Outline. Clinicopathologic Conference RAIN Case Presentation. Case Presentation. Pathology Presentation. Closing Remarks

Transcription

1 Outline Clinicopathologic Conference RAIN 2017 Case Presenter: Scott Caganap, MD Clinical Discussant: Gil Rabinovici, MD Pathology Discussant: Lea Grinberg, MD, PhD Case Presentation 1. History and Exam 2. Expert Opinion 3. Ancillary Testing 4. Final Diagnosis? Pathology Presentation Closing Remarks Case Presentation Year 1 Difficulty fixing up cars 68 year-old left-handed man with progressive cognitive impairment Accompanied by his wife who does most of the reporting Year 2 Year 3 Year 4 Trouble understanding his wife in conversation Hearing aid no improvement Repeating conversations, word-finding difficulty, substitute/mispronounce words Paucity of speech (down 25%), spoke with softer voice 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 1

2 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. 2

3 Examination General: Normal vital signs, 137 lbs., 5 7 Cooperative, well-groomed Alert, DSF 4 Mental Status Exam 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 3

4 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 4

5 Reflex Exam R palmar grasp Reflex Exam R palmomental & rooting reflex Snout reflex Sensory Exam Normal sensation to all modalities No extinction to DSS Normal stereognosis No instability during Romberg testing Slow, cautious Gait Exam Short-stride length Decreased arm-swing bilaterally One step backwards during retropulsion testing 5

6 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 50 th Annual Recent Advances in Neurology February 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 6

7 Approach to Patient with Cognitive Complaints Mental Status exam and neuropsychological testing Better define cognitive domains Physical neurological exam Cranial nerves Motor: UMN/LMN, parkinsonism Sensory loss Ataxia Gait Approach to Patient with Cognitive Complaints 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 Pathology Aβ Tau TDP-43 α-synuclein Common Causes of Neurodegenerative Dementia Disease Protein Anatomy Early Sxs Neuropsych AD Aβ, tau Medial temporal Posterior temporoparietal DLB FTD α-synuclein Aβ Tau TDP-43 FUS Frontal Occipital/temporal Basal ganglia Brainstem Frontal Anterior temporal VascD N/A Often frontal predominant (but variable) Memory loss, spatial disorientation Behavior spared Parkinsonism, RBD, Psychosis, fluctuations Disinihibition, apathy, personality changes Aphasia, executive dysfunction Motor-neuron disease Often dysexecutive, memory, visuospatial, behavioral Episodic memory Visuospatial Dysexecutive Visuospatial Dysexecutive Memory relatively spared Dysexecutive Memory may be spared Visuospatial usually spared Often executive functions worst, though variable 7

8 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 Speech Production Networks Key nodes: inferior frontal gyrus (BA 44), supplementary motor area (SMA), caudate Executive Control Network Lateral, fronto-parietal Cognitive Seeley et al. J Neurosci Salience Network Medial, fronto-insular Social-emotional behavior T-score T-score T-score Aberrant Motor Behavior Apathy Disinhibition Rosen et al. Brain 2005 Key tracts: aslan tract (AT), superior longitudinal fasciculus (SLF), fronto-striatal Gorno-Tempini et al. Neurology 2006 Mandelli et al. Brain

9 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 Case Summary Rabinovici et al., Continuum 2015 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 9

10 Common Causes of Neurodegenerative Dementia Disease Protein Anatomy Early Sxs Neuropsych AD Aβ, tau Medial temporal Parietal Frontal DLB FTD α-synuclein Aβ Tau TDP-43 FUS Frontal Occipital/temporal Brainstem Frontal Anterior temporal VascD N/A Often frontal predominant (but variable) Memory loss, spatial disorientation, social graces preserved Parkinsonism, RBD, Psychosis, fluctuations Disinihibition, apathy, personality changes, Aphasia, executive dysfunction Motor-neuron disease Often dysexecutive, memory, behavioral Episodic memory Visuospatial Dysexecutive Visuospatial Dysexecutive Memory relatively spared Dysexecutive Memory usually spared Visuospatial always spared 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 3-4/10 5, prevalence 15-22/10 5 Even more common when include associated disorders ALS, HS, CBD, PSP, CTE Clinical Syndromes: FTD PSP CBD nfvppa bvftd svppa FTLD-ALS FTLD-TAU FTLD-FUS FTLD-TDP Pathology: FTLD MAPT Genes C9ORF72 PGRN 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 Rabinovici and Miller. CNS Drugs 2010 Rascovsky et al. Brain

