The Spectrum of Neurodegenerative Dementia

The Spectrum of
Neurodegenerative Dementia
Russell Swerdlow, MD
• Objective dementia
• At least two defective cognitive domains
• Progressive worsening
• Normal consciousness
• No other potential causes apparent
*From McKhann et al, Neurology 34, 939-944.
Cognitive Domains
Judgment and Reasoning
Attention and concentration
Working memory/Attention/
Executive Functioning
Language/Executive Function/
Visuospatial Function
Other Studies
• Brain imaging
– CT or MRI
• Blood tests
– CBC, chemistries, LFTs, B12, thyroid
Gene and Biomarker Testing
May help increase certainty of diagnosis
May decrease certainty of diagnosis
May help predict MCI-to-AD conversion
Being developed to facilitate/refine early dx
– These efforts are primarily for research purposes
Available Gene/Biomarker Tests
Genetic Testing
Amyloid PET
AD Biomarker “Definitions”
• “Upstream” Biomarkers
– CSF Abeta
– Brain amyloid imaging by amyloid PET
• “Downstream” Biomarkers
– Tau or phospho-tau
2011 AD Criteria
• Probable AD Dementia
– Meets clinical AD criteria
– No alternate diagnosis
– Documented decline, biomarker, or mutation
• Possible AD Dementia
– Meets clinical AD criteria, BUT
– Atypical course (lacks clear progression) OR
– Biomarkers are negative OR
– Mixed presentation (criteria for other cause also met)
2011 MCI Clinical Criteria
• Concern regarding a change in cognition
– By patient, informant, or clinician
• Impairment in 1 or more cognitive domains
– Typically 1-1.5 SD below expected
• Preserved independence in functional abilities
– Mild problems allowed, but essentially independent
• Not demented
– No evidence of social or occupational impairment
2011 MCI Criteria: Types of MCI
• MCI of a Neurodegenerative Etiology
– Meets MCI clinical criteria, BUT
– Biomarkers not tested, OR
– Biomarkers tested but are ambiguous for AD, OR
– Biomarkers tested but are negative for AD
• MCI of the Alzheimer Type
– Meets MCI clinical criteria, AND
– At least 1 AD “downstream” biomarker is present
• Prodromal Alzheimer’s Dementia
– Meets MCI clinical criteria, AND
– There is “upstream” AD biomarker evidence
2011 Preclinical AD Criteria
• Stage 1 (Asymptomatic Cerebral Amyloidosis)
– Abnormal “upstream” biomarker
– Normal cognition
• Stage 2 (Amyloidosis+Degeneration)
– Abnormal “upstream” biomarker
– Abnormal “downstream” marker
– Normal cognition or slight decline
• Stage 3 (Amyloidosis+Degeneration+Cognitive Change)
– Abnormal “upstream” biomarker
– Abnormal “downstream” biomarker
– Longitudinal evidence of subtle cognitive decline
(between 30-50%)
Percent Effected
20 with
(between 10-30%)
(+Standard Deviation)
40 with
clinical AD
Clinical AD
25 with
preclinical AD
(~65% of those with
no cognitive decline)
15 with
no AD
Clinical AD
Clinical AD
Preclinical AD
AD Treatments
Cholinesterase inhibitors
Dietary Supplements
Amyloid Treatments
FTD: Clinical Criteria
(1) Acquired behavioral or cognitive deficits of
a) personality, with inappropriate activities, or
b) progressive language change
-problems with expression
-problems with word meaning/naming
Decline causes social/occupational dysfunction
Insidious and progressive
Degenerative in nature (no other etiology)
Not delirious
Not due to psychiatric disturbance
McKhann et al, Arch Neurol 2001;58:1803-1809
Primary Progressive Aphasia
• Inclusion Criteria (all required)
– Language main clinical feature
– Language main cause of ADL problems
– Problems started with language
• Exclusion Criteria (all required)
– Other medical disorder is more likely
– Psychiatric disorder is more likely
– Other cognitive domains initially perturbed
– Prominent initial behavioral disturbances
Non-Fluent/Agrammatic Variant PPA
• At least 1 of 3 core features
– Agrammatism
– Effortful, halting speech; apraxia of speech
• At least 2 of 3
– Impaired comp. of syntactically complex sentences
– Spared single word comprehension
– Spared object knowledge
• Imaging Support
– Left posterior frontal-insular atrophy
– Left posterior frontal-insular hypometabolism
Semantic Variant PPA
• Both core features present
– Impaired confrontation naming
– Impaired single word comprehension
• At least 3 present
Impaired object knowledge
Surface dyslexia or dysgraphia
Spared repetition
Spared speech production
• Imaging Support
– Predominant anterior temporal lobe atrophy
