A Lewy body (stained brown) in a brain cell of the substantia nigra in<unk> : The brown colour is positive immunohistochemistry staining for alpha-synuclein.|alt=Several brain cells stained in blue. The largest one, a neurone, with an approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears. The main pathological characteristics of<unk>  are cell death in the brain's basal ganglia (affecting up to 70% of the dopamine-secreting neurons in the substantia nigra pars compacta by the end of life). In<unk> , alpha-synuclein becomes misfolded and clump together with other alpha-synuclein. Cells are unable to remove these clumps, and the alpha-synuclein becomes cytotoxic, damaging the cells. These clumps can be seen in neurons under a microscope and are called Lewy bodies. Loss of neurons is accompanied by the death of astrocytes (star-shaped glial cells) and a significant increase in the number of microglia (another type of glial cell) in the substantia nigra. Braak staging is a way to explain the progression of the parts of the brain affected by<unk> . According to this staging,<unk>  starts in the medulla and the olfactory bulb before moving to the substantia nigra pars compacta and the rest of the midbrain/basal forebrain. Movement symptom onset is associated when the disease begins to affect the substantia nigra pars compacta. alt=Composite of three images, one in the top row (referred to in caption as A), two in the second row (referred to as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". The fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one sagittal and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem. Five major pathways in the brain connect other brain areas with the basal ganglia. These are known as the motor, oculomotor, associative, limbic, and orbitofrontal circuits, with names indicating the main projection area of each circuit. All of them are affected in<unk> , and their disruption explains many of the symptoms of the disease, since these circuits are involved in a wide variety of functions, including movement, attention and learning. Scientifically, the motor circuit has been examined the most intensively. An illustration of the dopamine pathways throughout the brain. A particular conceptual model of the motor circuit and its alteration with<unk>  has been of great influence since 1980, although some limitations have been pointed out which have led to modifications. In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in<unk> , demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. Drugs that are used to treat<unk> , conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias. Brain cell death Brain cells could be lost by several proposed mechanisms. One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurons forming inclusions called Lewy bodies. According to the Braak staging, a classification of the disease based on pathological findings proposed by Heiko Braak, Lewy bodies first appear in the olfactory bulb, medulla oblongata, and pontine tegmentum; individuals at this stage may be asymptomatic or may have early nonmotor symptoms (such as loss of sense of smell, or some sleep or automatic dysfunction). As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain, and finally, the neocortex. These brain sites are the main places of neuronal degeneration in<unk> , but Lewy bodies may not cause cell death and they may be protective (with the abnormal protein sequestered or walled off). Other forms of alpha-synuclein (e.g., oligomers) that are not aggregated in Lewy bodies and Lewy neurites may actually be the toxic forms of the protein. In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented. Other cell-death mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity. Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation, and neuronal death, but the mechanisms are not fully understood.
Parkinson's disease
Dementia with Lewy bodies
Parkinsonism
Antipsychotic
Parkinson-plus syndrome
Essential tremor
Alzheimer's disease
Progressive supranuclear palsy