1. Imaging in dementia / cognitive impairment
Dr Richard Perry
Consultant Neurologist
Imperial College Healthcare NHS Trust
UK AMY00125 February 2015

2. Overview Diagnosing dementia versus diagnosing cause of dementia
AD, FTD, MCI, prodromal and pre-clinical AD
Two phase approach
Is there a brain disease?
What is the cause of the brain disease
Diagnosis of Alzheimer’s Disease
How accurate is current diagnosis
What are the challenges?
MRI, FDG PET, Neuropsych, CSF, amyloid imaging
Frontotemporal Dementia

3. Diagnosing dementia vs diagnosing Alzheimer’s Disease
It is relatively straightforward to diagnose dementia in an elderly patients with typical symptoms and a moderate stage of dementia
Alzheimer’s Disease – less straightforward if:
Earlier in course of condition
Atypical presentation
Young Onset
Multiple pathologies

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. Beyond diagnosing dementia
The key questions that clinicians have to address are:
Does this patient have dementia?
If yes, is it a typical sub-type presentation?
If no, does the patient have objective evidence of impaired cognition?
If yes to this, does this patient have symptoms that are secondary to a brain disease?
If yes, what is the brain disease?
If no, is there a definite cause of the symptoms?

6. Pathology of Alzheimer’s Disease
β Amyloid – plaques, extracellular
Tau – abnormally hyperphosphorylated tau → neurofibrillary tangles
Plus neuronal and synaptic loss

7. When does Alzheimer’s Disease start?7

8. When does Alzheimer’s Disease start?
Fibrillar amyloid deposition as measured by PET imaging in carriers of autosomal dominant AD mutations

9. Alzheimer’s disease - diagnosis National Institute of Neurologic and Communicative Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association
Definite AD – clinical diagnosis with histopathological confirmation
Probable AD – typical clinical picture without histological confirmation
Sensitivity and specificity ca 80%
Usually made with help of blood tests, neuroimaging and neuropsychological assessment

10. Alzheimer’s disease without dementia? Mild Cognitive Impairment (MCI)
Cognitive decline greater that that expected for age and education level but does not interfere with ADLs
Can be seen as an entity with high risk for conversion to dementia 10

11. MCI not due to Alzheimer’s Disease
Depression and anxiety
Drugs
E.g beta blockers, anticholinergics - tricyclics, antiemetics, antispasmodics, antiarrythmics, analgesics
Cerebrovascular disease
Risk factors
Cognitive slowing, slowing of gait (wide-based)
Other neurodegenerative diseases
Dementia with Lewy Bodies, Frontotemporal Dementia
Ageing? Argyrophyllic grain disease?

12. Alzheimer’s Disease Typical and atypical presentations
40 % of EOAD may be non-amnestic
10% LOAD non-amnestic
Posterior Cortical Atrophy
Progressive aphasia
Logopenic aphasia
Progressive non-fluent aphasia
Dysexecutive / frontal AD

13. Investigations in Alzheimer’s Disease diagnosis
Neuropsychology
Structural brain imaging
FDG PET imaging
CSF

14. Diagnostics: Neuropsychology
Advantages
Low cost of technology
Portable
Disadvantages
Time consuming
Variance in population
Affected by culture and education
Lacks specificity and sensitivity e.g. depression or prodromal AD

15. Diagnostics - CSF Advantages Disadvantages
Pathology specific for tau and abeta
Sensitive
Disadvantages
Invasive
Dependent on processing and assay stability

16. How does imaging answer our clinical questions?
Markers of neuronal loss
MRI
Hippocampal atrophy
Focal atrophy
White matter hyperintensities - ? Vascular disease
FDG – PET
Pathology sensitive imaging
Amyloid PET imaging

17. Diagnostics – structural imaging
Advantages
Marker of neuronal loss
Patterns of atrophy
Exclude other pathologies e.g NPH, vascular changes
Not confined by educational / cultural factors
Quick, safe
Disadvantages
Not pathology specific
Insensitive in earliest disease
Dependent on experience of radiologist

18. White matter hyperintensities and cognitive impairment Cheese is yellow, the moon is yellow….
Cognitive impairment + WMH on imaging report ≠ vascular dementia
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

19. MRI and hippocampal atrophy
Definitely abnormal and reported as such is helpful
Definitely abnormal and reported as normal is not helpful
Possibly abnormal and reported as possibly abnormal is not very helpful
Normal hippocampi does not exclude AD

