Parkinson's Disease and Parkinsonism: Neuropathology

Abstract

Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein a-synuclein or the microtubule binding protein tau. In idiopathic Parkinson's disease (PD), a-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major a-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of a-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, a-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

“…Neuronal complex I is decreased both in areas universally affected by neurodegeneration, such as the SNc, areas with mild and/or variable neuronal loss, like the hippocampus and prefrontal cortex, and even areas believed to remain unaffected such as the cerebellar cortex and dentate nucleus [12]. Neuronal complex I deficiency appeared most pronounced in the SNc, putamen and cerebellar cortex, and mildest in the basal pontine nuclei and red nucleus, but regional differences were generally minor and all eight brain regions we examined showed decreased complex I staining.…”

“…Other affected areas comprise multiple brainstem and cholinergic nuclei, the hippocampus and the neocortex. Neuropathologically spared regions include the striatum, cerebellum, thalamus, red nucleus and the pontine nuclei [12].…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…PD affects numerous brain structures, then producing different nonmotor (e.g., drooling, changes in taste and smell, nausea and vomiting, constipation, bladder dysfunction, dementia and cognitive impairment, hallucinations, depression and anxiety, and others) and, in particular, motor (e.g., rigidity, bradykinesia, postural instability, tremor) anomalies [105]. Motor symptoms are predominantly caused by alterations in the basal ganglia circuitry triggered by the death of nigral dopaminergic neurons, the denervation of the striatum to which these degenerating neurons project, the formation of Lewy bodies in the cytosol of nigral neurons, and the loss of neuromelanin accumulated in the substantia nigra [106]. Current treatments include dopaminergic replacement therapies, which serve for symptom alleviation, but the disease lacks of efficacious disease-modifying therapies, despite the issue being widely investigated, even at the clinical level [107].…”

Markerless Analysis of Articulatory Movements in Patients With Parkinson's Disease

“…[1][2][3] Cardinal motor symptoms of PD are rest tremor, bradykinesia, and rigidity. 4,5 Other common motor signs involve the control of speech production, affecting motion and coordination of the articulatory organs (ie, tongue, lips, and jaw). These signs are commonly known as "dysarthria".…”