11 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 Atrophy Patterns in FTLD vs. AD Pathology-proven AD/FTLD vs. NC Distinct atrophy in AD and FTLD Common atrophy in AD and FTLD Rascovsky et al. Brain 2011 Rabinovici et al. AJADOD 2007 Amyloid vs. FDG-PET in Differential Diagnosis of AD vs. FTD AD (N=62, age 65, MMSE 22) FTD (N=45, age 65, MMSE 22) Amyloid (PIB) PET visual reads 90% sensitivity, 83% specificity Inter-rater agreement κ=0.96 FDG-PET visual reads 78% sensitivity*, 84% specificity Inter-rater agreement κ=0.72* 70 autopsy-proven cases PIB: Sensitivity 96%, Specificity 88% FDG: Sensitivity 88%, Specificity 89% * - p<0.05 vs. PIB Rabinovici et al. Neurology 2011 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

12 Primary Progressive Aphasia Progressive loss of language with relative preservation of other cognitive functions 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 1982 Gorno-Tempini et al. Neurology 2011 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 falls Armstrong et al. Neurol 2013 FTLD-TAU Clinical Syndromes: FTD bvftd FTLD-ALS FTLD-FUS FTLD-TDP Pathology: FTLD MAPT Genes C9ORF72 PGRN Rabinovici and Miller. CNS Drugs

13 FTLD-tau Pick s PSP CBD FTLD-FUS Neuropathological Dx in Clinical bvftd UCSF Neurodegenerative Brain Bank, N=117 TDP-A TDP-B TDP-C FTLD-TDP DPR (C9ORF72) Courtesy of David Perry, Lea Grinberg & Bill Seeley None Predicting Pathology in bvftd: Clinical Pearls FTLD-tau: Not helpful FTDC criteria FTLD-TDP Delusions more common (and more severe on NPI) More signs of MND None with visual misperception FTLD-FUS No difference in 6 core FTDC features at presentation or throughout follow-up Frequency of meeting possible or probable FTDC criteria Parkinsonism 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 FTD Autosomal Dominant Mutations Mutation C9orf72 MAPT GRN Age of DX Clinical MRI Unique clinical Neuropath bvftd, ALS FTD-ALS, (AD) Diffuse cortical, can be mild, thalamus, cerebellum ALS, psychiatric prodrome with slow progression FTLD-TDP B FTLD-TDP A FTLD-TDP (U) bvftd, PSP. CBS, (AD) Frontotemporal temporal > frontal Symmetry, addiction FTLD-Tau (usually 4R) bvftd, nfvppa, CBS, (AD) Asymmetric frontotemporal, parietal Asymmetric syndromes FTLD-TDP A 13

14 Genetic vs. Sporadic FTD Tau PET in FTD: [ 18 F]AV1451 Whitwell et al. Brain 2012 Spina et al. Neurology 2017 Final Conclusions Year 1 Difficulty fixing up cars Clinical dx: behavioral-variant FTD (with prominent language disturbance) Predicted pathology (in order of likelihood): 1. FTLD-TDP, type B; sporadic or C9ORF72 2. FTLD-TDP, type A/U 3. FTLD-Tau (Pick, PSP, CBD) less likely 4. AD unlikely to be primary pathology Year 2 Year 3 Year 4 Year 5 Trouble understanding his wife in conversation Hearing aid no improvement Repeating conversations, word-finding difficulty, substitute/mispronounce words Paucity of speech (down 25%), spoke with softer voice 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 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 ROS Dysphagia Bradykinesia Incontinence 14

15 Ancillary Testing Basic serum studies including B12 and TFTs were unremarkable Year 1 Year 2 Difficulty fixing up cars Trouble understanding his wife in conversation Hearing aid no improvement 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 3 Year 4 Year 5 Repeating conversations, word-finding difficulty, substitute/mispronounce words Paucity of speech (down 25%), spoke with softer voice 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 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 ROS Dysphagia Bradykinesia Incontinence 68 year-old left-handed man with progressive cognitive impairment MRI T1-Weighted Sequences 15

