This document discusses functional imaging techniques used to evaluate dementia. Perfusion imaging with 99mTc-HMPAO SPECT can help differentiate between Alzheimer's disease, vascular dementia, and dementia with Lewy bodies based on patterns of hypoperfusion. 18F-FDG PET is useful to identify hypometabolism in temporal and parietal regions in Alzheimer's and occipital hypometabolism in dementia with Lewy bodies. Tau tracers like AV-1451 PET can identify neurofibrillary tangles and stage tau pathology based on Braak staging. Molecular imaging provides in vivo methods to identify amyloid and tau proteins associated with different dementias.

1. FUNCTIONAL IMAGING IN
DEMENTIA
Jasim Jaleel
Junior Resident
Dept. of Nuclear Medicine

2. DEMENTIA
• Derived from Latin word demens meaning out of one’s mind
• Term ‘dementia’ is now replaced by ‘Major Neurocognitive
Impairment’.

3. DSM 5 CRITERIA
• Evidence of significant cognitive decline from a previous level of
performance in one or more cognitive domains:
- Learning and memory
- Language
- Executive function
- Complex attention
- Social cognition
• The cognitive deficits interfere with independence in everyday activities
• The cognitive deficits do not occur exclusively in the context of a delirium
• The cognitive deficits are not better explained by another mental disorder

4. Evaluation of a patient with dementia
• History Taking- ask for cognitive symptoms, motor symptoms,
autonomic symptoms and behavioural symptoms.
• General and Neurological Examination
• Cognitive Assessment- MMSE score
• Lab Investigations- blood glucose level, s. electrolyte, TFT, Vit B12
levels
• Neuroimaging

5. Causes of Dementia
IRREVERSIBLE
Alzheimer’s disease
Frontotemporal dementia (Pick’s
disease)
Parkinson’s disease dementia
Lewy Body dementia
Vascular diseases
Creutzfeld-Jakob disease
POTENTIALLY REVERSIBLE
Depression
Medication side-effects or
interactions
Thyroid disorders
Parathyroid disorders
Acute alcohol abuse
Anemia
Electrolyte imbalance

6. Dementia: Classification
Primary cerebral degenerations
• Alzheimer's disease
• Pick's disease
• Progressive supranuclear palsy
• Dementia with Lewy bodies
• Parkinson's disease and dementia
Cerebral infections and inflammatory
disorders
• Progressive multifocal
leucoencephalopathy(PML)
• Subacute sclerosing panencephalitis(SSPE)
• HIV infection
Cerebrovascular disease
Prion dementias
• Sporadic and familial Creutzfeldt-Jakob disease
• Kuru
Inherited metabolic and storage disorders
Metabolic and toxic causes
• Hypothyroidism
• Uraemia
Neoplasms
Miscellaneous
• Normal pressure hydrocephalus
• Post-cerebral irradiation

7. TYPES OF DEMENTIA
CORTICAL SUBCORTICAL MIXED
ALZHEIMER’S DISEASE PARKINSON’S DISEASE VASCULAR DEMENTIA
FRONTO TEMPORAL DEMENTIA HUNTINGTON’S DISEASE
CREUTZFELDT–JAKOB DISEASE NORMAL PRESSURE
HYDROCEPHALUS
LEWY BODY DEMENTIA HIV ASSO. DEMENTIA

8. Spectrum of Dementia
Frontotemporal
Dementia
4%
Hippocampal
Sclerosis
1%
Dementia With
Lewy Bodies
8%
Pure Vascular
Dementia
3%
Mixed Dementia
42%
Alzheimer's
Disease
42%
Barker WW, et al. Alzheimer Dis Assoc Disord. 2002;16:203-212.
DLB 8%
AD 42%MIXED DEMENTIA 42%
VD 3% FTD 4%
HIPPOCAMPAL
SCLEROSIS 1%

9. Alzheimer’s Dementia
• Most common cause of dementia
• World wide prevalence of 44 million (source: CDC and NCHS 2017)
• It’s a continuum of spectrum including preclinical AD, MCI, Mild AD,
Moderate AD and Severe AD according to NIAAA and IWG criteria.

