Alzheimer's disease
The genetic mechanisms of sporadic forms of Alzheimer's disease (including mutations on chromosomes 1 and 14) are not yet sufficiently understood. However, the morphological picture of the disease is highly specific.
Macroscopic changes There is an overall decrease in brain mass. Cortical atrophy is most pronounced in the frontotemporal and parieto-occipital regions. The relief of the hemispheres becomes smoothed: sulci are significantly widened on the superolateral surface. Internal structures also change, with enlargement of the brain ventricles.
Microscopic picture Pathological inclusions form in the brain tissue:
- Senile (neuritic) plaques: extracellular deposits of insoluble β-amyloid, which is formed from a transmembrane glycoprotein. Plaques (5–100 µm in size) are surrounded by degenerating neurons and glial cells. Upon silver impregnation, they are clearly identified in the cortex.
- Alzheimer's neurofibrillary tangles («tangles»): intracellular amyloid composed of hyperphosphorylated tau (τ) protein.
- Neuronal pathology: granulovacuolar degeneration, lipofuscinosis, and focal or diffuse death of cortical cells are observed.
Specific bodies are also found in neurons and dendrites: rounded argyrophilic Pick bodies and eosinophilic Hirano bodies (aggregates of actin filaments). Vessels are affected by amyloid angiopathy, with subsequent fibrosis and gliosis. Death in this disease most often results not from the brain damage itself, but from secondary infectious diseases.
Parkinsonism
Parkinsonism is a clinical syndrome that includes hypokinesia (reduced movement activity), muscular rigidity, characteristic resting tremor, and postural instability. In some cases, dementia accompanies the motor disorders.
Idiopathic type (accounting for the majority of cases), syndromes caused by specific etiological factors, and syndromes occurring as part of other degenerative pathologies are distinguished.
Pathogenesis and morphology of idiopathic parkinsonism The disease is based on the selective destruction of pigmented dopaminergic neurons in the brainstem. The primarily affected areas are the substantia nigra (substantia nigra) and the locus coeruleus (locus coeruleus). It is hypothesized that degeneration starts in the presynaptic axon terminals due to impaired retrograde transport of neurotrophic factors. Consequently, neurons die and are replaced by astrogliosis.
Lewy bodies—round eosinophilic inclusions—are found in surviving neurons. Electron microscopy shows that they consist of fine filaments with a dense core and loose periphery. They contain synuclein and ubiquitin. Notably, Lewy bodies are not an absolutely specific marker solely for Parkinson's disease.
Motor Neuron Diseases and ALS
The group of motor neuron diseases includes progressive muscular atrophy, progressive bulbar palsy, and amyotrophic lateral sclerosis (ALS). ALS stands out due to its extremely severe course and 100% mortality rate (only 5% of patients live longer than 5 years, dying from respiratory failure and pneumonia).
Mechanisms of neuronal death The exact etiology of ALS is unknown (the roles of viruses, prions, neurotoxins, and metals are debated), but the pathogenesis is clearly tied to excitotoxicity and oxidative stress:
- Neurotransmitters (glutamate, aspartate) excessively stimulate NMDA receptors.
- A pathological amount of calcium enters the cell.
- Synthesis of peroxynitrite, nitric oxide, and superoxide anions is activated.
In some patients, a mutation of the Cu/Zn superoxide dismutase enzyme on chromosome 21 (21q22) is detected, which deprives the cell of defense against free radicals.
Topography of lesions in ALS Unlike other forms, ALS involves the simultaneous destruction of both upper and lower motor neurons:
- Upper (central): Betz pyramidal cells in layer V of the motor cortex. Degeneration of the corticospinal tract develops in the internal capsule, cerebral peduncles, pons, medullary pyramids, and spinal cord funiculi.
- Lower (peripheral): cells of the anterior horns of the spinal cord and the motor nuclei of cranial nerves V, VII, IX, X, and XII.
Friedreich ataxia
This is a chronic progressive autosomal recessive disorder whose main manifestation is severe ataxia (coordination disorder). The disease more frequently affects males.
Genetics and pathogenesis The cause of the disease lies in a gene mutation at locus 9q13, which encodes the mitochondrial protein frataxin. Frataxin deficiency disrupts normal cellular antioxidant defense.
Morphological changes In the spinal cord, degeneration and gliosis of the posterior and lateral columns are observed. Furthermore, fasciculus gracilis is destroyed more severely than fasciculus cuneatus. There is massive cell loss in Clarke's column, dorsal root ganglia, the dentate nucleus of the cerebellum, Purkinje cells (in the upper vermis), and the nuclei of cranial nerves VIII, X, and XII.
The clinical picture is often supplemented by non-neurological pathology: a specific «Friedreich's foot» (contracture in plantar flexion) develops, along with kyphoscoliosis, diabetes mellitus, and severe cardiac damage (cardiomyopathy, valve defects).
Briefly: answers to topical questions
Which gene mutations lead to the development of Alzheimer's disease?
In sporadic forms of Alzheimer's disease, identified gene mutations, including those on chromosomes 14 and 1, play a role that remains currently undetermined. The APP gene encodes the amyloid precursor protein from which β-amyloid—a component of senile plaques—is formed.
What morphological changes occur in peripheral nerves in diabetic polyneuropathy?
In diabetic polyneuropathy, peripheral nerves undergo fiber degeneration and damage to their nourishing blood vessels (vasa nervorum).
Morphological changes include:
- Reduction in axon count—occurs as the disease progresses.
- Segmental demyelination—is observed predominantly in the distal parts of nerves.
- Edema and dystrophy—affect the nerve fibers.
- Thin fiber degeneration—is characteristic of unmyelinated C-fibers.
Which tumors develop from Schwann cells of peripheral nerves?
Tumors of the peripheral nervous system develop from cellular elements of the peripheral nerve sheaths—Schwann cells (lemmocytes) and perineural fibroblasts. These include:
- Schwannoma—a benign tumor originating from Schwann cells, growing eccentrically relative to the nerve and displacing its fibers.
- Neurofibroma—a mature benign tumor of the peripheral nervous system.
- Neurogenic sarcoma—an immature malignant tumor.
Schwannomas and neurofibromas are characterized by diffuse expression of S-100 protein, which is a marker of Schwann cell differentiation.
For the differential diagnosis of ALS: remember that it is the only pathology among motor neuron diseases where «everything dies at once»—BOTH upper (cortex) AND lower (spinal cord, cranial nerve nuclei) motor neurons are affected.
Class and exam questions
What is the fundamental difference in amyotrophic lateral sclerosis (ALS)?
ALS involves the simultaneous combined lesion of upper and lower motor neurons, whereas other diseases in this group involve only one level.
What forms the basis of senile plaques in Alzheimer's disease?
Plaques are primarily composed of extracellular insoluble deposits of β-amyloid, surrounded by glial cells and dystrophically altered neurons.
What inclusions are characteristic of idiopathic Parkinson's disease?
Parkinsonism is characterized by eosinophilic Lewy bodies localized in pigmented dopaminergic neurons containing synuclein and ubiquitin.
What leads to the death of patients with Alzheimer's disease and ALS?
In Alzheimer's disease, patients most often die from secondary infectious diseases, whereas in ALS, inevitable fatal outcome results from respiratory failure and pneumonia.
What else to study on this topic
- Morphological characteristics and outcomes of ischemic cerebral infarction
- Etiology and pathogenesis of intracerebral hemorrhages
- Changes in the leptomeninges in purulent leptomeningitis
- Microscopic appearance of the spinal cord in the paralytic stage of poliomyelitis
- Histological markers of rabies and multiple sclerosis
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