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DEMENTIA.

DEMENTIA. NEUROLOGY SUBSPECIALITY SEMINAR. Sept 20, 2006. DEMENTIA. Defn :- an acquired deterioration in cognitive abilities; - impairs the successful performance of activities of daily living. - affects > 4million Americans.

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DEMENTIA.

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  1. DEMENTIA. NEUROLOGY SUBSPECIALITY SEMINAR. Sept 20, 2006.

  2. DEMENTIA. Defn:- an acquired deterioration in cognitive abilities; - impairs the successful performance of activities of daily living. - affects > 4million Americans. * Cognitive abilities lost in dementia: Memory (most common), language, visuo- spatial ability, calculation, judgement.

  3. …ctnd • Neuropsychiatric & social deficits. - depression; - delusion; - agitation; - hallucination; - withdrawal; - insomnia; - disinhibition. * Dementia:- commonly progressive; - sometimes static or fluctuates dramatically from day to day.

  4. …ctnd MEMORY. Three major storage buffers - 1) WORKING ~ :- lasts <30sec; limited storage capacity; 7+2 bits of info in ~ . - ↑ ly vulnerable to distraction. TEST? → RAS, prefrontal & parietal lobe networks.

  5. …ctnd 2) EPISODIC ~ :- min – mths; or even yrs. - ‘what’, ‘where’, & ‘when’. - multiple ~/ day → informn consolidated. TEST? → Hippocampal Cpx: vulnerable to metabolic insults. New ~ → physiologic changes in synapses → Neocortex.

  6. …ctnd 3) REMOTE/LONG-TERM/ ~: wks – lifetime. - most of personal experiences and knowledge. → Lt anterior temporal cortex; ? Neocortex. - new protein synthesis required for ~. - stabilization process: physical changes at neuronal synapses .

  7. …ctnd Components of memory Fn. • Registration: frontal lobes, hippocampal complex. • Retention. • Stabilization. • Retrieval: frontal lobes.

  8. …ctnd * Semantic memory: anterior temporal neocortex. * Declarative memory: episodic memory prototypical example. * Procedural memory: Amygdala, basal ganglia, cerebellum, sensory cortex. * Executive Fn: planning, initiating, & regulating behaviour; frontal lobes.

  9. …ctnd FUNCTIONAL ANATOMY. Dementia:- the result of quantity & location of neuronal loss. Episodic memory: dorsomedial nucleus of the thalamus + medial temporal lobes. - Unilateral lesion: mild-moderate amnesia. - Bilateral lesion: severe anterograde learning disorder.

  10. …ctnd The medial temporal lobe memory system. • components: the hippocampus & adjacent cortex; fast, limited capacity. • Crucial fn: learning & establishing declarative memory & semantic assocn. • Learning →reorganization & consolidation → memory stored in neocortex.

  11. …ctnd • Cholinergic system: important role in memory → choline acetyltransferase, cholinergic receptors, Nucleus basalis of Meynert = deficient in AD. • Behavior & mood: NA, serotonergic, and dopaminergic pathways. • LTP: involved in memory acquisition & storage; occurs in the hippocampus.

  12. …ctnd CAUSES OF DEMENTIA. • Age group, country, access to medical care, racial/ethnic background. • Reversible / Irreversible. • The single strongest risk factor: AGE. • Benign forgetfulness of the elderly. • Mild cognitive impairment (MCI). MCI → AD (12% / yr).

  13. APPROACH TO THE PATIENT. • 3 MAJOR ISSUES: - most accurate Dx. - treatable or reversible component? - alleviation of burden on caregivers. Hx:- Onset, duration, tempo of progression. - Specific clinical patterns of disease. - Systemic diseases; drugs/toxins; - Occupation; deficiencies;psychiatric dis.

  14. …ctnd P/E. • Document dementia. • Systemic diseases. • Specific clinical findings of the dementias. • Detailed neurologic exam. COGNITIVE & NEUROPSYCHIATRIC exam - MMSE: confirm Dx, follow-up, Px. - Functional assessment.

  15. …ctnd LAB TESTS. - AAN: Routine- TFT, vit B12 level, CT/MRI.

  16. ALZHEIMER’S DISEASE (AD). EPIDEMIOLOGY. • Most common cause of dementia in western countries. • Most important risk factors: old age & + family Hx; other: female gender. • >70yrs : 10% significant memory loss (>50% due to AD);>85yrs: 20-40% of popl. • Env’tal factors: No significant role.

