13 rabinovicigrinbergcaganap cpc - ucsf cme · – presence of a known pathogenic mutation •...

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Clinicopathologic ConferenceRAIN 2017

Case Presenter: Scott Caganap, MDClinical Discussant: Gil Rabinovici, MD

Pathology Discussant: Lea Grinberg, MD, PhD

Outline• Case Presentation

1. History and Exam2. Expert Opinion3. Ancillary Testing4. Final Diagnosis?

• Pathology Presentation

• Closing Remarks

Case Presentation• 68 year-old left-handed man with progressive cognitive impairment

• Accompanied by his wife who does most of the reporting

Year 1• Difficulty fixing up cars

Year 2• Trouble understanding his wife in conversation• Hearing aid � no improvement

Year 3• Repeating conversations, word-finding difficulty, substitute/mispronounce words• Paucity of speech (down 25%), spoke with softer voice

Year 4

• Progressive difficulty with familiar tasks, stopped driving• Speech output down 80%, difficulty expressing himself � hand motions• No longer pursued hobbies, quit working, needed encouragement to keep up his hygiene• Increased sleep, daytime naps• Lacked insight, content mood

Year 5

• Nearly mute, unable to read or write• Excessive eating, weight gain, stuff large amounts of food in his mouth• Walk outside in only underwear• Repetitively paced in his yard in a particular pattern

68 year-old left-handed man with progressive cognitive impairment

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Review of Systems• Cognition:

– No fluctuations in cognition or level of arousal– Unclear if memory is an issue because he speaks

so rarely– Does not get lost in familiar environments– No issues recognizing his family, but may not

recognize former co-workers occasionally

Review of Systems• Psychiatric:

– Approximately 10 years ago, he had a recurrent delusion in which he suspected his wife of infidelity, but this resolved with marriage counseling

– No illusions, misperceptions, or hallucinations

Review of Systems• Neurologic:

– No changes in vision– Difficulty swallowing (pills, large solids); coughs

during meals– Intermittently kicked his legs while sleeping– Generally slower movements– No tremor, weakness, incoordination, or recurrent

falls– Occasional urinary incontinence

Personal History• PMH: BPH s/p laser surgery• MEDS: tamsulosin, NKDA• FH: two healthy sons; biological family not known• Social History:

– Raised in foster care. Lost foster parents at a young age.

– Grew up in central California. Completed the twelfth grade without difficulty.

– Most recently worked a part-time job as a dishwasher. Previously employed as a mechanic at an auto shop.

– Rare alcohol consumption. No tobacco or illicit drug use.

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Examination• General:

– Normal vital signs, 137 lbs., 5’7”– Cooperative, well-groomed

Mental Status Exam• Alert, DSF 4• Flat affect, slow to respond• Unable to spell WORLD backward, DSB 0• Oriented to self, city, month, and date, but not season, year, or place

• Word registration 3/3, recall 0/3

Mental Status Exam• Sparse speech, up to 4-word sentences, grammatically correct

• Used hand gestures when attempting to speak• Named only a few simple objects• Can repeat a simple sentence• Unable to perform multi-step tasks

Mental Status Exam• Unable to copy intersecting pentagons• Could not pantomime blow-a-kiss or whistle• Unable to perform 3-step hand movement task (Luria test) on both sides

• MMSE 8/30

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Cranial Nerve Exam• VFF, no extinction to DSS• PERRLA• EOMI except for limitation in up-gaze, gaze impersistence

• Normal saccades, no nystagmus

Cranial Nerve Exam• Mild hypophonia and guttural dysarthria• Moderate hypomimia, full facial strength• Mildly diminished hearing bilaterally• Symmetric palate elevation• Normal tongue movements, no fasciculation

Motor Exam• Occasional BUE fasciculation• Paratonia in all extremities• Slowing of movements in all extremities (R>L)• Reduced amplitude finger/foot tapping• No postural or rest tremor• Full strength

Coordination Exam• Intention tremor during FNF testing on R• No dysmetria• Unable to perform RAMs

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Reflex Exam Reflex Exam• R palmar grasp• R palmomental & rooting reflex• Snout reflex

Sensory Exam• Normal sensation to all modalities• No extinction to DSS• Normal stereognosis• No instability during Romberg testing

Gait Exam• Slow, cautious• Short-stride length• Decreased arm-swing bilaterally• One step backwards during retropulsiontesting

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Expert Opinion• What are your thoughts Dr. Rabinovici?

– Differential Diagnosis?– Further Workup?– Leading Diagnosis?– Expected Underlying Pathology?

Clinicopathological Conference:68 year-old with 5 years of cognitive and

behavioral decline

Gil Rabinovici, M.D.Associate Professor of Neurology, UCSF

50th Annual Recent Advances in NeurologyFebruary 10, 2017

Disclosures

• Research support – Avid Radiopharmaceuticals/Eli Lilly, GE Healthcare,

Piramal Imaging

– NIH (NIA, NINDS, NCATS), American College of Radiology, Alzheimer’s Association, Tau Consortium, Association for Frontotemporal Degeneration, Michael J Fox Foundation

• Consulting/honoraria– Eisai, Genentech, Lundbeck, Merck, Putnam, Roche

Approach to Patient with Cognitive Complaints

• HPI probes cognitive domains– Memory: misplacing items, repetitive questions, missing

appointments or bills, remote memory– Visuospatial: navigation, spatial relationships, object and

face recognition– Language: production and comprehension, motor speech,

reading and writing– Executive: decision-making, judgment, multi-tasking,

concentration/focus– Behavior: personality changes, depression, anxiety, apathy,

disinhibition, psychosis– Motor

• First or early symptoms particularly helpful• PMH, Meds, FH, SH may offer valuable clues

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• Mental Status exam and neuro-psychological testing– Better define cognitive domains

• Physical neurological exam– Cranial nerves– Motor: UMN/LMN, parkinsonism – Sensory loss– Ataxia– Gait


• Labs: exclude “treatable” metabolic or infectious causes– Mandatory

• Chem 20, CBC, B12, TSH

– Discretionary• RPR/FTA-ABS, HIV, homocysteine/methylmalonic acid,

LP, rheumatologic, paraneoplastic, heavy metals, etc.

– Imaging (MRI preferred)– Exclude tumor, SDH, NPH, etc.– Evaluate for vascular lesions– Pattern of atrophy

From Clinical Syndrome to PathologyAβ

Tau

α-synuclein

TDP-43

Common Causes of Neurodegenerative Dementia

Disease Protein Anatomy Early Sxs NeuropsychAD Aβ, tau Medial temporal

Posterior temporoparietalMemory loss,spatial disorientationBehavior spared

Episodic memoryVisuospatialDysexecutive

DLB α-synucleinAβ

FrontalOccipital/temporalBasal gangliaBrainstem

Parkinsonism, RBD,Psychosis, fluctuations

VisuospatialDysexecutiveMemory relatively spared

FTD TauTDP-43FUS

FrontalAnterior temporal

Disinihibition, apathy, personality changesAphasia, executive dysfunctionMotor-neuron disease

DysexecutiveMemory may be sparedVisuospatial usually spared

VascD N/A Often frontal predominant (but variable)

Often dysexecutive, memory, visuospatial, behavioral

Often executive functions worst, though variable

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History: Cognitive Symptoms• First symptom: “difficulty performing skilled tasks”

(e.g. car repairs)– Executive, motor planning or output, procedural memory

• Language decline– “Difficulty understanding his wife” – comprehension, attention– Decreased speech output, short sentences– Mispronouncing words, soft voice, mutism - motor speech– Repeating previous conversations

• Episodic memory, perseveration– Unable to read or write: pervasive language deficits

History: Behavioral Symptoms• Apathetic!

– Loss of initiative, interest in hobbies, personal hygiene, hyper-somnolence

• Blissfully unaware– Poor insight, not perturbed by deficits

• Repetitive motor behaviors, pacing• Disinhibition

– Walking around in underwear• Overeating

Frontal Circuits: Cognition & Behavior

Seeley et al. J Neurosci. 2007Rosen et al. Brain 2005

Aberrant Motor Behavior

Apathy

DisinhibitionT-score

T-score

T-score

Executive Control Network – Lateral, fronto-parietalCognitive

Salience Network –Medial, fronto-insularSocial-emotional behavior

Speech Production Networks

Key nodes: inferior frontal gyrus (BA 44), supplementary motor area (SMA), caudate

Key tracts: aslan tract (AT), superior longitudinal fasciculus (SLF), fronto-striatal

Gorno-Tempini et al. Neurology 2006Mandelli et al. Brain 2016

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Additional History• Dysphagia • Occasional urinary incontinence• Delusion of marital infidelity 10 years ago, no hallucinations

• No sleep disturbance• No major medical co-morbidities, Rx• Family history unknown

Exam: Pertinent Positives and Negatives• Thin (5’7”, 137 lbs.) despite over-eating• Cognitively globally impaired (but knows exact date)• Slow, apathetic, little speech output, orobuccal

apraxia• Digits forwards 4, backwards 0; working memory

disproportionately affected vs. repetition• Saccades intact; hypophonic, guttaral dysarthria• UE fasciculations; mild hyper-reflexia, R Babinski• Hypomimia, bradykinesia R>L, slow gait with

decreased arm swing• Intention tremor on R, no truncal or limb ataxia

Rabinovici et al., Continuum 2015

Case Summary• Chronic, progressive course and absence of co-morbidities consistent with primary neurodegenerative disease

• Cognitive: Early and disproportionate executive dysfunction and motor speech

• Behavior: Apathy > disinhibition, overeating• Motor: UMN/LMN; mild extra-pyramidal• Localization:

– Dorsolateral and dorsomedial prefrontal cortex, L>R

– UMN and C-spine LMN, basal ganglia

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Common Causes of Neurodegenerative Dementia

Disease Protein Anatomy Early Sxs NeuropsychAD Aβ, tau Medial temporal

ParietalFrontal

Memory loss,spatial disorientation,social graces preserved

Episodic memoryVisuospatialDysexecutive

DLB α-synucleinAβ

FrontalOccipital/temporalBrainstem

Parkinsonism, RBD,Psychosis, fluctuations

VisuospatialDysexecutiveMemory relatively spared

FTD TauTDP-43FUS

FrontalAnterior temporal

Disinihibition, apathy, personality changes,Aphasia, executive dysfunctionMotor-neuron disease

DysexecutiveMemory usually sparedVisuospatial always spared

VascD N/A Often frontal predominant (but variable)

Often dysexecutive, memory, behavioral

Often executive functions worst, though variable

Frontotemporal Dementia• Family of clinicopathologic syndromes

– Progressive changes in behavior or language– Neurodegeneration of frontal or anterior temporal lobes

• Common cause of pre-senile dementia– 5% of all dementia, most common cause of early-onset dementia (<65 years)

– Incidence 3-4/105, prevalence 15-22/105

– Even more common when include associated disorders ALS, HS, CBD, PSP, CTE

PSP CBD nfvPPA bvFTD svPPA FTLD-ALS

FTLD-TAU FTLD-TDP

MAPT PGRN

Clinical Syndromes: FTD

Pathology: FTLD

Genes

FTLD-FUS

C9ORF72

Rabinovici and Miller. CNS Drugs 2010

Behavioral-Variant FTD: Clinical Criteria(3 of 6 for “Possible bvFTD”)

• Early behavioral disinhibition • Early apathy or inertia -• Early loss of emotional reactivity/sympathy and empathy

• Perseverative, stereotyped or compulsive/ritualistic behavior

• Hyper-orality and dietary changes -• Executive-predominant cognitive dysfunction

Rascovsky et al. Brain 2011

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Behavioral-Variant FTD: Clinical Criteria(3 of 6 for “Possible bvFTD”)

• Early behavioral disinhibition - +/-• Early apathy or inertia - �• Early loss of emotional reactivity/sympathy and empathy - No

• Perseverative, stereotyped or compulsive/ritualistic behavior - �

• Hyper-orality and dietary changes - �• Executive-predominant cognitive dysfunction –perhaps early on, now too impaired to judge

Rascovsky et al. Brain 2011

Atrophy Patterns in FTLD vs. ADPathology-proven AD/FTLD vs. NC

Common atrophy in AD and FTLD

Distinct atrophy in AD and FTLD

Rabinovici et al. AJADOD 2007

Amyloid vs. FDG-PET in Differential Diagnosis of AD vs. FTD

Rabinovici et al. Neurology 2011

AD (N=62, age 65, MMSE 22)FTD (N=45, age 65, MMSE 22)Amyloid (PIB) PET visual reads

90% sensitivity, 83% specificityInter-rater agreement κ=0.96

FDG-PET visual reads78% sensitivity*, 84% specificityInter-rater agreement κ=0.72*

70 autopsy-proven casesPIB: Sensitivity 96%, Specificity 88%FDG: Sensitivity 88%, Specificity 89%

* - p<0.05 vs. PIB

bvFTD – Probable or Definite• Probable bvFTD

– Meets criteria for possible bvFTD– Significant functional decline– Frontal/anterior temporal pattern on MRI/FDG

• bvFTD with definite FTLD pathology– Histopathological evidence on bx/autopsy– Presence of a known pathogenic mutation

• Exclusions– Deficits better accounted for by other medical,

neurological or psychiatric disorder– Biomarkers strongly indicative of AD or other

process Rascovsky et al. Brain 2011

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Primary Progressive Aphasia

• Non-fluent/agrammatic variant (nfvPPA)– Effortful speech, agrammatism, motor speech deficits– Pathology: FTLD-Tau > FTLD-TDP

• Semantic variant (svPPA)– Fluent, grammatically correct speech with loss of word and object meaning– Pathology: FTLD-TDP

• Logopenic variant (lvPPA)– Hesitant speech with word finding difficulty, poor repetition– Pathology: AD

Mesulam, Ann Neurol 1982Gorno-Tempini et al. Neurology 2011

Progressive loss of language with relative preservation of other cognitive functions

Progressive Supranuclear Palsy

• Richardson’s Syndrome– Vertical gaze palsies, postural instability with early

falls, axial-predominant parkinsonism– Highly specific but not sensitive at early stages

• Cognitive decline– Executive dysfunction, slowed processing speed,

impaired working memory

• Behavioral symptoms– Apathy, depression, impulsivity

• Atypical phenotypes– PSP-parkinsonism, pure akinesia with gait

freezing (PAGF), nonfluent PPA, bvFTD

Clinical Phenotypes of Corticobasal Degeneration

• Corticobasal syndrome (CBS)– Asymmetric limb rigidity/akinesia, dystonia, myoclonus– Orobuccal/limb apraxia, cortical sensory loss, alien limb

• Frontal behavioral-spatial syndrome– Executive dysfunction, behavior/personality changes,

visuospatial deficits• Nonfluent primary progressive aphasia

– Effortful speech, agrammatism, apraxia of speech• PSP syndrome

– Symmetric, supranuclear gaze palsies, early fallsArmstrong et al. Neurol 2013

bvFTD FTLD-ALS

FTLD-TAU FTLD-TDP

MAPT PGRN

Clinical Syndromes: FTD

Pathology: FTLD

Genes

FTLD-FUS

C9ORF72

Rabinovici and Miller. CNS Drugs 2010

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Pick’s PSP CBD

TDP-A TDP-B TDP-C

FTLD-TDP

FTLD-tau

DPR(C9ORF72)

FTLD-FUSNeuropathological Dx in Clinical bvFTDUCSF Neurodegenerative Brain Bank, N=117

Courtesy of David Perry, Lea Grinberg & Bill Seeley

� None � Delusions more common (and more severe on NPI)