– Predominant anterior temporal lobe hypometabolism
Logopenic Variant PPA
• Both core features present
– Impaired single word retrieval
– Impaired repetition
• At least 3 features present
– Errors in spontaneous speech and naming
– Spared single word comp./object knowledge
– Spared motor speech
– Absence of frank agrammatism
• Imaging support
– Left posterior perisylvian/parietal atrophy
– Left posterior perisylvian/parietal hypometabolism
PPA Etiology Predictions
• Non-fluent/agrammatic
– Most often tau-postitive
– FTLD spectrum (may evolve into CBD or PSP)
– If familial, consider checking MAPT gene; also PGRN gene
• Semantic
– Most often TDP
– FTLD spectrum
– If familial, consider checking PGRN gene
• Logopenic
– Most often AD pathology
– Could consider checking for AD biomarkers
Behavioral Variant FTD Criteria
• Progressive deterioration of behavior/cognition
• Possible bvFTD (need 3 of 6)
Disinhibition (lost social skills, manners, impulsive)
Apathy or inertia
Lost sympathy or empathy
Stereotyped or compulsive/ritualistic behaviors
Hyperorality/dietary changes
NP with executive >memory and VP dysfunction
• Probable bvFTD
– Meets possible bvFTD criteria
– Exhibits significant functioanl decelin
– Imaging c/w bvFTD (frontal/anterior temporal atrophy or hypomet.)
• Biggest recent finding:
– C9ORF72
– Familial and sporadic cases reported
– Especially prevalant in familial FTD-MND
Dementia with Lewy Bodies
• Central feature
– Progressive dementia
• Core features (2 for probable, 1 for possible)
– Fluctuating cognition/variable attention+alertness
– Recurrent visual hallucinations
– Spontaneous features of parkinsonism
• Suggestive features (almost equal weight)
– REM sleep behavior disorder
– Severe neuroleptic sensitivity
– Low dopamine transporter uptake in BG
• Supportive features
– Falls, LOC, autonomic dysfunction, delusions
Temporal Sequence
• DLB: dementia before or with parkinsonism
• PDD: dementia evolves after PD established
Pre-Mortem DLB vs. AD
Dopamine transporter (DAT) imaging
Metaiodobenzyl guanidine (MIBG) scintigraphy
FDG PET (occipital hypometabolism)
Relative hippocampal sparing on MRI
Post Mortem DLB vs. AD
• 60% of time AD and LB pathology co-exist
Cogniform Disorder
• Complaints/performance issues excessive (need 2 of 9)
– Mild-mod injury with deficits worse than expected
– Inconsistencies between complaints, deficits, injury
– Inconsistencies between deficits and observed state
– Temporal course not typical of that expected
– Inconsistencies across multiple evaluations
– Strange patterns on cog testing
– Inconsistencies in sx or complaints over time
– Issues with specific Validity tests (e.g. testing of effort)
– Issues with parts of other tests that inform Validity
• Deficits play out in everyday life
– In addition to excessive complaints/poor testing on eval, sx pervade daily
function (“sick role”)
• Specify if:
– Evidence of external incentive, interpersonal incentive, or NOS
Dorsolateral Prefrontal Area
(Brodmann’s 9 and 10)
Dorsolateral Head of Caudate
Medial Temporal
Lateral Dorsomedial GPi; SNR
Parahippo. Gyrus
VA and DM Thalamus
Entorhinal Cortex
Medial Temporal-Thalamic Circuit (memory storage)
activation and
search functions)
• AD
McKhann GM, Knopman DS, Chertkow H, et al. 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. Alzheimers Dement 2011;7:263-269.
Albert MS, Dekosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to
Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association
workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:270-279.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease:
Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on
diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-292.
Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its
variants. Neurology 2011;76:1006-1014.
• bvFTD
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the
behavioural variant of frontotemporal dementia. Brain 2011;134:2456-2477.
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies:
third report of the DLB Consortium. Neurology 2005;65:1863-1872.
• Cogniform Disorder
Delis DC, Wetter SR. Cogniform Disorder and Cogniform Condition: proposed diagnoses for excessive
cognitive symptoms. Arch Clin Neuropsychol 2007;22:589-604.

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