  17. …ctnd PATHOLOGY. - Hippocampus, temporal cortex, nucleus basalis of Meynert: severe pathology. • Microscopy: Neuritic plaques, NFTs. • Neuritic plaqes:Aβ amyloid, proteoglycans, Apo є4, α1antichymotripsin. Aβ amyloid in cerebral arterioles: amyloid angiopathy→ cerebral lobar hemorrhages.

  18. ..ctnd -NFTs:silver staining, twisted neurofilaments in neuronal cytoplasm. • ↓ Ach, choline acetyltransferase, & nicotinic cholinergic receptors in cortex. • ↓ NE levels in locus coeruleus (brain stem). GENETICS. • APP gene, chrom 21. • Presenilin-1 (PS-1) on chrom 14; S182.

  19. …ctnd 3) Presenilin-2 (PS-2): chrom 1; STM2. * Both 2) & 3)→ ↑ plasma Aβ42 amyloid. 4) Apo є gene: chrom 19 – late onset familial & sporadic AD. * three alleles: 2, 3, 4; Apo є 4 allele has strong association with AD. • Apo є testing: in demented patients who meet clinical criteria of AD.

  20. …ctnd CM. • cognitive ∆es begin with memory impairment → language & visuospatial deficits. • 20% of pts: Nonmemory complaints such as → word-finding, organizational, or navigational difficulty.

  21. …ctnd EARLY STAGES. • Subtle memory loss; benign forgetfulness. • MCI: memory loss < 1.5 SD from normal. • Progressive interference with daily activities. • Patients : Anosognosia OR considerable insight. • ∆ of env’t may be bewildering.

  22. …ctnd MIDDLE STAGES. • Unable to work, easily lost, confused. • Requires daily supervision. • Social conduct, routine behaviours: OK. • Naming → Comprhension → Fluency. • Apraxia. • Visuospatial deficits.

  23. …ctnd LATE STAGES. • Some pts: ambulation W/o purpose. • Judgement, reason, cognition are lost. • Delusions: common; Capgras synd(10%). • Disinhibition, aggression ↔ passivity. • Disturbed sleep-wake patterns. • Some pts: parkinsonian features; but rarely have tremor.

  24. …ctnd END-STAGE. • Rigid, mute, incontinent, & bedridden. • The simplest tasks need aid. • ↑ DTR; myoclonic jerks ( spont.,induced) • Generalized Szs may occur. • DEATH: 20 to malnutrition, secondary infections, pulmonary emboli,or Ht disease *Typical duration of AD: 8 – 10yrs[ 1-25yrs].

  25. …ctnd DIAGNOSIS. • EARLY:- R/O other etiologies of dementia. - CT/MRI may be normal. • As AD PROGRESSES. * CT/MR: diffuse cortical & hippocampal atrophy; 20 enlargement of ventricles. * Fnal imaging studies. * EEG, routine CSF exam: Normal. * Blood Apo є genotyping.

  26. …ctnd Rx. • No cure; No highly effective drug. • Mx focuses on: - judicious cholinesterase inhibitor use, - Smc Mx of behavioural disorders, - building rapport with the pt, family members, & other caregivers.

  27. …ctnd • FDA approved cholinesterase inhibitors: - Tacrine ( expensive, hepatotoxicity.) - Donepezil (Not hepatotoxc, 5-10mg qd.) - Rivastigmine. - Galantamine. ═> * improve caregiver ratings, * ↓ rate of cognitve test score decline over a period of upto 3 yrs.

  28. …ctnd • ERT : controversial results on protection. • Antioxidants:- in moderately advanced AD. * selegline. * Vit E 1000U BID (inexpensive, ↓SE). ═> both slowed institutionalization & progression to death. • (one study): Memantine [ an NMDA receptor antagonist]- slowing of disease progression over a 28 wk course.

  29. …ctnd • Vaccination Vs Aβ protein: not safe in human trials. • SSRIs: for mild-moderate depression. • Mx of behavioural disturbances.

  30. VASCULAR DEMENTIA. • Two general categories: 1)Multi-infarct dementia. - multiple strokes → chronic cognitive deficits. - Strokes: large or small; several d/t regions of the brain. - Occurrence of dementia → total volume of damaged cortex.

