Neurodegenerative & Demyelinating Disease

Dementias and Their Proteins

Alzheimer disease. The most common dementia. Extracellular β-amyloid plaques form from cleavage of amyloid precursor protein (APP), whose gene lies on chromosome 21, so Alzheimer disease appears early in Down syndrome. Intracellular neurofibrillary tangles are made of hyperphosphorylated tau. The brain shows widespread cortical and hippocampal atrophy, and acetylcholine is decreased from loss of cholinergic neurons (nucleus basalis of Meynert). Acetylcholinesterase inhibitors (donepezil) and the NMDA antagonist memantine give modest benefit.

Genetics. Early-onset familial Alzheimer disease involves APP (chromosome 21), presenilin-1 (chromosome 14), or presenilin-2 (chromosome 1). For late-onset disease, the ApoE4 allele (chromosome 19) raises risk, whereas ApoE2 is protective.

Dementia with Lewy bodies. Dementia plus recurrent visual hallucinations, spontaneous parkinsonism, fluctuating cognition, and REM sleep behavior disorder, with cortical Lewy bodies. Patients are severely sensitive to antipsychotics. When cognitive decline precedes or accompanies the parkinsonism, think Lewy body dementia rather than Parkinson disease.

Frontotemporal (Pick) dementia. Younger onset, with early personality and behavior change (disinhibition, apathy) or aphasia while memory is relatively spared. Frontotemporal atrophy is accompanied by tau-positive Pick bodies or TDP-43 inclusions.

Sort by tempo. Alzheimer disease is slow and progressive. Vascular dementia is stepwise, worsening after each infarct. Creutzfeldt-Jakob disease, a prion disease in which misfolded β-sheet prion protein causes spongiform change, is rapidly progressive over weeks to months with startle myoclonus; CSF 14-3-3 protein and periodic sharp-wave complexes on EEG support it. Reversible causes to exclude are vitamin B12 deficiency, hypothyroidism, and normal pressure hydrocephalus.

Normal pressure hydrocephalus is "wet, wacky, and wobbly": urinary incontinence, dementia, and a magnetic gait from enlarged ventricles, potentially reversible with a shunt.

Movement and Motor Neuron Disorders

Parkinson disease. Loss of dopaminergic neurons in the substantia nigra pars compacta, seen as depigmentation, with intracytoplasmic α-synuclein Lewy bodies. The cardinal signs are TRAP: resting (pill-rolling) Tremor, cogwheel Rigidity, Akinesia or bradykinesia, and Postural instability, plus masked facies and a shuffling gait. Levodopa with carbidopa replaces the missing dopamine.

Huntington disease. Autosomal dominant CAG trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4, with anticipation (earlier, worse disease in successive generations). Atrophy of the caudate and putamen, with loss of GABAergic and cholinergic neurons, causes ex vacuo dilation that makes the frontal horns look like boxcars. Chorea, dementia, and psychiatric change begin in the 30s to 40s. Other trinucleotide repeats: CGG in fragile X, CTG in myotonic dystrophy, GAA in Friedreich ataxia.

Amyotrophic lateral sclerosis (ALS). Degeneration of both upper motor neurons (lateral corticospinal tract: spasticity, hyperreflexia, Babinski sign) and lower motor neurons (anterior horn: atrophy, fasciculations), with NO sensory or sphincter loss. Some familial cases carry SOD1 (superoxide dismutase) mutations, and C9orf72 repeat expansions link familial ALS with frontotemporal dementia. Riluzole, which decreases glutamate release, modestly prolongs survival.

Demyelinating Disease

Multiple sclerosis (MS). Autoimmune demyelination of CNS white matter targeting oligodendrocytes, classically in a woman aged 20–40 with a relapsing-remitting course. Lesions are disseminated in time and space: optic neuritis, internuclear ophthalmoplegia (MLF lesion), scanning speech, intention tremor, Uhthoff phenomenon (heat worsens symptoms), Lhermitte sign (electric shocks on neck flexion), and bladder dysfunction. Charcot's classic triad is scanning speech, intention tremor, and nystagmus (SIN).

MS diagnosis and treatment. MRI shows periventricular white-matter plaques oriented perpendicular to the ventricles (Dawson fingers), and CSF shows oligoclonal IgG bands with an increased IgG index. Acute attacks receive IV glucocorticoids. Disease-modifying agents include interferon-β, glatiramer, and natalizumab (anti-VLA-4 integrin), which carries a risk of PML. Baclofen treats spasticity, and fatigue is addressed as well.

Guillain-Barré syndrome. Acute inflammatory demyelinating polyradiculopathy: symmetric ASCENDING weakness and areflexia, often after Campylobacter jejuni or CMV infection, from molecular mimicry against peripheral (Schwann cell) myelin. CSF shows albuminocytologic dissociation (high protein, normal cell count). Watch for respiratory failure and autonomic instability. Treat with IVIG or plasmapheresis, NOT steroids. The Miller Fisher variant causes ophthalmoplegia, ataxia, and areflexia.

Progressive multifocal leukoencephalopathy (PML). Reactivation of JC virus destroys oligodendrocytes in immunosuppressed patients, such as those with AIDS and a low CD4 count or those receiving natalizumab or rituximab. MRI shows multifocal, nonenhancing white-matter lesions; focal deficits progress rapidly, and the disease is often fatal.

Osmotic demyelination syndrome (central pontine myelinolysis). Follows OVERLY RAPID correction of chronic hyponatremia, so sodium should rise by less than about 8 mEq/L per 24 hours. Demyelination of the pons causes acute paralysis, dysarthria, dysphagia, diplopia, and locked-in syndrome.

Low to high, your pons will die; high to low, your brain will blow: correcting hypernatremia too fast causes cerebral edema.

Neurotransmitter Changes

Disease-specific shifts. Each disorder has a characteristic neurochemical imbalance, and Parkinson and Huntington diseases are neurochemical opposites, which explains why dopamine blockers can worsen parkinsonism yet quiet chorea.