11. Mild Cognitive Impairment
• Like dementia, it cannot be diagnosed by any laboratory tests.
• MMSE scores 24-27
• There will be mild tau and amyloid deposition, which can be imaged
earlier than with MRI.
• If we can diagnose AD at level of MCI, the progression can be halted
or retarded by medical interventions

13. NIAAA diagnostic criteria for MCI
• Evidence of change in cognition as compared to previous level
• Impairment in one or more cognitive domains including memory,
executive functions, attention, language and visuospatial skills.
• Preservation of independence in functional abilities
• Patient is not demented

14. NIAAA diagnostic criteria for Alzheimer’s
disease
• Patient is demented
• Insidious onset
• Clear cut history of worsening of symptoms
• Amnestic presentation – loss of memory of recently learned
information
or
Non amnestic presentation – Loss of executive functions, attention,
language and visuospatial skill
• Structural brain injuries and other causes of dementias ruled out

15. Fronto-Temporal Dementia
• It is divided to 3 subtypes.
A. bvFTD – Behavioural variant FTD
B. svPPA- semantic variant Primary Progressive Aphasia
C. PNFA- progressive agrammatic/non-fluent aphasia
Bradley’s Neurology in Clinical Practice, (2015, Elsevier)

16. Dementia with Lewy Bodies
• Second most common cause of dementia
• It is characterised by deposition of Lewy Bodies in cortex and
brainstem

17. Bradley’s Neurology in Clinical Practice, (2015, Elsevier)

18. Vascular Dementia
• Now termed as Vascular Cognitive Impairment (VCI)
• Subtypes are
1. Multi infarct Dementia
2. Subcortical ischemic vascular dementia
3. Dementia related to strategic strokes
4. perfusion related dementia
5. Haemorrhagic stroke related dementia
6. dementia asso. with arteriopathies
7. Mixed dementia

19. AHA-ASA CRITERIA FOR VCI
• There is cognitive impairment and imaging evidence of
cerebrovascular disease and
A. There is a clear temporal relationship between a vascular event
(e.g., clinical stroke) and onset of cognitive deficits, or
B. There is a clear relationship in the severity and pattern of cognitive
impairment and the presence of diffuse, subcortical cerebrovascular
disease pathology.
• 2. There is no history of gradually progressive cognitive deficits before
or after the stroke that suggests the presence of a nonvascular
neurodegenerative disorder.

20. IMAGING IN DEMENTIA
STRUCTURAL FUNCTIONAL
PERFUSION
IMAGING METABOLIC IMAGING
PATHOLOGIAL/
MOLECULAR
IMAGING
99mTc ECD SPECT/CT
99mTc HMPAO SPECT/CT
18F-FDG PET/CT
TAU PET/CT
AMYLOID PET/CT
99mTc TRODAT
CT
MRI

21. STRUCTURAL IMAGING

22. STRUCTURAL IMAGING
• CT Scan
• MRI Scan

23. Computed Tomography
• Important in identifying causes of secondary dementia
• Useful in identifying
1. Intracranial neoplasms
2. Space occupying lesions like SDH
3. Normal Pressure Hydrocephalus
4. Vascular changes in Vascular Dementia

24. Intracranial neoplasm
Chronic SDH

25. Normal Pressure Hydrocephalus
Multiple infarcts in vascular dementia

26. Advantages
• Less expensive
• More available
• Shorter time of investigation
• Can rule out the rare and treatable causes of dementia
• Useful in cases where MRI is C/I such as metal prosthesis

27. Disadvantages
• Lower spatial resolution
• Lower sensitivity
• Inability to measure progression of disease process

28. Magnetic Resonance Imaging
• Considered superior to CT in evaluation of Dementia due to better
image resolution and contrast.
• Main findings to look for when interpreting MRI in dementia are
1. atrophy of brain parenchyma
2. Infarcts
3.white matter lesions

29. Diagnosis MRI Findings
Alzheimer’s Dementia Medial Temporal Lobe atrophy
Parietal lobe atrophy
Hippocampal Atrophy
Fronto-Temporal Dementia Asymmetrical Frontal and Temporal Lobe atrophy
Vascular Dementia global atrophy
diffuse white matter lesions,
lacunar and strategic infarcts
Dementia with Lewy Bodies Normal MRI

30. T1W MRI coronal section showing loss of hippocampal volume,
Medial temporal lobe atrophy. s/o AD

32. Vascular Dementia

33. T2 and FLAIR image showing atrophy of Left temporal lobe with
Normal Right temporal lobe. Suggestive of FrontoTemporal Dementia

34. FUNCTIONAL IMAGING

35. PERFUSION IMAGING

36. PERFUSION IMAGING
• 99mTc Ethyl cysteinate dimer (99mTc ECD)
• 99mTc- hexamethylpropyleneamineoxim (99mTc HMPAO)
• Lipophilic in nature
• Crosses blood brain barrier
• After crossing BBB, become hydrophilic and thus remain there
• It is thus used to asses cerebral blood flow (CBF)

37. 99mTc-HMPAO 99mTc-ECD
Lipophilic
Intracellular conversion to polar species
( Glutathione)
Greater cerebral extraction but back diffusion
Cleared from the blood relatively less rapidly
Distributed more in the basal ganglia, frontal lobe &
cerebellum
Brain uptake is 3-4%
Lipophilic
Ionisation to non-diffusible metabolites by esterases in brain
cells
Greater retention fraction due to lesser back diffusion
Cleared from the blood rapidly, & hence higher brain-to-soft
tissue activity & greater contrast
More in the occipital & parietal lobes
7-8%
Grey matter to white matter ratio is 2-3:1
Excretion is by liver(50%) and Kidney (40%)
4:1
Kidneys (75%) and Liver (20%)
Ana M. Catafau. Brain SPECT in Clinical Practice. J Nucl Med 2001; 42.

