Brait-Fahn-Schwartz Disease: A Unique Co-Occurrence of Parkinson’s Disease and Amyotrophic Lateral Sclerosis
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PROVIDER: S-EPMC10601670 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Recent evidence supports an association between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Indeed, prospective population-based studies demonstrated that about one-third of ALS patients develop parkinsonian (PK) signs, even though different neuronal circuitries are involved. In this context, proteomics represents a valuable tool to identify unique and shared pathological pathways. Here, we used two-dimensional electrophoresis to obtain the proteomic profile of peripheral blood mononuclear cells (PBMCs) from PD and ALS patients including a small cohort of ALS patients with parkinsonian signs (ALS-PK). After the removal of protein spots correlating with confounding factors, we applied a sparse partial least square discriminant analysis followed by recursive feature elimination to obtain two protein classifiers able to discriminate (i) PD and ALS patients (30 spots) and (ii) ALS-PK patients among all ALS subjects (20 spots). Functionally, the glycolysis pathway was significantly overrepresented in the first signature, while extracellular interactions and intracellular signaling were enriched in the second signature. These results represent molecular evidence at the periphery for the classification of ALS-PK as ALS patients that manifest parkinsonian signs, rather than comorbid patients suffering from both ALS and PD. Moreover, we confirmed that low levels of fibrinogen in PBMCs is a characteristic feature of PD, also when compared with another movement disorder. Collectively, we provide evidence that peripheral protein signatures are a tool to differentially investigate neurodegenerative diseases and highlight altered biochemical pathways.
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Project description:Patients with amyotrophic lateral sclerosis (ALS) have a motor disorder and cognitive difficulties, including difficulty with action verbs. However, the basis for the action verb impairment is unknown. Thirty-six participants with ALS and 22 with Parkinson's disease (PD) were assessed on a simple, two-alternative forced-choice associativity judgment task, where performance was untimed and did not depend on motor functioning. We probed 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns. Performance was related to T1 MRI imaging of gray matter atrophy. Patients with ALS were significantly impaired relative to healthy senior control participants only for action verbs. Patients with PD did not differ from controls for all word categories. Regression analyses related action verb performance in ALS to motor-associated cortices, but action verb judgments in PD were not related to cortical atrophy. These findings are consistent with the hypothesis that action verb difficulty in ALS is related in part to the degradation of action-related conceptual knowledge represented in motor-associated cortex.
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Project description:Parkinson's disease (PD) is a movement disorder that afflicts over one million in the U.S.; amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is less prevalent but also has a high incidence. The two disorders sometimes present together, making a comparative study of interest. Both ALS and PD are neurodegenerative diseases, and are characterized by the presence of intraneuronal inclusions; however, different classes of neurons are affected and the primary protein in the inclusions differs between the diseases, and in some cases is different in distinct forms of the same disease. These observations might suggest that the more general approach of proteostasis pathway alteration would be a powerful one in treating these disorders. Examining results from human genetics and studies in model organisms, as well as from biochemical and biophysical characterization of the proteins involved in both diseases, we find that most instances of PD can be considered as arising from the misfolding, and self-association to a toxic species, of the small neuronal protein ?-synuclein, and that proteostasis strategies are likely to be of value for this disorder. For ALS, the situation is much more complex and less clear-cut; the available data are most consistent with a view that ALS may actually be a family of disorders, presenting similarly but arising from distinct and nonoverlapping causes, including mislocalization of some properly folded proteins and derangement of RNA quality control pathways. Applying proteostasis approaches to this disease may require rethinking or broadening the concept of what proteostasis means.
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Project description:Serum creatinine and C-reactive protein have been proposed as potential biomarkers for neurodegenerative diseases, including amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease. However, longitudinal studies investigating temporal patterns of these biomarkers, including the phase before diagnosis, are rare. We performed a case-control study including all newly diagnosed patients with amyotrophic lateral sclerosis (N = 525), multiple sclerosis (N = 1815) or Parkinson's disease (N = 3797) during 2006-2013 in Stockholm, Sweden, who participated in the Stockholm CREAtinine Measurements (SCREAM) project. For each case, we randomly selected up to five controls from SCREAM that were individually matched to the case by age, sex and county of residence (N = 2625 for amyotrophic lateral sclerosis, N = 9063 for multiple sclerosis and 18 960 for Parkinson's disease). We collected for both the cases and the controls testing results of serum creatinine and C-reactive protein performed by healthcare providers in Stockholm during the study period. Median levels of creatinine and C-reactive protein were visualized using locally weighted smoothing curves among cases and controls. A linear mixed model was also applied to explore temporal changes within an individual. Compared to controls, patients with amyotrophic lateral sclerosis had lower levels of creatinine from 2 years before diagnosis onwards. In contrast, patients with amyotrophic lateral sclerosis had lower levels of C-reactive protein before diagnosis but higher levels after diagnosis, compared to controls. Focusing the 2 years before to 2 years after diagnosis, patients with amyotrophic lateral sclerosis displayed statistically significantly decreasing level of creatinine from 1 year before diagnosis until 2 years after diagnosis, whereas increasing level of C-reactive protein from diagnosis until 2 years after diagnosis. There were no similar patterns noted among patients with multiple sclerosis or Parkinson's disease, or the controls of the three patient groups. Patients with amyotrophic lateral sclerosis display distinct temporal patterns of creatinine and C-reactive protein before and after diagnosis, compared to amyotrophic lateral sclerosis-free controls or patients with multiple sclerosis and Parkinson's disease.
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Project description:Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against ?-amyloid (A?) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of A? and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (CYP2E1) and an increase in the amount of ?-Synuclein (?SYN) relevant to PD. The findings on the association between alcohol consumption and ALS are inconsistent; a recent population-based study suggests that alcohol drinking seems to not influence the risk of developing ALS. Additional research is needed to clarify the potential etiological involvement of alcohol intake in causing or resulting in major neurodegenerative diseases, which will eventually lead to potential therapeutics against these alcoholic neurodegenerative diseases.
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Project description:This SuperSeries is composed of the following subset Series: GSE39642: NanoString nCounter immune-related gene expression in blood sorted CD14+CD16- monocytes from sALS, fALS and HC subjects GSE39643: NanoString miRNA profiling of peripheral blood sorted CD14+CD16- monocytes from amyotrophic lateral sclerosis, multiple sclerosis and healthy control subjects Refer to individual Series
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