Creutzfeldt-Jakob Disease, Parkinson's Disease & Huntington's Disease

Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy, technically categorized as an infectious disease. The pathology of CJD stems from the accumulation of misfolded prion protein (PrP), which undergoes a transformation from an alpha-helix conformation (PrPc) to beta-pleated sheets (PrPsc). PrPsc induces the transformation of normal PrPc into more of itself, catalyzing prion accumulation. Histological manifestations of CJD involve vacuole formation, predominantly in gray matter structures like the caudate nucleus and putamen, that eventually evolve into cysts without accompanying inflammation, resulting in the characteristic ‘spongy’ appearance of the grain. Clinically, CJD presents as rapidly progressing dementia over weeks to months, with myoclonus being a cardinal motor symptom. EEG can be helpful in diagnosis, showing periodic sharp wave complexes

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder with 100% penetrance. HD arises from a CAG trinucleotide repeat expansion on chromosome 4. HD also displays anticipation, a phenomenon where subsequent generations manifest the disease at an earlier age and with increased severity due to the expansion of the trinucleotide repeat. Notably, paternal inheritance usually results in more severe disease outcomes due to higher CAG expansion during spermatogenesis. Pathologically, HD causes significant striatum atrophy, especially in the caudate nucleus, leading to the appearance of enlarged ventricles (hydrocephalus ex-vacuo). Loss of the inhibitory neurotransmitter GABA is the most common biochemical change. Clinically, it typically manifests between ages 30-50, and leads to chorea—rapid, involuntary or arrhythmic movement involving the face, trunk, and extremities. However, psychobehavioral changes (aggression, apathy, depression) often arise years before the onset of motor symptoms.

Parkinson's Disease is a neurodegenerative disorder primarily characterized by bradykinesia, or slowed movement. In patients presenting with parkinsonism—a syndrome that mirrors Parkinson's Disease symptoms—distinct clinical features can be observed. These include a "pill-rolling" tremor, typified by an involuntary circular movement of the fingers; "cogwheel" rigidity, which is a ratchety pattern evident upon passive movement of the extremities; pronounced postural instability leading to a heightened risk of falling; and a shuffling gait, a consequence of the combined effects of bradykinesia and postural instability.

Parkinson's disease (PD) stems from the degeneration of dopaminergic neurons in the substantia nigra's pars compacta region, resulting in decreased dopamine levels. In PD, there is a noticeable pale appearance in the substantia nigra due to this neuronal loss, as the dopaminergic neurons typically contain dark pigmented neuromelanin. Lewy bodies are also found in the substantia nigra in PD.

The underlying mechanism driving the motor dysfunction in Parkinson's disease is multifaceted. The loss of function in the substantia nigra leads to the disinhibition of the striatum. This, in turn, activates the subthalamic nucleus, which subsequently inhibits the thalamus, leading to decreased motor function. Dysfunction in the substantia nigra also activates the striatum, further stimulating the subthalamic nucleus and inhibiting the thalamus, thereby exacerbating motor dysfunction.

Symptoms of Parkinsonism can arise from certain drugs and conditions. First-generation antipsychotics, which are D2 dopamine antagonists, are known to elicit Parkinsonism symptoms. Additionally, in the context of Wilson's disease—a defect in copper metabolism that results in cirrhosis—there is an accumulation of copper in the striatum. This, coupled with the direct binding of dopamine by free copper, can induce Parkinsonism. Deep brain stimulation, a neurosurgical procedure that implants electrode in the brain that inhibit the subthalamic nucleus, can be used to improve symptoms in PD.