� More signs of MND

� None with visual misperception

FTLD-tau: FTLD-TDP� Younger age at onset,

presentation, and death

� More oral exploration

� More severe NPI anxiety, euphoria, apathy, disinhibition, aberrant motor, sleep disturbance, eating behavior

� Worse verbal memory and more design fluency repetitions

FTLD-FUS

� FTDC criteria

• No difference in 6 core FTDC features at presentation or throughout follow-up

• Frequency of meeting possible or probable FTDC criteria

� Parkinsonism

Not helpful

Predicting Pathology in bvFTD: Clinical Pearls FTD Autosomal Dominant MutationsMutation C9orf72 MAPT GRN

Age of DX 56 52 62

Clinical bvFTD, ALSFTD-ALS, (AD)

bvFTD, PSP. CBS, (AD)

bvFTD, nfvPPA, CBS, (AD)

MRI Diffuse cortical, can be mild, thalamus,cerebellum

Frontotemporaltemporal > frontal

Asymmetric frontotemporal, parietal

Unique clinical

ALS, psychiatricprodrome with slow progression

Symmetry, addiction

Asymmetric syndromes

Neuropath FTLD-TDP BFTLD-TDP AFTLD-TDP (U)

FTLD-Tau(usually 4R)

FTLD-TDP A

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Genetic vs. Sporadic FTD

Whitwell et al. Brain 2012

Tau PET in FTD: [18F]AV1451

Spina et al. Neurology 2017

Final Conclusions• Clinical dx: behavioral-variant FTD (with

prominent language disturbance)

• Predicted pathology (in order of likelihood):1. FTLD-TDP, type B; sporadic or C9ORF722. FTLD-TDP, type A/U3. FTLD-Tau (Pick, PSP, CBD) less likely4. AD unlikely to be primary pathology




Year 4


Year 5



ROSROS• Dysphagia• Bradykinesia• Incontinence

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Ancillary Testing• Basic serum studies including B12 and TFTs were unremarkable

• MRI Brain: – No mass lesions or ischemic changes– Subtle generalized atrophy, ? anterior predominance,

no lateralization

• FDG-PET: global hypometabolism with sparing of bilateral occipital cortices and posterior cingulate




Year 4


Year 5



ROSROS• Dysphagia• Bradykinesia• Incontinence

MRI T1-Weighted Sequences

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Ancillary Testing• MRI Brain: severe L>R atrophy

– Lateral and medial frontal lobes– Anterior and medial temporal lobes

• PIB-PET: negative

Expert Opinion• Interpretation of Imaging?• Final Diagnosis and Pathology? Change your mind?




Year 4


Year 5



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Year 6• Marked progression of apathy• Decline in mobility and functional independence• No longer following commands

Year 7• No longer responding to voice• Significant weight loss, feeding tube placement• Bedridden• Hospice

68 year-old left-handed man with progressive cognitive impairment Pathology Discussion• Dr. Grinberg, what are the range of pathological findings that can be seen in a patient presenting with these signs and symptoms?

• What did the autopsy show?

RAIN 2017CPC

Pathology

Lea T. Grinberg, M.D Ph.DAssociate Professor of Neurology and PathologyUCSF

Frontotemporal lobar degeneration (FTLD)

SD FTD-MNDbvFTD PSPSCBSPNFA

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SD FTD-MND

FTLD-tau FTLD-TDP*

Pick’s3R tau

CBD4R tau

PSP4R tau

FTDP-17(MAPT)

Tau NOSMST/AGD

FTLD-FUSFTLD-3

(CHMP2b)

bvFTD PSPSCBS

Alzheimer’sDisease

PNFA

Type CType D(VCP)

Type B(C9orf72)(TARDP?)

*Harmonized scheme

aFTLD-U

NIFID???

(FUS)

BIBDType A

(PGRN)(C9orf72)

Courtesy W. Seeley, UCSF


SD FTD-MND

FTLD-tau FTLD-TDP*

Pick’s3R tau

CBD4R tau

PSP4R tau

FTDP-17(MAPT)

Tau NOSMST/AGD

FTLD-FUSFTLD-3

(CHMP2b)

bvFTD PSPSCBS

Alzheimer’sDisease

PNFA

Type CType D(VCP)

Type B(C9orf72)(TARDP?)

