Degenerative and Dementing Disorders

DEGENERATIVE AND DEMENTING DISORDERS

Parkinson disease (PD) is a progressive neurodegenerative disease that involves genetic and environmental factors. The SNCA gene (alpha-synuclein) has been iden-tified as a risk factor, and gene mutations and multiplications are associated with familial PD, but the majority of cases are sporadic. PD is due to loss of dopaminergic neurons in the substantia nigra, leading to tremor, rigidity, and akinesia.

•         Parkinson disease is the idiopathic form

•         Parkinson syndrome is secondary to known injuries to the substantia nigra (e.g., infection, vascular condition, toxic insult).

Parkinson disease is common, affecting 2% of the population. Clinical onset is typi-cally in decades 5–8. Loss of dopaminergic neurons is still unexplained, though theories emphasize oxidative stress. Pesticides and meperidine have been associated with increased risk, while smoking and caffeine are protective.

On gross examination there is pallor of the substantia nigra. Histology shows loss of pigmented (dopaminergic) neurons in the substantia nigra. Residual neurons show Lewy bodies, which are intracytoplasmic round eosinophilic inclusions that contain α-synuclein. Electron microscopy shows filaments most likely of cytoskeletal origin. There is also a secondary degeneration of dopaminergic axons in the striatum.

Loss of the extrapyramidal nigrostriatal pathway leads to inhibition of movement of proximal muscles and disruption of fine regulation of distal muscles. Involvement of the amygdala, cingulate gyrus and higher cortical regions causes dementia and psychosis.

About 60% of patients experience dementia 12 years after diagnosis; 50% also expe-rience depression and psychosis. Those treated with medication (combination car-bidopa and levodopa) and surgery (deep brain stimulation) will become refractory to therapy.

A clinical diagnosis is difficult to make early in disease because symptoms overlap with other conditions. Early symptoms include hyposmia, constipation, and fatigue. Key features are bradykinesia, rigidity, tremor and postural instability. Early in the disease course, a response to levodopa can help confirm the diagnosis. Imaging studies are not useful in most cases.

Huntington disease (HD) is an autosomal dominant disorder. It is characterized pathologically by the degeneration of GABAergic neurons of the caudate nucleus, and clinically by involuntary movements, cognitive decline, and behavioral changes.

•         Affects those of northwestern European descent

•         Has an incidence in high-prevalence regions of 1/12,000–20,000

•         Gene (HTT), located on chromosome 4, codes for a protein called huntingtin

•   Mutations due to expansion of unstable cytosine-adenine-guanine (CAG) repeats

•   Shows features of anticipation and genomic imprinting

The pathophysiology is that loss of caudate nucleus GABAergic neurons removes inhibitory influences on extrapyramidal circuits, thus leading to chorea.

Clinical onset is typically in decades 3–5. The chorea is characterized by sudden, unexpected, and purposeless contractions of proximal muscles while awake. Psychi-atric symptoms may predate motor symptoms. Disease progression leads to depen-dency and death.

Gross examination shows atrophy of the caudate nucleus with secondary ventricular dilatation. Histology shows loss of small neurons in the caudate nucleus followed by loss of the larger neurons.

A definitive diagnosis can be based on clinical symptoms with an affected parent. Otherwise, DNA determination is the gold standard. Prenatal diagnosis and pre-implantation diagnostics are available. Treatment is medical therapeutics for chorea (dopamine receptor blocking or depleting agents).

Alzheimer disease (AD) causes 60% of all cases of dementia. It is the most common cause of dementia in people age >65.

•         Incidence is 2% at age 65 and doubles every 5 years

•         Risk factors include aging and significant head trauma

Aluminum is an epiphenomenon, not a risk factor

•         Protective factors include high level of education and smoking

About 5–10% of AD cases are hereditary, early onset, and transmitted as an autoso-mal dominant trait. There are 3 genes that cause autosomal dominant AD:

•         APP (amyloid precursor protein)

•         Presenilin 1 and 2 (PSEN1 and 2)

Carriers of APP and PSEN1 mutations develop early- onset AD. Other AD suscepti-bility genes have been identified. APOE is the largest effect locus for late-onset AD.

AD is characterized by amyloid-β deposition, neurofibrillary angle formation, and neuronal degeneration.

•         Abnormal proteins. Aβ amyloid is a 42-residue peptide derived from a normal transmembrane protein, the amyloid precursor protein (APP). There is also an abnormal tau (a microtubule-associated protein).

•         Neuritic plaques have a core of Aβ amyloid and are surrounded by abnormal neurites.

