Parkinson's disease: Mechanisms and models

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

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Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

https://www.pnas.org/content/pnas/95/11/6469.full.pdf

α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

Dietary polyphenols and the prevention of diseases

We read with interest the recent excellent review by Reynolds on the role of folic acid and the risks and benefits of its supplementation in the nervous system.1 It emphasises the beneficial importance of folate on the numerous methylation processes in combination with S-adenosylmethionine (SAM), which donates its methyl group to prevent hyperhomocysteinaemia.1 However SAM deficiency, which is associated with, for example, cognitive decline and/or mood disturbances, and increased total homocysteine levels, which support onset of vascular disease, may also caused by drugs, for example, levodopa.2,3 Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by the ubiquitious enzyme catechol-O-methyltransferase (COMT) in blood, peripheral tissues and in nigrostriatal neurons.2,3 COMT requires Mg2+ as cofactor and …

https://jnnp.bmj.com/content/jnnp/74/4/549.1.full.pdf

Benefit of folic acid supplementation in parkinsonian patients treated with levodopa.

There is good evidence that patients with Parkinson’s disease have respiratory chain dysfunction in their substantia nigra. Since mitochondrial cytopathies due to enzyme defects in the respiratory cha

Unaltered Respiratory Chain Enzyme Activity and Mitochondrial DNA in Skeletal Muscle from Patients with Idiopathic Parkinson’s Syndrome

Recently distorted chromatic contour perception has been demonstrated in Parkinson's disease (PD). The aim of our study is to determine the clinical factors which influence chromatic contour perception in PD. Chromatic and achromatic contour perception, colour discrimination and clinical data were evaluated in 73 patients with PD. We used a computer-aided method to determine the chromatic fusion time (CFT) which indicates the acuity of monochromatic contour perception. Chromatic CFT was generally shortened in patients as compared to controls (p < 0.01), whereas achromatic CFT was not significantly different. Variance analysis revealed the ability of colour discrimination and the risk of visual hallucinations as statistically significant (p < 0.05) variables influencing contour perception of certain stimuli. In contrast, disease stage, disease duration and disease severity have no relevant effect on chromatic contour perception in Parkinson's disease. On the basis of those properties one may suggest that distorted chromatic contour perception is due to an impairment at a central stage of visual processing in PD and an imbalance of the serotonergic system. Whether CFT is a reliable method to predict the individual risk of hallucinosis in PD has to be evaluated.

Visual hallucinosis: the major clinical determinant of distorted chromatic contour perception in Parkinson's disease.

Parkinsonism unmasked by lovastatin

Visual perseveration (VP) is defined as persistence or recurrence of visual images, when the stimulus is no longer present. We report three patients with occipital cortical lesions in the right hemisphere and VP. Electroencephalography showed epileptic abnormalities in all cases. In one patient synchronous electroencephalic recordings during the onset of palinopsia - a subtype of VP - revealed, that VP was associated with a clear cut right occipital seizure with a secondary diffusion of the discharge over both hemispheres, which has not been reported in combination with the onset of palinopsia heretofore. In all three patients sensory seizures have to be considered as probable cause of VP.

Wilfried Kuhn

Papers

Benefit of folic acid supplementation in parkinsonian patients treated with levodopa.

Unaltered Respiratory Chain Enzyme Activity and Mitochondrial DNA in Skeletal Muscle from Patients with Idiopathic Parkinson’s Syndrome

Visual hallucinosis: the major clinical determinant of distorted chromatic contour perception in Parkinson's disease.

Parkinsonism unmasked by lovastatin

Palinopsia as sensory epileptic phenomenon.