*Harmonized scheme

aFTLD-U

NIFID???

(FUS)

BIBDType A

(PGRN)(C9orf72)

Courtesy W. Seeley, UCSF

Weight: 1066 g

R

UCSF/MAC Neurodegenerative Disease Brain Bank

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1. Moderate dorsolateral frontal and insula atrophy2. Mild ventral frontal and temporal atrophy3. Caudate is flat4. Hippocampus is relatively spared

Example of negative immunohistochemical assay

100 µm

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Beta-amyloid

Scarce number of diffuse and

neuritic plaques in the primary

visual area (occipital cortex)

TDP-43

*

ITG

Scale bars: 10 µm

unclassifiable: neuronal cytoplasmatic and nuclear inclusions, threads, glial inclusions in all cortical layers

SN

ITG

IFG

3R- and 4 Repeat-tau

RD4 RD3

Entorhinal cortex

Scale bars: 10 µm

Atypical neuronal/glial 4R-tauopathy (limbic and peri-limbic

Ubiquitin IHC, cerebellar granule cells

The signature pathologyImmunohistochemistry for p62 - cerebellum

pathognomonic of C9orf72 expansions

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Final Neuropathological DiagnosesPrimary diagnosis: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions FTLD-TDP, unclassifiable

Contributing diagnosis : 4-repeat tauopathy, not otherwise specified

Incidental diagnosis: Alzheimer’s disease neuropathological change (ADNC)2

Low ADNC, NIA-AA Criteria (A1, B1, C0)Thal Amyloid Plaque Phase 1Braak Neurofibrillary Degeneration Stage 1CERAD Neuritic Plaque Score none,

Case Summary• Our patient developed cognitive impairment in his mid-60’s that progressed over 7 years– Cognitive domains:

1. Executive2. Behavior + Language

– Brain Imaging:1. Anterior-predominant hypometabolism2. Severe L>R frontal & anterior temporal lobe atrophy

• Clinical Dx: behavioral-variant FrontotemporalDementia

• Pathological Dx: FTLD-TDP associated with mutation in C9ORF72

behavioral-variantFrontotemporal Dementia

Epidemiology• FTD is 2nd most common cause of early-onset neurodegenerative dementia (after AD)

• Prevalence:– 15-22 per 100K persons 45-64 yo– 10% occurs in patients <45 yo– 30% occurs in patients >65 yo

• bvFTD accounts for >50% of autopsy-confirmed FTLD

Knopman et al, J Mol Neurosci 2011Snowden et al, Brain 2011

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Genetics• 40% of FTD is associated with autosomal dominant inheritance

• bvFTD & agrammatic PPA are most common phenotypes

• Mutations in 8 genes account for 50% of familial FTD

• C9ORF72 mutation is most common genetic abnormality in familial FTD (12%) and familial ALS (23%) Rohrer et al, Neurology 2009

Le Ber, Rev Neurol 2013DeJesus-Hernandez et al, Neuron 2011

Criteria for bvFTD• Gradual onset and progressive deterioration of behavior and/or cognition– Disinhibition– Apathy– Ritualistic behavior– Hyperorality

• Frontal and/or anterior temporal pattern on MRI or PET

Rascovsky et al, Brain 2011

Management• No approved therapies for FTD• Supportive care

– Power of attorney– Swallow evaluation– Physical therapy

• Genetic counseling

Finger, Continuum 2016

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Acknowledgements• The patient and his family• UCSF Memory and Aging Center• Discussants:

– Dr. Gil Rabinovici– Dr. Lea Grinberg

• RAIN 2017 Co-Chairs:– Dr. Stephen Hauser– Dr. Andy Josephson

13 rabinovicigrinbergcaganap cpc - ucsf cme · – presence of a known pathogenic mutation •...

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