•         Neurofibrillary tangles are intraneuronal aggregates of insoluble cytoskeletal elements, mainly composed of abnormally phosphorylated tau forming paired helical filaments.

•         Cerebral amyloid angiopathy is accumulation of Aβ amyloid within the media of small and medium-size intracortical and leptomeningeal arteries; it may occur by itself and cause intracerebral hemorrhage.

•         Additional changes include granulovacuolar degeneration and Hirano bod-ies, which develop in the hippocampus and are less significant diagnostically.

Affected areas are involved in learning and memory. Lesions involve the neocortex, hippocampus, and several subcortical nuclei including forebrain cholinergic nuclei (i.e., basal nucleus of Meynert). The earliest and most severely affected are the hip-pocampus and temporal lobe. Small numbers of neuritic plaques and neurofibrillary tangles also form in intellectually normal aging persons.

Macroscopic changes include atrophy of affected regions, producing brains that are smaller (atrophic), with thinner gyri and wider sulci. Hippocampi and temporal lobes are markedly atrophic.

Clinical manifestations have insidious onset, typically beginning in decades 7–8. They include progressive memory impairment, especially related to recent events; alterations in mood and behavior; progressive disorientation; and aphasia (loss of language skills) and apraxia (loss of learned motor skills). Within 5–10 years patients become mute and bedridden.

No effective treatment is available for AD but there is mild improvement with inhibi-tors of acetylcholinesterase (e.g., tacrine).

Lewy body dementia is a progressive brain disease associated with the formation of Lewy bodies in neurons involving neocortex and subcortical nuclei. The etio-pathogenesis is obscure, with no known risk factors; it is the second leading cause of degenerative dementia in the elderly.

The histopathological hallmark is the Lewy body. Neuron loss accompanies Lewy body formation. Sites involved include the neocortex (especially the limbic system and cingulate gyrus), and subcortical nuclei, including basal nucleus of Meynert, amygdala, and substantia nigra.

The involvement of the neocortex and substantia nigra is responsible for cogni-tive deterioration and parkinsonism. Clinical manifestations include memory loss, parkinsonism, and visual hallucinations. There is a possible treatment benefit from cholinesterase inhibitors.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset, progressive motor neuron disease.

The clinical diagnosis is supported by a biopsy of muscles. The etiopathogenesis is obscure; 5–10% of cases are hereditary, and a small number are caused by mutation of the gene encoding zinc-copper superoxide dismutase on chromosome 21.

•         Loss of upper motor neurons produces hyperreflexia and spasticity. In some cases, involvement of cranial nerve nuclei also occurs.

•         Loss of lower motor neurons produces weakness, atrophy, and fasciculations.

There is no cure for ALS. Ultimately, involvement of respiratory muscles will lead to death.

Friedreich ataxia is an autosomal recessive disorder which leads to degeneration of nerve tissue in the spinal cord, especially those sensory neurons connected to the cerebellum affecting muscle movement of the arms and legs. Onset is early child-hood.

Friedreich ataxia is caused by the expansion of an unstable triplet nucleotide repeat (GAA repeats in the first intron) in the frataxin gene on chromosome 9. The frataxin protein is essential for mitochondrial function by helping in mitochondrial iron regulation; in the absence of frataxin, mitochondrial iron builds up, leading to free radical damage and mitochondrial dysfunction.

Clinical manifestations include gait ataxia, dysarthria, hand clumsiness, loss of sense of position, impaired vibratory sensation, and loss of tendon reflexes. There is an increased incidence of heart disorders and diabetes. Patients become wheelchair-bound by age 5.

Wilson disease

Acute intermittent porphyria is an autosomal dominant defect in porphyrin metabo-lism with deficient uroporphyrinogen synthase. Both porphobilinogen and ami-nolevulinic acid are increased. Urine is initially colorless but on exposure to light turns dark red. Patients may develop recurrent severe abdominal pain, psychosis, neuropathy, and dementia.

Vitamin B12 deficiency causes megaloblastic anemia, demyelination of the spinal cord posterior columns and lateral corticospinal tracts (subacute combined degen-eration of the spinal tract). It also causes dementia and peripheral neuropathy.

Alcohol abuse causes generalized cortical and cerebellar atrophy, as well as Wer-nicke-Korsakoff syndrome. The neurologic disease is usually related to thiamine deficiency. There can be hemorrhages in the mamillary bodies and the walls of the third and fourth ventricles. Neuronal loss and gliosis may be prominent.

•         Wernicke encephalopathy has reversible confusion, ataxia, and nystagmus.

•         Korsakoff psychosis is more severe and has irreversible anterograde and ret-rograde amnesia.

•         Central pontine myelinolysis may cause death.