Dementia and Degenerative Disorders PDF

## Dementia and Degenerative Disorders ### I. Basic Principles - Characterized by loss of neurons within the gray matter - Often due to accumulation of protein which damages neurons. ### II. Alzheimer Disease (AD) - Degenerative disease of cortex; most common cause of dementia. - **Clinical Feat...

## Dementia and Degenerative Disorders ### I. Basic Principles - Characterized by loss of neurons within the gray matter - Often due to accumulation of protein which damages neurons. ### II. Alzheimer Disease (AD) - Degenerative disease of cortex; most common cause of dementia. - **Clinical Features:** - Slow-onset memory loss (begins with short-term memory loss and progresses to long-term memory loss) and progressive disorientation. - Loss of learned motor skills and language. - Changes in behavior and personality. - Patients become mute and bedridden; infection is a common cause of death. - Focal neurologic deficits are not seen in early disease. - **Most cases (95%) are sporadic and seen in the elderly** - Risk increases with age (doubles every 5 years after the age of 60). - ε4 allele of apolipoprotein E (APOE) is associated with increased risk, ε2 allele with decreased risk. - **Early-onset AD is seen in** - Familial cases-associated with presenilin 1 and presenilin 2 mutations. - Down syndrome-commonly occurs by 40 years of age. - **Morphologic Features include** - Cerebral atrophy with narrowing of the gyri, widening of the sulci, and dilation of the ventricles. - **Neuritic Plaques:** extracellular core comprised of Aβ amyloid with entangled neuritic processes. - Aβ amyloid is derived from amyloid precursor protein (APP), which is coded on chromosome 21. APP normally undergoes alpha cleavage; beta cleavage results in Aβ amyloid. - Amyloid may also deposit around vessels, increasing the risk of hemorrhage. - **Neurofibrillary Tangles:** intracellular aggregates of fibers composed of hyperphosphorylated tau protein. - Tau is a microtubule-associated protein. - Loss of cholinergic neurons in the nucleus basalis of Meynert. - **Diagnosis is made by clinical and pathological correlation.** - Presumptive diagnosis is made clinically after excluding other causes. - Confirmed by histology at autopsy (when possible). ### III. Vascular Dementia - Multifocal infarction and injury due to hypertension, atherosclerosis, or vasculitis. - 2nd most common cause of dementia. ### IV. Pick Disease - Degenerative disease of the frontal and temporal cortex; spares the parietal and occipital lobes. - Characterized by round aggregates of tau protein (Pick bodies) in neurons of the cortex. - Behavioral and language symptoms arise early; eventually progresses to dementia. ### V. Parkinson Disease - Degenerative loss of dopaminergic neurons in the substantia nigra of the basal ganglia. - Nigrostriatal pathway of basal ganglia uses dopamine to initiate movement. - Common disorder related to aging; seen in 2% of older adults. - Unknown etiology; historically, rare cases were related to MPTP exposure (a contaminant in illicit drugs). - **Clinical features ('TRAP')** - Tremor-pill rolling tremor at rest; disappears with movement. - Rigidity-cogwheel rigidity in the extremities. - Akinesia/bradykinesia-slowing of voluntary movement; expressionless face. - Postural instability and shuffling gait. - **Histology reveals loss of pigmented neurons in the substantia nigra and round, eosinophilic inclusions of a-synuclein (Lewy bodies) in affected neurons.** - Dementia is a common feature of late disease. - Early-onset dementia is suggestive of Lewy body dementia, which is characterized by dementia, hallucinations and parkinsonian features; histology reveals cortical Lewy bodies. ### VI. Huntington Disease - Degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia. - Autosomal dominant disorder (chromosome 4) characterized by expanded trinucleotide repeats (CAG) in the huntingtin gene. - Further expansion of repeats during spermatogenesis leads to anticipation. - Presents with chorea that can progress to dementia and depression; average age at presentation is 40 years. - Suicide is a common cause of death. ### VII. Normal Pressure Hydrocephalus - Increased CSF resulting in dilated ventricles. - Can cause dementia in adults; usually idiopathic. - Presents as triad of urinary incontinence, gait instability, and dementia ("wet, wobbly, and wacky"). - Lumbar puncture improves symptoms; treatment is ventriculoperitoneal shunting. ### VIII. Spongiform Encephalopathy - Degenerative disease due to prion protein. - Prion protein is normally expressed in CNS neurons in an a-helical configuration (PrPc). - Disease arises with conversion to a β-pleated conformation (PrPsc). - Conversion can be sporadic, inherited (familial forms of disease), or transmitted. - Pathologic protein is not degradable and converts normal protein into the pathologic form, resulting in a vicious cycle. - Damage to neurons and glial cells is characterized by intracellular vacuoles (spongy degeneration). - Creutzfeldt-Jakob disease (CJD) is the most common spongiform encephalopathy. - Usually sporadic; rarely can arise due to exposure to prion-infected human tissue (e.g., human growth hormone or corneal transplant). - Presents as rapidly progressive dementia associated with ataxia (cerebellar involvement) and startle myoclonus. - Periodic sharp waves are seen on EEG. - Results in death, usually in < 1 year. - Variant CJD is a special form of disease that is related to exposure to bovine spongiform encephalopathy ('mad cow'). - Familial fatal insomnia is an inherited form of prion disease characterized by severe insomnia and an exaggerated startle response.