Transcript Cognitive Decline - Hopkins Medicine

Cognitive Decline
• AD (family history; usually begins as aMCI, in 70’s, 80’s)
• Pick Complex
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FTLD (Semantic Dementia, bvFTD, PNFA); FTLD-t; FTLD-u
Progressive Supranuclear Palsy
Corticobasal Degeneration
Pick’s Disease
ALS-FTD
• Vascular
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Multiple infarcts
Small vessel disease
Vasculitis (e.g. CNS Vasculitis, Wegener’s)
Amyloid angiopathy
CADASIL
• Dementia with Lewy Bodies
• Parkinson’s Disease, Parkinson’s Plus syndromes
• Neoplastic (mets, primary brain tumors, carcinomatous or lymphomatous
meningitis)
• Paraneoplastic (limbic or extralimbic) encephalitis
• Normal pressure hydrocephalus
Shortness of Breath
• CHF
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Cardiomyopathy
Acute MI
Neurogenic (e.g. SAH, stroke)
Atrial fibrillation
• Pneumonia
– Aspiration (Dysphagia)
– Infectious
– Interstitial
• Idiopathic Pulmonary Fibrosis
• Neuromuscular Disease
– ALS
– MG
– Polymyositis, dermatomyositis
Dysphagia
• Obstructive
• Neurogenic
– Brain
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Neurodegenerative (e.g. PSP)
Vascular (usually brainstem when chronic)
Tumor
Infection
Motor Neuron (e.g. ALS)
NM junction (e.g. MG)
Lower motor neuron (e.g. GBS)
Muscle (e.g. Polymyositis; oculopharyngeal muscular
dystrophy)
Renal Failure
• Dehydration
– Poor intake secondary to dysphagia
– Vomiting (hyponatremia, hyperkalemia)
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Dye
Medications
Infections
Amyloidosis
Wegener’s (affects brain, lung, as well as kidney)
AD
• Progressive decline in memory & 1+ other domain of
cognition
• family history (but not especially important unless
there is family history of early onset AD, in 40’s or 50’s;
usually APP or presenilin I or II mutation)
• usually begins as amnestic MCI
• Usually begins in 70’s or 80’s
• Histology: Amyloid plaques & neurofibrillary tangles
• Can’t account for dysphagia, SOB, gait impairment, or
renal failure. AD patients have poor p.o. intake
because they forget to eat.
Pick Complex: Clinical Subtypes
• FTLD (Semantic Dementia, bvFTD, PNFA)
– Primary Progressive Aphasia &/or
– Change in personality, comportment, behavior
• Progressive Supranuclear Palsy syndrome
– Dysphagia, Dysarthria (UMN, “spastic”), pseudobulbar
lability
– Falls, Gait Disorder
– Impaired eye movements
– Dementia
– Usually begins in 50’s or 60’s
• Corticobasal Syndrome (spastic hemiparesis, apraxia)
• ALS-FTD
– Dysphagia, Dysarthria (UMN + LMN)
– Falls, Gait Disorder, Weakness, Spasticity
– Usually begins in 40’s, 50’s, or 60’s
All can be associated with Parkinsonism, Rigidity, Tremor
Pathological Classification of FTLD/Pick
Complex
• Tau-opathies
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Pick’s Disease (Pick bodies)
PSP
Corticobasal degeneration
ALS-Parkinsonism-Dementia Complex of Guam
Tangle dominant dementia
Diffuse neurofibrillary tangle demenia with
calcifications
– Agyrophilic grain disease
– Sporadic multisystem tauopathy
Pathological Classification of FTLD/Pick
Complex
• Ubiquitinopathies
– TDP 43: FTLD-U types 1-4 (ALS-FTD, FTD, ALS)
– FTLD-PLS
– FTLD-non-TDP (many have hippocampal sclerosis)
• Other
– DLDH: Dementia Lacking Distinctive Histology
– Basophilic inclusion body disease
– FTLD+ CHMP2B
– Neurofilament inclusion body disease
Vascular Cognitive Decline
• Multiple infarcts
– Just has one lacune
• Small vessel disease
– Mild to moderate
• Vasculitis
– No large vessel strokes
– No headaches
• Amyloid angiopathy
– No hemorrhage on CT (but dx requires gradient
echo/susceptability/ “hemosiderin” MRI
• CADASIL
– Too old, no family history, no headache
Dementia with Lewy Bodies
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Parkinsonism (tremor, rigidity, gait disorder…)
Hallucinations
Marked fluctuations in mental state
Marked visuospatial deficits
Autonomic dysfunction
– Orthostatic hypotention
• Sensitivity to neuroleptics
Can’t account for dysphagia, SOB, gait impairment, or renal failure
Parkinson’s
• Parkinson’s Disease
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Unilateral onset
Bradykinesia, bradyphrenia
Tremor
Rigidity
Gait disorder, falls
Subcortical cognitive decline
Can have dysphagia and dementia, but usually not so
prominent
• Parkinson’s Plus syndromes:
– Multisystem Atrophy
– Shy-Drager
Neoplastic
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Brain mets
primary brain tumors
carcinomatous or lymphomatous meningitis
Gliomatosis cerebrii
Paraneoplastic encephalitis
• CT negative for tumor
• Too chronic for neoplastic meningitis or
gliomatosis cerebrii
Infectious
• HIV
– Subcortical cognitive decline
• Slow, poor recall, poor executive dysfunction
• Lyme
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Sero-positive, + CSF
Can cause arrhythmia
No fever
Too chronic
• West Nile
– No fever
– Too chronic
What can account for cognitive decline
+ SOB + Dysphagia?
