2/10/2017
Outline
Clinicopathologic Conference
RAIN 2017
Case Presenter: Scott Caganap, MD
Clinical Discussant: Gil Rabinovici, MD
Pathology Discussant: Lea Grinberg, MD, PhD
• Case Presentation
1.
2.
3.
4.
History and Exam
Expert Opinion
Ancillary Testing
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
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
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2/10/2017
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
• 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
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
• 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
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
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
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 retropulsion
testing
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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 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
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2/10/2017
Approach to Patient with
Cognitive Complaints
Approach to Patient with
Cognitive Complaints
• Labs: exclude “treatable” metabolic or
infectious causes
• Mental Status exam and neuropsychological testing
– Mandatory
– Better define cognitive domains
• Chem 20, CBC, B12, TSH
– Discretionary
• Physical neurological exam
• RPR/FTA-ABS, HIV, homocysteine/methylmalonic acid,
LP, rheumatologic, paraneoplastic, heavy metals, etc.
– Cranial nerves
– Motor: UMN/LMN, parkinsonism
– Sensory loss
– Ataxia
– Gait
– Imaging (MRI preferred)
– Exclude tumor, SDH, NPH, etc.
– Evaluate for vascular lesions
– Pattern of atrophy
From Clinical Syndrome to Pathology
Common Causes of
Neurodegenerative Dementia
Aβ
Disease
Tau
TDP-43
α-synuclein
Protein
Anatomy
AD
Aβ, tau
Medial temporal
Posterior temporoparietal
DLB
α-synuclein
Aβ
FTD
Tau
TDP-43
FUS
Frontal
Occipital/temporal
Basal ganglia
Brainstem
VascD
N/A
Frontal
Anterior temporal
Often frontal predominant
(but variable)
Early Sxs
Neuropsych
Memory loss,
spatial disorientation
Behavior spared
Episodic memory
Visuospatial
Dysexecutive
Disinihibition, apathy,
personality changes
Aphasia, executive
dysfunction
Motor-neuron disease
Dysexecutive
Memory may be spared
Visuospatial usually spared
Parkinsonism, RBD,
Psychosis, fluctuations
Often dysexecutive,
memory, visuospatial,
behavioral
Visuospatial
Dysexecutive
Memory relatively spared
Often executive functions
worst, though variable
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History: Cognitive Symptoms
History: Behavioral
Symptoms
• First symptom: “difficulty performing skilled tasks”
(e.g. car repairs)
• Apathetic!
• Language decline
• Blissfully unaware
– Executive, motor planning or output, procedural memory
–
–
–
–
“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
Frontal Circuits: Cognition & Behavior
– Loss of initiative, interest in hobbies, personal
hygiene, hyper-somnolence
– Poor insight, not perturbed by deficits
• Repetitive motor behaviors, pacing
• Disinhibition
– Walking around in underwear
• Overeating
Speech Production Networks
Key nodes: inferior frontal gyrus (BA 44), supplementary motor area
(SMA), caudate
T-score
Executive Control
Network – Lateral,
fronto-parietal
Cognitive
Salience Network –
Medial, fronto-insular
Social-emotional
behavior
Seeley et al. J Neurosci. 2007
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 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
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:
Rabinovici et al., Continuum 2015
– Dorsolateral and dorsomedial prefrontal cortex,
L>R
– UMN and C-spine LMN, basal ganglia
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Frontotemporal Dementia
Common Causes of
Neurodegenerative Dementia
Disease
Protein
Anatomy
AD
Aβ, tau
DLB
α-synuclein
Aβ
FTD
Tau
TDP-43
FUS
VascD
N/A
Early Sxs
Neuropsych
Medial temporal
Parietal
Frontal
Memory loss,
spatial disorientation,
social graces preserved
Episodic memory
Visuospatial
Dysexecutive
Frontal
Anterior temporal
