Dementias and Degenerative Disorders

Impairment in ≥2 cognitive domains (e.g. aphasia, apraxia, agnosia, or impaired executive function)

Deficits interfere with activities of daily living

Gradual and continual decline

Other causes of dementia excluded

Acute or subacute onset of altered cognitive function characterized by waxing and waning consciousness / attention.

• Desc: Impairment in a single or multiple domains of cognitive function which does not impair performance
• - Amnestic subtype
• - Single, nonmemory subtype
• - Multiple, nonmemory subtype
• PX: 80% develop dementia in 6 years
• TX: Donepezil slows progression to dementia

Desc: requires impairment in 2 or more domains of cognitive function with memory being most affected

• Epi: Most comon dementia, 10% >65 y/o and 50% >80
• RF's: Female, Age, Low Education, Downs, Head Injury, APOE, Genetic

Path: accumulation of plaques and tangles

• Si/Sx:
• - Begins with short-term (semantic) memories followed by episodic then working memory (procedural spared)
• - Language anomia, poor comprehension
• - Behavioral Symptoms (e.g. delusions)

• DX:
• - LP: inc Tau, ubiquitin, 14-3-3; dec Aβ42
• - MRI: atrophy (especially hippocampal/MTL)
• - PET/SPECT/fMRI: rarietotemporal hypometabolism
• - Micro: amyloid plaques and tangles

• TX:
• - Donezepil (Aricept) AChEi
• - Galantamine (Reminyl) AChEi + allosteric modulator
• - Rivastigminev(Exelon) AChEi + butyrylcholinesterase
• - Memantine (Namenda) anti-NMDAr
• - Vitamin E

Epi: Younger onset (50's)

• Path:
• - 20% inherited (Chr 17, full penetrance) and 80% sporadic
• - FTD-17: inherited form, Chr 17, abnl Tau, a/w parkinsonism
• - FTD-MN: seen in ALS. SOD mutation on Chr 9
• - FTD-ldh: lacks distinctive histopathology, Ubiq+
• - FTD-picks: tau-positive inclusions s/ Chr 17 mutation

• Si/Sx:
• - Early behavioral / psychiatric changes including disinhibition, hypersexuality, poor hygeine
• - Emotional blunting and mental rigidity

DX: MRI showed frontal and anterior temporal wasting

• TX: SSRI's

• Epi: 2nd most common dementia after AD. 20-50% of stroke victims
• Si/Sx: dementia with evidence of cerebrovascular disease and a temporal correlation with them (abrupt onset, punctuated decline)

• Path: multiple etiologies
• - Chronic hypoperfusion of white matter
• - Lacunar infarctions (Binswanger’s disease)
  
• DX: MRI showed PVWM disease
• 
  TX:
• - AChEIs
• - Neurostimulants (Ritalin, Bromocriptine, Modafinil)
• - Underlying vascular RF's

Epi: 3rd most common clinically (~20%)

• Path: Most sporadic.
• - Synucleinopathy with Lewy Bodies that stain positive for it as well as ubiquitin
• - Senile plaques and tangles (<AD)

• Si/Sx: Chronic progression of demention with relative spating of memory and impairment of attention, verbal fluency, speed, and visuospatial tasks
• - Superimposed fluctuations in attention / alertness
• - Hallucinations (80%)
• - Parkinsonism
• - May also have falls, syncope, LOC, neuroleptic sensitivity, delusions, and REM b/h d/o

DX: MRI often normal vs diffuse atrophy

• TX:
• - AChEi's
• - Dopaminergic Agents
• - Atypical Neuroleptics
• - SSRI's
• - CZP and Melatonin for REM b/h d/o
• - Fludrocortisone / Midodrin for autonomic symptoms

• Alzheimer's Disease
• Corticobasal Ganglionic Degeneration
• Frontotemporal Dementia
• Pick's Disease
• Progressive Supranuclear Palsy

Nonfluent aphasia with decreased speech output progressing to mutism

• Dementia with Lewy Bodies
• Parkinson's Disease
• Multiple System Atrophy

• Triad of:
• - Dementia (bradyphrenia, dysorganized frontal, imp. WM)
• - Urinary Incontinence
• - Gait Ataxia

• DX:
• - MRI showing ventriculomegaly > atrophy
• - LP followed by cognitive assessment (MOCHA)

TX: Shunt

Group of rapidly progressive dementing disorders characterized by Ataxia, Myoclonus, and Pyramidal / Extrapyramidal Signs

• Subtypes:
• - sporadic (sCJD = 85%)
• - iatrogenic (iCJD = %)
• - variant (vCJG = %)

• Path:
• - Normal prion protein (PrPC) is in an a-helix
• - Infectious prion protein (PrPSC) is in a β-pleated sheet conformation and catalyzes PrPC to PrPSC
• - PrPSC is protease-resistant and accumulates in plaques

• DX:
• - CSF 14-3-3: sens. 95%, spec 85%
• - EEG slow waves --> 0.5-1 Hz periodic sharp waves
• - MRI showed inc T2 in cortex and thalamus (cortical ribbon and pulvinar signs)

Onset: 50-75 y/o

Course: acute or subacute onset lasting ~7 months

Early cognitive memory, concentration, personality changes) and neurovegetative (dec app, imp sleep) signs

Followed by development of Ataxia, Myoclonus, and both Pyramidal and Extrapyramidal signs

Onset: 27 years

Duration: 14 months

Seen in people homozygous for Met/Met at codon 129 of PRNP grane

Early psychiatric and sensory symptoms followed by dementia, myoclonus, and ataxia

Direct nnoculation of the patient by medical equipment or grafting (e.g. corneal, dural, or pericardial grafts)

Mutation of PRNO at 178 (Asp to Arg) in addition to Met/Met at 129

Onset: 48 (25-61)

Duration: 6m - 3y

• Insomnia followed by
• Dysautonomia (hypertension, tachycardia, hyperhydrosis)
• Ataxia
• Myoclonus
• Tremor

Cognitive function is often spared until later in the disease