39. Measure Diagnostic standard Differential Sensitivity Specificity Reference
SPECT HMPAO Clinical (probable AD) AD vs normals 91% 86% Johnson et al. J
Nucl Med 1993
SPECT HMPAO (progressing vs
non-progressing MCI)
Longitudinal clinical (probable AD) Pre-AD vs stable MCI 78% 71% Johnson et al.
Neurology 1998
SPECT HMPAO Clinical AD vs DLB 65% 87% Loboteses et al.
Neurology 2001
SPECT HMPAO Histopathology AD vs other
dementias/normal
63% 93% Jagust et al.
Neurology 2001
SPECT 133Xe & HMPAO Histopathology AD vs other dementias 86% 73% Bonte et al. J Nucl
Med 1997
Overall range of sensitivity &
specificity
77 +/-14 82 +/- 11
Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia. Dougall NJ et al. Dougall NJ 2004
Nov-Dec;12(6):554-70. Am J Geriatr Psychiatry. 2004 Nov-Dec;12(6):554-70.

40. DIAGNOSIS FINDINGS
ALZHEIMER’S DEMENTIA B/L (or U/L) post CBF abnormality
FRONTO-TEMPORAL DEMENTIA B/L (or U/L) ant. CBF abnormality
VASCULAR DEMENTIA Patchy CBF abnormality
LEWY BODY DEMENTIA B/L post CBF abnormality (occipital hypoperfusion is
charechterstic)

41. Vascular Dementia
Alzheimer’s Disease
Normal scan
Fronto-temporal Dementia
DLB

42. • Most useful in differentiating between AD and VD
• Least useful in differentiating between AD and DLB

43. METABOLIC IMAGING

44. 18F-FDG PET/CT
• To assess cerebral metabolism.
• Hypometabolism in seen in dementia.
• Progressive reduction in glucose metabolism has been shown to
occur years before appearance of clinical symptoms in patients with
Dementia .

45. diagnosis hypometabolism
Mild Cognitive Impairment • Posterior cingulate gyrus
• para hippocampal gyri
Alzheimer’s Dementia • Parieto- temporal (symmetrical or asymmetrical) including
posterior cingulate and precuneus
• Preserved metabolism in sensorimotor and visual cortices,
b/l basal ganglia and thalami, cerebellum
Advanced Alzheimer’s Disease Extensive hypometabolism extending upto parieto- temporal
region and even to frontal lobe.
Occipital lobe is spared

46. ALZHEIMER’S DISEASE

47. Healthy Control MCI AD

48. Fronto temporal Dementia • Ventromedial and anterior portions of frontal lobe
• anterior and ventral temporal region
• extending to subcortical and medial thalamic
structures as disease progress
Dementia with Lewy Bodies • Occipital cortex
• temporal and parietal cortex
• typically spares posterior cingulate cortex
Vascular Dementia Focal cortical, subcortical, deep grey nuclei and
cerebellar hypometabolism

49. FTD

50. DLB with b/l temporal parietal and visual cortex hypometabolism

51. VD with hypometabolism in right occipital, left thalamus, left putamen

52. Reference Subjects sensitivity specificity
Mosconi et al., 2008 AD vs healthy control
(n=314 )
99% 98%
Chen et al., 2008 AD vs healthy control
(n=112)
90% 85%
Panegyres et al., 2009 AD vs non-AD dementia
(n=96)
AD- 78% AD- 81%
Non-AD- >95%
Silverman et al., 2001 AD vs non-AD dementia
(n=138)
89% 83%
Minoshima et al., 2001 AD vs DLB (n=21) 90% 82%
Foster et al., 2007 AD vs FTD (n=45) 97% 86%
Effectiveness and Safety of 18F-FDG PET in the Evaluation of Dementia: A Review of the Recent Literature
Nicolaas I. Bohnen, David S.W. Djang, Karl Herholz, Yoshimi Anzai and Satoshi Minoshima
THE JOURNAL OF NUCLEAR MEDICINE Vol. 53 No. 1 January 2012
a pooled diagnostic accuracy of 93% was reported with a sensitivity of 96%
and a specificity of 90%.