16 Ancillary Testing MRI Brain: severe L>R atrophy Lateral and medial frontal lobes Anterior and medial temporal lobes PIB-PET: negative Expert Opinion Year 1 Difficulty fixing up cars Interpretation of Imaging? Final Diagnosis and Pathology? Change your mind? Year 2 Year 3 Trouble understanding his wife in conversation Hearing aid no improvement Repeating conversations, word-finding difficulty, substitute/mispronounce words Paucity of speech (down 25%), spoke with softer voice Year 4 Year 5 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 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 16

17 68 year-old left-handed man with progressive cognitive impairment Pathology Discussion Year 6 Year 7 Marked progression of apathy Decline in mobility and functional independence No longer following commands No longer responding to voice Significant weight loss, feeding tube placement Bedridden Hospice 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 2017 CPC Pathology bvftd SD PNFA FTD-MND CBS PSPS Frontotemporal lobar degeneration (FTLD) Lea T. Grinberg, M.D Ph.D Associate Professor of Neurology and Pathology UCSF 17

18 bvftd SD PNFA FTD-MND CBS PSPS bvftd SD PNFA FTD-MND CBS PSPS Frontotemporal lobar degeneration (FTLD) Alzheimer s Disease Frontotemporal lobar degeneration (FTLD) Alzheimer s Disease FTLD-tau FTLD-TDP* FTLD-FUS FTLD-3 (CHMP2b) FTLD-tau FTLD-TDP* FTLD-FUS FTLD-3 (CHMP2b) Pick s 3R tau CBD 4R tau PSP 4R tau Type A (PGRN) (C9orf72) Type B (C9orf72) (TARDP?) aftld-u BIBD Pick s 3R tau CBD 4R tau PSP 4R tau Type A (PGRN) (C9orf72) Type B (C9orf72) (TARDP?) aftld-u BIBD FTDP-17 (MAPT) Tau NOS MST/AGD Type C Type D (VCP) NIFID??? (FUS) FTDP-17 (MAPT) Tau NOS MST/AGD Type C Type D (VCP) NIFID??? (FUS) Courtesy W. Seeley, UCSF *Harmonized scheme Courtesy W. Seeley, UCSF *Harmonized scheme Weight: 1066 g UCSF/MAC Neurodegenerative Disease Brain Bank R 18

19 1. Moderate dorsolateral frontal and insula atrophy 2. Mild ventral frontal and temporal atrophy 3. Caudate is flat 4. Hippocampus is relatively spared 100 µm Example of negative immunohistochemical assay 19

20 Beta-amyloid TDP-43 ITG IFG * SN ITG Scarce number of diffuse and neuritic plaques in the primary visual area (occipital cortex) unclassifiable: neuronal cytoplasmatic and nuclear inclusions, threads, glial inclusions in all cortical layers Scale bars: 10 µm 3R- and 4 Repeat-tau Immunohistochemistry for p62 - cerebellum The signature pathology Atypical neuronal/glial 4R-tauopathy (limbic and peri-limbic RD4 RD3 Entorhinal cortex Scale bars: 10 µm pathognomonic of C9orf72 expansions Ubiquitin IHC, cerebellar granule cells 20

21 Final Neuropathological Diagnoses Primary 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 1 Braak Neurofibrillary Degeneration Stage 1 CERAD Neuritic Plaque Score none, Case Summary Our patient developed cognitive impairment in his mid- 60 s that progressed over 7 years Cognitive domains: 1. Executive 2. Behavior + Language Brain Imaging: 1. Anterior-predominant hypometabolism 2. Severe L>R frontal & anterior temporal lobe atrophy Clinical Dx: behavioral-variant Frontotemporal Dementia Pathological Dx: FTLD-TDP associated with mutation in C9ORF72 behavioral-variant Frontotemporal Dementia Epidemiology FTD is 2 nd most common cause of early-onset neurodegenerative dementia (after AD) Prevalence: per 100K persons yo 10% occurs in patients <45 yo 30% occurs in patients >65 yo bvftd accounts for >50% of autopsyconfirmed FTLD Knopman et al, J Mol Neurosci 2011 Snowden et al, Brain

22 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 2013 DeJesus-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

23 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 23