• “Proteinopathies” – protein misfolding disorders
• ALS-FTD
– Usually ubiquitin-opathy
• usually TDP-43; transactivation response (TAR) DNA binding protein,
molecular weight 43 kDa
– Nuclear protein involved in transcription, alternative splicing
– Cytoplasmic inclusions
• 4 subtypes; distinct distributions cause SD, ALS-FTD or bvFTD, bvFTD
– Many have progranulin mutation 17q21 (PRGN);
– Others have mutations in 9q21-12 (VCP) or 9p21-13 or CHMP2B
– Family history in 7.7% (ALS) to 62.% (FTD; FTLD-U)
• Geser et al., 2009; Archives of Neurology
– Bulbar onset with dysphagia and respiratory difficulty in 32-38%
– Onset is usually in 40’s-60’s, disease duration 1-4 years
What can account for cognitive decline
+ SOB + Dysphagia?
• Progressive Supranuclear Palsy
– Dysphagia & dysarthria, Falls, Parkinsonism/Rigidity,
Vertical Eye Movement Impairment, Dementia or Aphasia
– Tau-opathy (another protein misfolding disorder), specific
isoform often causes PSP
– Many have mutations in Chr 3 or 17q21 (MAPT) –
associated with variable isoforms of tau
– Same mutation can cause PSP in 1 family member,
corticobasal syndrome in another, and progressive
nonfluent aphasia or bvFTD (types of FTLD-t) in another
• Usually starts in 50’s or 60’s with duration of 6-12
years.
Does Exam Help?
• AD should have normal neurological exam except dementia
• ALS-FTD should have:
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Fasciculations (LMN)
Hyperreflexia (“reflexes appeared symmetric”)
Babinski &/or Hoffman signs (UMN)
Weakness (limb or bulbar); 3+ limbs but “poor effort”
Dysarthria (usually present if neurogenic dysphagia is present)
Dementia
• PSP should have:
– Impaired eye movements, dysphagia/dysarthria, rigidity or
tremor, gait impairment, dementia
Does Imaging Help?
• AD:
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Bilateral temporoparietal atrophy on CT, MRI
Bilateral temporoparietal hypoperfusion on SPECT
Bilateral temporoparietal hypometabolism on PET
(+PIB in amyloid PET)
• ALS-FTD
– Asymmetric fronto/temporal atrophy on CT, MRI
– Asymmetric fronto/temporal abnormalities on PET or SPECT or
MRS
• PSP (and other tau-opathies)
– May see frontal &/or parietal atrophy on CT, MRI
– + midbrain & superior cerebellar peduncle atrophy for PSP
• Vascular Dementia
– Strokes and/or white matter disease on CT, MRI
– Microhemorrhages on GRE/SWI MRI for amyloid angiopathy
Clinical Diagnosis
• Mixed dementia
– Protein-opathy (with some evidence of vascular
disease +/- AD)
• Most likely tau-opathy unless fasciculations or
hyperreflexia were missed on exam
– May have presented late due to his “cognitive
reserve”
• Physicists and other highly educated people often
compensate well for substantial cognitive decline
• This man’s obvious onset was about age 75, but decline
might well have started in his 60’s