20. MRI and focal atrophy
Hippocampal atrophy – biomarker of neuronal degeneration in MCI secondary to AD diagnosis
Dependent on skill of radiologist
Visual rating scales
Quantitative analysis available
bvFTD
Semantic dementia
Posterior Cortical Atrophy

21. Investigations and cascade of events in neurodegenerative disease (AD) Towards pathology sensitive investigations

22. Developing PET ligands for amyloid - pathology sensitive investigation
PIB Klunk et al 2004
Pittsburgh Compound B, collaboration with Uppsala
High affinity for fibrillar amyloid
Short half life – need to be near a cyclotron and radiochemistry lab
!8 Fluro compounds developed
Nordberg, A. et al. (2010) The use of PET in Alzheimer disease
Nat. Rev. Neurol. doi: /nrneurol

23. Florbetapir - Amyvid
Originally developed as AV-45 by Avid radiopharmaceuticals
Detection of amyloid plaques
Half life 110 minutes
Uptake 30 minutes
10 minute PET scan
Result positive or negative
Grey scale
Pivotal pathological study, Clarke et al Lancet Neurol 2012
59 end of life patients, sensitivity 92% and specificity 100 %

24. Florbetapir - Amyvid
FDA approved Licensed in patients with cognitive impairment who are being evaluated for Alzheimers disease (AD) and other causes of cognitive impairment
UK guidelines recommend use by dementia experts in cases of possible AD where previous Ix inconclusive and where diagnostic clarity changes management
A scan for amyloid plaques, not a scan for Alzheimer’s Disease
Negative scan – highly unlikely that cognitive impairment due to AD pathology

25. Our approach to amyloid PET imaging
Through a Multidisciplinary Team
Neuroradiologists and nuclear medicine physicians with neurologists, psychiatrists, geriatricians
Discuss the case of each request and review MRI imaging
Review PET imaging post scan

26. Case 1 - 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

27. Case 1 - RD Referred for second opinion Husband felt that memory OK
Daughter reported her as repetitive and more noticeable symptoms over last year
ACE -96, MMSE 28 – one point on orientation and one on memory

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

29. Case 3 - BS CSF tau level = 1004 CSF abeta level = 379
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

30. Case 2 -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
Had MRI imaging, FDG PET imaging and neuropsych before referral

31. Case 2 - VW

32. Case 3 - LC Progressive memory deficits corroborated by husband
Previous Hx of ME, anxiety, and depression
MMSE 26/30
Neuropsych suggest a specific mild deficit in delayed recall of information, particularly for visual information. Given the multiple factors involved, it is not clear what may be contributing to the deficit in recall of information observed.
MRI unremarkable

33. Case 3 - LC

34. Case 4 - DT Walking memory speech
Emotional change after loosing son in RTA 8 yrs previously
Decreased motivation
Muddled
Not really forgetful
MMSE 17/ , and 22/30 in 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

35. Case 4 DT

36. Case 5
49 year old woman
18/ 12 progressive loss of memory, visuospatial function, executive function.
Myoclonic jerks
No FH
MMSE 22/30
Genetics negative for PS-1, PS-2, and APP

37. Case 5

38. Amyloid imaging in Young Onset Dementia
80 early onset dementia subjects
Amyloid PET discordant with clinical Dx in 25%
Changes in management in 50% of cases
Zwan MD AAIC 2014

39. 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 / medical co-morbities / Normal Pressure Hydrocephalus

40. Before and after an amyloid scan
Open discussion with patient and family about what scan is for
Discussion about what they want to know
Discussion about what a positive scan or negative scan would mean in their own situation

41. After an amyloid scan Negative scan
Was scan good quality and a clear read?
Cognitive impairment highly unlikely to be due to Alzheimer’s Disease
Caution in > 80’s
What is causing the cognitive impairment?
Follow up
Positive scan
Positive for amyloid plaque, may be supportive of a diagnosis of Alzheimer’s Disease
Interpretation needs caution and context
Age (? Apo E status)
Cognitive deficits
Possibility of dual pathology
Evidence of neuronal loss
May lay ground for working diagnosis and management plan

42. 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. Amyvid now available for use within guidelines

43. Conclusions Detection of amyloid is not a diagnosis of AD
Amyloid PET results must be interpreted in the context of a comprehensive clinical evaluation – see MDT with neuroradiology
Negative scan effectively excludes amyloid pathology
Has greatest utility in young onset dementia, atypical presentations, differentiating from AD from FTD, and in cases where there are multiple pathologies, e.g. depression, vascular