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,

Cognitive Domains Judgment and Reasoning Attention and concentration Praxis Executive Language Visuospatial 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 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

with clinical AD (between 30-50%) with MCI* (between 10-30%) with preclinical AD (~65% of those with no cognitive decline) 15 with no AD (A)(B) Percent Effected (+Standard Deviation) 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 of a)personality, with inappropriate activities, or b)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:

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 CIRCUIT Dorsolateral Prefrontal Area (Brodmann’s 9 and 10) Dorsolateral Head of Caudate Lateral Dorsomedial GPi; SN R GPe STN VA and DM Thalamus Glu GABA Glu GABA Medial Temporal-Thalamic Circuit (memory storage) Dorsolateral- Prefrontal Pathway (memory activation and search functions) Hippocampus Parahippo. Gyrus Entorhinal Cortex Medial Temporal Lobe

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: – 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: – 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: PPA – Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76: bvFTD – Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134: 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: Cogniform Disorder – Delis DC, Wetter SR. Cogniform Disorder and Cogniform Condition: proposed diagnoses for excessive cognitive symptoms. Arch Clin Neuropsychol 2007;22: