Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis.

- Posted in Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis. by English by

Accumulating evidence suggests defective energy metabolism in ALS patients, which contributes to weight loss and a poor prognosis.

Lipid metabolism disorders have been widely reported in patients with ALS, presenting with hypercholesterolemia, hypertriglyceridemia, and other mixed dyslipidemias. Leptin, an adipokine, plays a neuroprotective role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Nagel et al. suggested that leptin concentrations were positively correlated with the survival rate in ALS patients, indicating protective effects of leptin in patients with ALS.

Serum leptin concentration is strongly correlated with body weight or BMI, which was also confirmed in this study written by scientists from Chinese Academy of Medical Sciences. And higher body weight and BMI have been found to be associated with a lower risk of ALS and better prognosis in ALS patients.

Adipokines are a group of factors released or secreted by adipose tissue and have many physiological functions, such as fat distribution, energy expenditure, appetite and satiety regulation, insulin secretion and sensitivity, and inflammation.

Previous studies on the biological functions of adiponectin provide some evidence that adiponectin is beneficial in ALS. As one of the most abundant adipokines secreted by adipocytes, adiponectin functions in multiple physiological processes, including insulin sensitization, glucose regulation, lipid metabolism, and anti-inflammatory and antiapoptotic activities.

Fifty-two subjects were recruited between October 2020 and January 2022 among patients newly diagnosed with ALS in the Neurology Department of Peking Union Medical College Hospital. The study also included 24 healthy participants to compare adipokines and other metabolic biomarkers.

When comparing adipokines in patients and controls, the authors, found significant differences in the levels of adiponectin, adipsin, resistin, and visfatin between the two groups.

ALS patients had higher levels of adipokines (adiponectin, adipsin, resistin, and visfatin) and other metabolic biomarkers [C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and plasminogen activator inhibitor type 1] than controls.

Leptin levels in serum were positively correlated with body mass index, body fat, and visceral fat index.

Adiponectin was positively correlated with the visceral fat index and showed a positive correlation with the ALSFRS-R and a negative correlation with baseline disease progression.

Lower leptin and adiponectin levels were correlated with faster disease progression. After adjusting for confounders, lower adiponectin levels and higher visfatin levels were independently correlated with faster disease progression.

Berberine, an isoquinoline alkaloid, has been shown to increase adiponectin expression, which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both omega-3 fatty acids, have also shown increased plasma adiponectin. Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.

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Alterations of the serum and CSF ferritin levels and the diagnosis and prognosis of amyotrophic lateral sclerosis.

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The Amyotrophic Lateral Sclerosis diagnostic challenges necessitate more robust diagnostic and prognostic methods. A potential biomarker in this regard is the alterations of ferritin levels in the serum and cerebrospinal fluid of patients compared to controls.

The cerebrospinal fluid and serum ferritin levels were measured in 50 Amyotrophic Lateral Sclerosis cases and 50 control patients with predefined exclusion criteria. The ELISA method was utilized for laboratory measurement and was statistically analyzed using the SPSS.

Heightened serum ferritin levels in cases were not statistically significant, however, cerebrospinal fluid ferritin levels were significantly higher in Amyotrophic Lateral Sclerosis patients.

Serum ferritin levels were significantly negatively correlated with the disease duration and were significantly positively correlated with the disease progression rate.

Heightened cerebrospinal fluid ferritin levels can be used for the diagnosis of Amyotrophic Lateral Sclerosis. The correlation between the serum ferritin levels with the DPR and its correlation with the disease duration suggests potential prognostic utilities.

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A Machine-Learning Derived Huntington's Disease Progression Model: Insights for Clinical Trial Design.

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Applying machine-learning algorithms to large datasets such as those available in Huntington's disease offers the opportunity to discover hidden patterns, often not discernible to clinical observation.

A computer model of Huntington's disease progression is missing.

Longitudinal data encompassing 2079 assessment measures from four observational studies were integrated and machine-learning methods were applied to develop a probabilistic model of disease progression. The model was validated using a separate Enroll-HD dataset and compared with existing clinical reference assessments and CAG-age product.

Nine disease states were discovered based on 44 motor, cognitive, and functional measures, which correlated with reference assessments.

The validation set included 3158 participants of whom 61.5% had manifest disease. Analysis of transition times showed that "early-disease" states 1 and 2, which occur before motor diagnosis, lasted ~16 years.

Increasing numbers of participants had motor onset during "transition" states 3 to 5, which collectively lasted ~10 years, and the "late-disease" states 6 to 9 also lasted ~10 years. The annual probability of conversion from one of the nine identified disease states to the next ranged from 5% to 27%.

The natural history of Huntington's disease can be described by nine disease states of increasing severity. The ability to derive characteristics of disease states and probabilities for progression through these states will improve trial design and participant selection. © 2021 International Parkinson and Movement Disorder Society.

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Prognosis of amnestic mild cognitive impairment: clinical and immunological correlations.

- Posted in Prognosis of amnestic mild cognitive impairment: clinical and immunological correlations. by English by

To determine the long-term prognosis of the cognitive deficits progression in elderly people with amnestic mild cognitive impairment based on the analysis of the initial clinical and immunological parameters.

This study is based on a clinical and follow-up study of 252 outpatients with aMCI, who were observed in the Federal State Budgetary Scientific Institution «Mental Health Research Center» from 2018 to 2020.

The psychometric assessment complex included the following scales and tests: MMSE, MoCA, The 10 words test, BNT, David Wechsler's Scale, subtest 6, CDT, Memory test of 5 geometric shapes, BVRT Test, DRS - Mattis Dementia Rating Scale: Verbal fluency, DRS - Mattis Dementia Rating Scale, The Munsterberg Test.