53. FDG PET/CT: Limitations
• Brain FDG retention is a nonspecific indicator of metabolism
• Can be deranged for a variety of reasons (e.g., ischemia or
inflammation)
• In certain individuals findings may be irrelevant or only indirectly
related to any AD-related process

54. PATHOLOGICAL IMAGING

55. 99mTc TRODAT
• To differentiate DLB from AD
• Patients with DLB accumulation of Lewy Bodies in Striatum
Loss of functional dopaminergic neurons
Decreased levels of Dopamine transporter
proteins (DAT) in striatum

56. • 99mTc-labeled TRODAT binds to dopamine transporter with high
selectivity
• In patients with DLB, there will be less TRODAT binding.
• In patients with AD, it will be similar to normal people.

57. DLB AD

58. MOLECULAR IMAGING

59. Molecular Imaging
• Amyloid PET Imaging
• Tau PET Imaging

60. TAU IMAGING
• Tau is a microtubule associated protein which is essential for neuronal
stability and neuronal nutrient transport
• Hyperphosphorylated Tau proteins are called Neurofibrillary tangles
(NFT).
• Based of spread of NFTs, Braak staging has been proposed.

61. • Stage I and II – NFT confined to entorhinal cortex.
Clinically silent cases
• Stage III and IV – Limbic regions also involved.
Represent Early AD and MCI
• Stage V and VI – Neocortex also involved.
Represent fully developed AD

62. • Tau tracers can be of 2 types:
A. Specific Tau tracers
B. Non specific Tau Tracers

63. Non-specific tracers
• FDDNP is the first developed PET tracer in AD, initially developed for
amyloid, showed a moderate affinity to Tau proteins also.
• Diadvantages:-
1. Lacked sensitivity and specificity for tau proteins.
2. was metabolised and cleared rapidly.
3. needed a long scanning time.

64. specific tau tracers
3 different families of Tau tracers
• aryquinoline derivatives: THK523, THK5117 and THK5351.
• pyrido-indole derivative: AV-1451(also known as T807 and
Flortaucipir) and T808.
• phenyl/pyridinyl-butadienyl-benzothiazole/benzothiazolium
derivative: PBB3.

66. Novel tau tracers
• RO6931643, RO6924963, RO658948 was developed by Honor et al.
High affinity binders at [3H]808 binding sites on tau aggregates.
• Lansoprazole labelled with 11C or 18F is a potential tau PET tracer, but
no human studies have been reported to date.
• The tracer we use in our department is 18F labelled AD-ML-104.

67. • From the prev study (unpublished data) carried out in our
department, the conclusion was made that there was an inverse
correlation with Tau deposition and FDG uptake in brain.

70. Amyloid Imaging
• Early identification of amyloid deposits plays an important role in
early identification of MCI and AD.
• Amyloid targeted tracers go and bind with Aβ amyloid deposits when
they reach necessary size.

71. • First study was anti-β amyloid study
• It was a monoclonal Fab segment targeting β amyloid protein
• Labelled with 99mTc for SPECT imaging

72. 18F-FDDNP
• First PET tracer was 18F-FDDNP.
• It was a nonspecific amyloid tracer which also showed binding with
Tau protein
• It also showed significant cortical and white matter retention
• Highest retention was in entorhinal cortex and amygdala

73. 11C- Pittsburg component B (PiB)
• Binds with insoluble fibrillary A β, not with amorphous A β particle.
• Had more of cortical retention
• White matter retention was comparatively low.
• In patients with AD, deposition was seen in frontal and parietal cortex

76. Newer 18F tracers
• 18F- florbetapir
• 18F- flutemetamol
• 18F- florbetaben

78. RADIOPHARMACEUTUCAL SUBJECTS SENSITIVITY SPECIFICITY
Florbetaben Visual HC vs MCI vs AD 97% 67%
quantitative NA NA
Florbetapir visual HC vs MCI vs AD 90% 81%
quantitative 96% 93%
Flutemetamol visual HC vs MCI vs AD 95% 69%
quantitative 94% 68%
TOTAL visual 93% 66%
quantitative 94% 79%
Diagnostic accuracy of 18F amyloid PET tracers for the diagnosis of Alzheimer’s disease: a systematic review and meta-
analysis Elizabeth Morris Anastasia Chalkidou Alexander Hammers Janet Peacock Jennifer Summers& Stephen Keevil
Eur J Nucl Med Mol Imaging October 2015

79. Benefits of amyloid imaging
• Non- invasive
• Direct measure of amyloid status
• Early detection of AD
• Prognosis of AD
• Increased diagnostic certainity
• Monitor effectiveness of anti Aβ therapy

80. Short comings
• Cannot differentiate AD from other β amyloid diseases such as DLB.
• Cannot determine the severity of dementia
• Significantly increased white matter binding

81. THANK YOU…