The Spectrum of Neurodegenerative Dementia

Russell Swerdlow, MD

NINCDS-ADRDA Criteria

• 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• Praxis• Executive• Language• Visuospatial• Memory

Memory

Attention

Working memory/Attention/Executive Functioning

Memory

Language/Executive Function/Praxis

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• FDG PET• CSF • Amyloid PET

AD Biomarker “Definitions”

• “Upstream” Biomarkers– CSF Abeta– Brain amyloid imaging by amyloid PET

• “Downstream” Biomarkers– Tau or phospho-tau– FDG PET– MRI

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

100

40 withclinical AD

(between 30-50%)60

20 withMCI*

(between 10-30%)

40

25 withpreclinical AD

(~65% of those withno cognitive decline)

15 with no AD

(A) (B)

01020304050

60708090

100

Perc

ent E

ffect

ed

(+St

anda

rd D

evia

tion)

Clinical AD Clinical AD+

MCI

Clinical AD+

MCI+

Preclinical AD

AD Treatments

• Cholinesterase inhibitors• Memantine• Axona• Dietary Supplements• Amyloid Treatments

FTD: Clinical Criteria

(1) Acquired behavioral or cognitive deficits ofa) personality, with inappropriate activities, orb) progressive language change

-problems with expression-problems with word meaning/naming

(2) Decline causes social/occupational dysfunction(3) Insidious and progressive(4) Degenerative in nature (no other etiology)(5) Not delirious(6) 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.)

bvFTD

• 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

MEMORY CIRCUITDorsolateral Prefrontal Area

(Brodmann’s 9 and 10)

Dorsolateral Head of Caudate

Lateral Dorsomedial GPi; SNR

GPe

STN

VA and DM Thalamus

Glu

GABA

GABA

Glu

GABA

GABA

Medial Temporal-Thalamic Circuit (memory storage)

Dorsolateral-PrefrontalPathway(memoryactivation andsearch functions)

HippocampusParahippo. Gyrus

Entorhinal Cortex

Medial TemporalLobe

References• 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.

• PPA– 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.

• DLB– 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.