VW

  28. Case 7 - LC • Progressive memory deficits corroborated by husband • Previous Hx of ME, anxiety, and depression • MMSE 26/30 • Neuropsych showed memory deficits and attentional dysfunction consistent with MCI • MRI unremarkable

  29. Case 8 - DT • Walking memory speech • Emotional change after loosing son in RTA 8 yrs previously • Decreased motivation • Muddled • Not really forgetful • MMSE17/20 2014, and 22/30 2011 • Neuropsych showed reduced encoding but normal delayed recall, poor attentional and executive dysfunction – felt to be not consistent with AD but suggestive of frontal-subcortical dementia • Diagnosed VaD and depression

  30. Case 8 DT

  31. Case 9 - AH • Retired policeman, 66 yrs ol • 1 year Hx of memory deficits, repetitive • Scored 29/30 on MMSE • Neuropsych found patchy deficits on memory, - recommended therapy for symptoms of anxiety / depresion • MRI brain

  32. Case 9 - AH • CSF examination • Abeta 1422 • Total tau 490 • Evidence of neuronal loss – progressive • Not Alzheimer’s Disease • Some mild behavioural features • ? Atypical presentation of Frontotemporal Dementia

  33. Which patients are suitable for amyloid imaging? • It’s a new area, so we are still calibrating • Currently, we are focusing on: • Younger patients – less probability of ‘false positive’ • Atypical AD presentations – e.g. PCA, Progressive Aphasia • AD / FTD differentiation • MCI if clarification helpful • Multiple possible causes of cognitive impairment e.g depression / vascular

  34. Conclusions • Investigations support clinical diagnosis • Investigations can be thought of as biomarkers that are: • Supportive of neurodegeneration and / or • Pathology or disease specific • Familiarity with Ix important and important to review actual pictures • Amyloid imaging e.g. Amyvidnow available for use within guidelines

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