  31. …ctnd * Hx:- discrete episodes of sudden, stepwise neurologic deterioration. - HTN, DM, CAD. * P/E:- focal neurologic deficits. * Neuroimaging: multiple areas of infarction. • Normal aging:cerebral amyloid angiopathy of aging→ Hemorrhagic lobar stroke. • AD + amyloid angiopathy:↑ cerebral infarction.

  32. …ctnd 2) Diffuse white matter disease. / Binswanger’s Disease/. - insidious onset dementia, progresses slowly. - early Sms: mild confusion, apathy, depression, psychosis, personality ∆es, memory or executive fns. - Later: Judgement difficulties, dependence on others.

  33. …ctnd - euphoria, elation, depression, or aggressive behaviour. - Both pyramidal & cerebellar Sns may be present in the same pt; gait disorder:50%. - Advanced disease:urinary incontinence, with or w/o pseudobulbar palsy. Minority of pts: Szs & myoclonic jerks. * Pts usually have a Hx of HTN.

  34. …ctnd CADASIL. • AD; diffuse white matter disease. • Progressive dementia; 5th-7th decade, • Multiple family members; Hx of migraine with or w/o HTN. • Skin Bx: Xc dense bodies( media of aa.) • Mutations in the notch 3 gene. • No known Rx.

  35. …ctnd Rx of Vascular Dementia. • Rx of HTN, DM, atherosclerosis. • Recovery of lost cognitive Fn not likely. - Anticholinesterase Cpds appear to be useful.

  36. FRONTOTEMPORAL DEMENTIAS & RELATED DISORDERS. FRONTOTEMPORAL DEMENTIA. - Often b/n 50 & 70 yrs; prevalence ~AD. • M=F; Sporadic or familial. • Behavioral Sms often predominate in the early stages, unlike AD. • Clinically heterogenous: disinhibition, dementa, apraxia, parkinsonism, motor neuron disease.

  37. …ctnd • Many families: AD pattern; • Mutations: tau gene, chrom 17. • Other families: chrom 3 & 9 linked to FTD. • Early Sms: cognitive, behavioral, & sties motor abnormalities→ degeneration of anterior frontal & temporal regions, basal ganglia & motor neurons.

  38. …ctnd * Cognitive presentations: - spare memory, - involve planning, judgement, or language. - insight severely impaired. * Behavioural deficits: - apathy, disinhibition, weight gain, - food fetishes, compulsions, euphoria.

  39. …ctnd * Asymmetric Lt frontal cases: Nonfluent aphasias → → Mutism. * Lt anterior temporal degeneration: Semantic dementia → visual agnosia. ═> primary progressive aphasia. * Rt frontal or temporal cases: loss of empathy, disinhibition, antisocial behavior.

  40. …ctnd • Memory & visuospatial skills are relatively spared in most FTD pts. • Anatomic hallmark of FTD: marked atrophy of temporal &/or frontal lobes. • Microscopy: gliosis & neuronal loss; swollen neurons with tau staining cytoplasmic inclusions. • Depletion of seratonergic & glutamatergic neurons; cholinergic system relatively OK.

  41. …ctnd Pick’s disease:-same anatomic involvement as FTD, but Pick’s bodies stain for both silver & tau. Rx of FTD. • Smc; No Rx to slow progression or improve cognitive Fn. • Serotonin-modifying antidepressants → behavioral changes in FTD.

  42. …ctnd PROGRESSIVE SUPRANUCLEAR PALSY. • A sporadic neurodegenerative disease. • 6th-7th decades; unknown etiology. • Progresses faster than PD:Death in 5-10yr • Falls & a vertical supranuclear gaze palsy → symmetric rigidity & dementia. • Xc: a stiff, unstable posture with hyper- extension of the neck & slow gait; freq’t falls.

  43. …ctnd • Freq’t falls due to axial rigidity, inability to look down, & bad judgement. • Tremor is distinctly uncommon. • Dementia often precede the motor synd. & usually present at the time of presentation. • PSP often confused with PD[ 20% of pts: dementia, often 20 to DLB.]

  44. …ctnd • * Dementia in PD: - ↑ ing age; - a long disease duration; - ↑ ing severity of extrapyramidal Sns; - presence of depression. • MRI: midbrain atrophy. • PET: symmetric frontal & striatal hypometabolism.

  45. Rx: response generally not highly effective for antiparkinsonian medications.

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