Disinihibition, apathy,
personality changes,
Aphasia, executive
dysfunction
Motor-neuron disease
Dysexecutive
Memory usually spared
Visuospatial always spared
Frontal
Occipital/temporal
Brainstem
Parkinsonism, RBD,
Psychosis, fluctuations
Often frontal predominant
(but variable)
Often dysexecutive,
memory, behavioral
Visuospatial
Dysexecutive
Memory relatively spared
Often executive functions
worst, though variable
CBD
nfvPPA
– 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
Behavioral-Variant FTD: Clinical Criteria
(3 of 6 for “Possible bvFTD”)
Clinical Syndromes: FTD
PSP
• Family of clinicopathologic syndromes
bvFTD svPPA FTLD-ALS
• Early behavioral disinhibition
• Early apathy or inertia -
FTLD-TAU
FTLD-FUS
FTLD-TDP
Pathology: FTLD
MAPT
Genes
C9ORF72
• Early loss of emotional reactivity/sympathy and
empathy
• Perseverative, stereotyped or compulsive/ritualistic
behavior
• Hyper-orality and dietary changes -
PGRN
Rabinovici and Miller. CNS Drugs 2010
• 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 - +/-
Atrophy Patterns in FTLD vs. AD
Pathology-proven AD/FTLD vs. NC
Distinct atrophy in AD and FTLD
• Early apathy or inertia - • Early loss of emotional reactivity/sympathy and
empathy - No
• Perseverative, stereotyped or compulsive/ritualistic
behavior - Common atrophy in AD and FTLD
• Hyper-orality and dietary changes - • Executive-predominant cognitive dysfunction –
perhaps early on, now too impaired to judge
Rascovsky et al. Brain 2011
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%
Rabinovici et al. AJADOD 2007
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
* - p<0.05 vs. PIB
Rabinovici et al. Neurology 2011
• 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
Progressive loss of language with relative
preservation of other cognitive functions
•
Non-fluent/agrammatic variant
(nfvPPA)
–
–
•
–
Fluent, grammatically correct
speech with loss of word and
object meaning
Pathology: FTLD-TDP
–
Hesitant speech with word
finding difficulty, poor
repetition
Pathology: AD
– Vertical gaze palsies, postural instability with early
falls, axial-predominant parkinsonism
– Highly specific but not sensitive at early stages
– Executive dysfunction, slowed processing speed,
impaired working memory
• Behavioral symptoms
– Apathy, depression, impulsivity
Logopenic variant (lvPPA)
–
• Richardson’s Syndrome
• Cognitive decline
Semantic variant (svPPA)
–
•
Effortful speech,
agrammatism, motor speech
deficits
Pathology: FTLD-Tau >
FTLD-TDP
Progressive Supranuclear Palsy
• Atypical phenotypes
Mesulam, Ann Neurol 1982
Gorno-Tempini et al. Neurology 2011
Clinical Phenotypes of Corticobasal
Degeneration
– PSP-parkinsonism, pure akinesia with gait
freezing (PAGF), nonfluent PPA, bvFTD
Clinical Syndromes: FTD
bvFTD
• Corticobasal syndrome (CBS)
FTLD-ALS
– 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
FTLD-TAU
• Nonfluent primary progressive aphasia
FTLD-FUS
FTLD-TDP
Pathology: FTLD
– Effortful speech, agrammatism, apraxia of speech
• PSP syndrome
– Symmetric, supranuclear gaze palsies, early falls
Armstrong et al. Neurol 2013
MAPT
Genes
C9ORF72
PGRN
Rabinovici and Miller. CNS Drugs 2010
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Neuropathological Dx in Clinical bvFTD
FTLD-tau
Pick’s
PSP
CBD
FTLD-FUS
TDP-A
TDP-B
TDP-C
DPR
(C9ORF72)
FTLD-TDP
Predicting Pathology in bvFTD: Clinical Pearls
FTLD-tau:
None
FTLD-TDP
Delusions more common
(and more severe on NPI)
FTLD-FUS
Younger age at onset,
presentation, and death
More signs of MND
More oral exploration
None with visual
misperception
More severe NPI anxiety,
euphoria, apathy,
disinhibition, aberrant
motor, sleep disturbance,
eating behavior
Worse verbal memory and
more design fluency
repetitions
Not helpful
FTDC criteria
• No difference in 6 core FTDC features at presentation or throughout follow-up
UCSF Neurodegenerative Brain Bank, N=117
Courtesy of David Perry, Lea Grinberg & Bill Seeley
FTD Autosomal Dominant Mutations
Mutation
C9orf72
MAPT
GRN
Age of DX
56
52
62
Clinical
bvFTD, ALS
FTD-ALS, (AD)
bvFTD, PSP.
