Alzheimer's Disease
The genetic mechanisms of sporadic Alzheimer's disease (including mutations on chromosomes 1 and 14) are still under investigation. However, the morphological hallmarks of the disease are highly specific.
Macroscopic Changes There is a generalized reduction in brain weight. Cortical atrophy is most pronounced in the frontotemporal and parieto-occipital regions. The sulci on the superolateral surface are widened due to gyral narrowing, and the cerebral ventricles show compensatory enlargement (hydrocephalus ex vacuo).
Microscopic Findings Pathological inclusions accumulate within the brain tissue:
- Senile (neuritic) plaques: Extracellular deposits of insoluble β-amyloid, derived from amyloid precursor protein (APP). These plaques (measuring 5–100 µm) are surrounded by dystrophic neurites and reactive glial cells. They are clearly visualized using silver impregnation techniques in the cortex.
- Neurofibrillary tangles: Intracellular aggregates composed of hyperphosphorylated tau (τ) protein.
- Neuronal loss: Granulovacuolar degeneration, accumulation of lipofuscin, and focal-to-diffuse neuronal death in the cerebral cortex.
Specific inclusions may also be found in neurons and dendrites, such as rounded argyrophilic Pick bodies and eosinophilic Hirano bodies (actin filament aggregates). Blood vessels are frequently affected by cerebral amyloid angiopathy, accompanied by fibrosis and gliosis. Death in Alzheimer's disease typically results not from the primary brain pathology, but from secondary complications such as intercurrent infections (e.g., aspiration pneumonia).
Parkinson's Disease
Parkinsonism is a clinical syndrome comprising hypokinesia (reduced amplitude and speed of movement), muscle rigidity, a characteristic resting tremor, and postural instability. In advanced stages, cognitive impairment and dementia may develop.
Idiopathic Parkinson's disease accounts for the vast majority of cases, alongside secondary forms caused by specific etiiological factors or occurring within other neurodegenerative conditions.
Pathogenesis and Morphology of Idiopathic Parkinsonism At the core of the disease is the selective degeneration of pigmented dopaminergic neurons in the brainstem, predominantly affecting the substantia nigra and the locus coeruleus. Degeneration is thought to begin at presynaptic axon terminals due to impaired retrograde transport of neurotrophic factors. As neurons undergo apoptosis, reactive astrogliosis occurs in the affected regions.
Surviving neurons frequently contain Lewy bodies—round, eosinophilic, intracytoplasmic inclusions. Electron microscopy reveals that they consist of a dense core surrounded by a pale halo, composed primarily of $\alpha$-synuclein and ubiquitin. Note that Lewy bodies are also found in other synucleinopathies, such as dementia with Lewy bodies.
Death in Parkinson's disease is often hastened by immobility-related complications, recurrent falls, and aspiration pneumonia.
Motor Neuron Diseases and ALS
Motor neuron diseases include progressive muscular atrophy, progressive bulbar palsy, and amyotrophic lateral sclerosis (ALS). ALS is distinguished by its aggressive, relentlessly progressive course and near-100% mortality (most patients succumb to respiratory failure within 3 to 5 years of symptom onset).
Mechanisms of Neuronal Death The exact etiology of sporadic ALS remains unknown (with viral, prion, neurotoxic, and metal toxicity hypotheses discussed), but the pathogenesis is strongly driven by excitotoxicity and oxidative stress:
- Excess extracellular neurotransmitters (glutamate, aspartate) hyperactivate postsynaptic NMDA receptors.
- Pathological influx of calcium ions into the neuron triggers destructive enzymatic cascades.
- Increased production of peroxynitrite, nitric oxide, and superoxide radicals leads to oxidative damage.
A subset of familial ALS cases involves mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) on chromosome 21 (21q22), impairing the cell's ability to neutralize free radicals.
Topography of Lesions in ALS Unlike other selective motor neuron disorders, ALS features the simultaneous degeneration of both upper and lower motor neurons:
- Upper motor neurons: Betz pyramidal cells in layer V of the motor cortex. Degeneration extends down the corticospinal tracts through the internal capsule, cerebral peduncles, pons, medullary pyramids, and lateral funiculi of the spinal cord.
- Lower motor neurons: Anterior horn cells of the spinal cord and the motor nuclei of cranial nerves (V, VII, IX, X, XII).
Friedreich Ataxia
Friedreich ataxia is an autosomal recessive inherited disorder characterized clinically by progressive gait and limb ataxia, loss of proprioception, and absent deep tendon reflexes. It typically manifests in childhood.
Genetics and Pathogenesis The condition is caused by a trinucleotide (GAA) repeat expansion in the FXN gene on locus 9q13, which encodes the mitochondrial protein frataxin. Frataxin deficiency leads to iron dysregulation in mitochondria and impaired cellular antioxidant defenses.
Morphological Changes In the spinal cord, degeneration and reactive gliosis are prominent in the posterior columns and spinocerebellar tracts. Notably, the fasciculus gracilis is more severely affected than the fasciculus cuneatus. There is massive neuronal loss in Clarke's column, dorsal root ganglia, the dentate nucleus of the cerebellum, Purkinje cells (predominantly in the superior cerebellar vermis), and the sensory-related cranial nerve nuclei.
The clinical picture is frequently complicated by non-neurological manifestations, including the classic 'Friedreich foot' (pes cavus and hammer toes), kyphoscoliosis, hypertrophic cardiomyopathy, and diabetes mellitus.