Cognitive Decline

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Cognitive Decline

  1. 1. Cognitive Decline • AD (family history; usually begins as aMCI, in 70’s, 80’s) • Pick Complex – FTLD (Semantic Dementia, bvFTD, PNFA); FTLD-t; FTLD-u – Progressive Supranuclear Palsy – Corticobasal Degeneration – Pick’s Disease – ALS-FTD • Vascular – 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
  2. 2. Shortness of Breath • CHF – Cardiomyopathy – Acute MI – Neurogenic (e.g. SAH, stroke) – Atrial fibrillation • Pneumonia – Aspiration (Dysphagia) – Infectious – Interstitial • Idiopathic Pulmonary Fibrosis • Neuromuscular Disease – ALS – MG – Polymyositis, dermatomyositis
  3. 3. Dysphagia • Obstructive • Neurogenic – Brain • 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)
  4. 4. Renal Failure • Dehydration – Poor intake secondary to dysphagia – Vomiting (hyponatremia, hyperkalemia) • Dye • Medications • Infections • Amyloidosis • Wegener’s (affects brain, lung, as well as kidney)
  5. 5. 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.
  6. 6. 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
  7. 7. Pathological Classification of FTLD/Pick Complex • Tau-opathies – 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
  8. 8. 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
  9. 9. 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
  10. 10. Dementia with Lewy Bodies • 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
  11. 11. Parkinson’s • Parkinson’s Disease – 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
  12. 12. Neoplastic • 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
  13. 13. Infectious • HIV – Subcortical cognitive decline • Slow, poor recall, poor executive dysfunction • Lyme – Sero-positive, + CSF – Can cause arrhythmia – No fever – Too chronic • West Nile – No fever – Too chronic
  14. 14. 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
  15. 15. 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.
  16. 16. Does Exam Help? • AD should have normal neurological exam except dementia • ALS-FTD should have: – 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
  17. 17. Does Imaging Help? • AD: – 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
  18. 18. 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

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