CBS, (AD)
bvFTD, nfvPPA,
CBS, (AD)
MRI
Diffuse cortical,
can be mild,
thalamus,
cerebellum
ALS,
psychiatric
prodrome with
slow progression
Frontotemporal Asymmetric
temporal >
frontotemporal,
frontal
parietal
Unique
clinical
Symmetry,
addiction
Asymmetric
syndromes
FTLD-Tau
(usually 4R)
FTLD-TDP A
• Frequency of meeting possible or probable FTDC criteria
Parkinsonism
Neuropath FTLD-TDP B
FTLD-TDP A
FTLD-TDP (U)
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Genetic vs. Sporadic FTD
Whitwell et al. Brain 2012
Final Conclusions
• Clinical dx: behavioral-variant FTD (with
prominent language disturbance)
• Predicted pathology (in order of
likelihood):
1.
2.
3.
4.
FTLD-TDP, type B; sporadic or C9ORF72
FTLD-TDP, type A/U
FTLD-Tau (Pick, PSP, CBD) less likely
AD unlikely to be primary pathology
Tau PET in FTD: [18F]AV1451
Spina et al. Neurology 2017
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
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
ROS
• Dysphagia
• Bradykinesia
• Incontinence
68 year-old left-handed man with progressive cognitive impairment
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Ancillary Testing
Year 1
• Difficulty fixing up cars
• Basic serum studies including B12 and TFTs were
unremarkable
Year 2
• Trouble understanding his wife in conversation
• Hearing aid no improvement
• MRI Brain:
Year 3
• Repeating conversations, word-finding difficulty, substitute/mispronounce words
• Paucity of speech (down 25%), spoke with softer voice
– 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
• 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
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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 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
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
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Pathology Discussion
68 year-old left-handed man with progressive cognitive impairment
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
RAIN 2017
CPC
Pathology
• 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?
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
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2/10/2017
bvFTD
SD
FTD-MND
PNFA
CBS
PSPS
Pick’s
3R tau
FTDP-17
(MAPT)
CBD
4R tau
FTLD-TDP*
PSP
4R tau
Tau NOS
MST/AGD
Type A
Type B
(C9orf72)
(TARDP?)
Type C
Type D
(VCP)
Courtesy W. Seeley, UCSF
aFTLD-U
NIFID
FTLD-tau
(CHMP2b)
BIBD
Pick’s
3R tau
???
FTDP-17
(FUS)
(MAPT)
*Harmonized scheme
Weight: 1066 g
FTD-MND
PNFA
CBS
PSPS
Alzheimer’s
Disease
Frontotemporal lobar degeneration (FTLD)
FTLD-3
FTLD-FUS
(PGRN)
(C9orf72)
SD
Alzheimer’s
Disease
Frontotemporal lobar degeneration (FTLD)
FTLD-tau
bvFTD
CBD
4R tau
FTLD-TDP*
PSP
4R tau
Tau NOS
MST/AGD
Type A
Type B
(PGRN)
(C9orf72)
(C9orf72)
(TARDP?)
Type C
Type D
(VCP)
FTLD-3
FTLD-FUS
aFTLD-U
NIFID
Courtesy W. Seeley, UCSF
(CHMP2b)
BIBD
???
(FUS)
*Harmonized scheme
UCSF/MAC Neurodegenerative
Disease Brain Bank
R
18
2/10/2017
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
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TDP-43
Beta-amyloid
IFG
ITG
*
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
Immunohistochemistry
for p62 - cerebellum
The signature pathology
3R- and 4 Repeat-tau
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
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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 mid60’s that progressed over 7 years
– Cognitive domains:
1.
2.
Executive
Behavior + Language
1.
2.
Anterior-predominant hypometabolism
Severe L>R frontal & anterior temporal lobe atrophy
– Brain Imaging:
• Clinical Dx: behavioral-variant Frontotemporal
Dementia
• Pathological Dx: FTLD-TDP associated with mutation
in C9ORF72
Epidemiology
behavioral-variant
Frontotemporal Dementia
• 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 autopsyconfirmed FTLD
Knopman et al, J Mol Neurosci 2011
Snowden 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 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
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
23