As part of the study, the level of cytokines in the blood serum was determined in all patients by enzyme immunoassay, using diagnostic kits manufactured by Cytokine LLC.

In patients with a progression of aMCI syndrome, an increase in proinflammatory cytokines IL-1, IL-6, IL-8, TNF-α is initially detected, which may reflect the level of systemic inflammation or functional insufficiency of anti-inflammatory mechanisms.

In turn, the group with a subsequent improvement in cognitive functioning, on the contrary, is distinguished by an initially increased level of the anti-inflammatory interleukin system.

The scientists here provide new data on the presence of systemic inflammation and immune disturbances and their association with clinical course of disease in the majority of elderly patients with aMCI.

Signs of a chronic low-level systemic inflammatory response in patients with aMCI is the unfavorable prognosis criterion: in such patients, cognitive deficit significantly progresses or dementia due to Alzheimer disease develops within three years.

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Efficacy and safety of combination therapy with pramipexole and levodopa vs levodopa monotherapy in patients with Parkinson disease: A systematic review and meta-analysis.

- Posted in Efficacy and safety of combination therapy with pramipexole and levodopa vs levodopa monotherapy in patients with Parkinson disease: A systematic review and meta-analysis. by English by

Pramipexole or levodopa treatment has been suggested as a therapeutic method for Parkinson disease. Nonetheless, the combined effects of 2 drugs for Parkinson disease patients are not completely understood.The aim of this systematic review was to evaluate the clinical efficacy and safety of Pramipexole plus levodopa combination therapy in the treatment of Parkinson disease compared to that of levodopaL monotherapy, in order to confer a reference for clinical practice.

Randomized controlled trials of Pramipexole plus levodopa for Parkinson disease published up to April, 2020 were retrieved. Standardized mean difference, odds ratio, and 95% confidence interval were calculated and heterogeneity was measured with the I2 test. Sensitivity analysis was also carried out. The outcomes of interest were as follows: the efficacy, unified Parkinson disease rating scale scores, Hamilton depression rating scale score or adverse events.

Twenty-four RCTs with 2171 participants were included. Clinical efficacy of Pramipexole plus levodopa combination therapy was significantly better than levodopa monotherapy.

The Hamilton depression rating scale score showed significant decrease in the Pramipexole plus levodopa combination therapy compared to L monotherapy. In contrast to levodopa monotherapy, Pramipexole plus levodopa combination therapy reduced the number of any adverse events obviously in Parkinson disease patients.

Moreover, the safety profile of Pramipexole plus levodopa combination therapy was found to be better than that of levodopa monotherapy. Further well-designed, multicenter RCTs are needed to confirm the findings of this systematic review of the literature of the field.

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Thermoregulatory dysfunction in Parkinson's disease.

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Thermoregulatory dysfunction is considered to be the least investigated among all the autonomic disorders in Parkinson disease. Pathophysiological mechanisms of this phenomena involve as central, as peripheric parts of nervous system.

Dopamine deficiency in combination with peripheric autonomic dysfunction leads to temperature balance disturbance, which may be expressed by various clinical symptoms. Dopaminergic innervation of preoptic-anterior hypothalamus area plays a crucial role in thermoregulation function of central nervous system.

Current thermoregulatory tests give possibility not only to reveal sudomotor and heat dissipation disorders in patients with Parkinson disease, but also to make differential diagnosis with other neurodegenerative disorders. Early detection and treatment of thermoregulatory dysfunction may improve quality of life in patients with Parkinson disease.

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Simultaneous visualization and quantification of copper (II) ions in Alzheimer's disease by a near-infrared fluorescence probe.

- Posted in Simultaneous visualization and quantification of copper (II) ions in Alzheimer's disease by a near-infrared fluorescence probe. by English by

The abnormal accumulation of copper ions is considered to be one of the pathological factors of Alzheimer's disease, but the internal relationship between Cu and Alzheimer's disease progression is still not fully clear.

In this work, a sensitive and selective near-infrared fluorescent copper ion probe was designed for quantification and visualization of Cu level in lysates, living cells, living zebrafish and brain tissues of drosophila and mice with Alzheimer's disease.

By using this probe, the authors demonstrated that the content of Cu in the brains of Alzheimer's disease mice and drosophila enhanced nearly 3.5-fold and 4-fold than that of normal mice and drosophila, respectively.

More importantly, pathogenesis analysis revealed that elevated Cu led to changes in factors closely associated with Alzheimer's disease, such as the increasing of reactive oxygen species, the aggregation of amyloid-β protein and nerve cell cytotoxicity.

These findings could promote the understanding of the roles between Cu and Alzheimer's disease.

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Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease.

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Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease.

This retrospective observational cohort study evaluated patients referred for Lyme disease to a Maryland academic center between 2000-2013 who lacked evidence for Borrelia burgdorferi infection. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions.

Of 1261 referred patients, 1061 had no findings of active Lyme disease, with 690 receiving other diagnoses.

Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression, fibromyalgia, chronic fatigue syndrome, migraine disorder, osteoarthritis and sleep disorder/apnea.

Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis, malignancy, Parkinson's disease, sarcoidosis or amyotrophic lateral sclerosis.

Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

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Impaired Color Discrimination in Alzheimer Disease Dementia.

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Patients with Alzheimer disease dementia often show impaired orientation and navigation. Signage offers an opportunity to compensate for these deficits, communicate information efficiently and facilitate way finding. Certain properties of signs such as colors and contrasts may beneficially affect the uptake and processing of information particularly in ADD patients.

Thirty-six healthy older adults and 30 ADD patients performed a computerized color perception task that required discriminating different color combinations. The effects of different contrast features on performance accuracy and speed in the 2 experimental groups were examined by nonparametric mixed analysis of variances.

Analyses revealed a significant effect of contrast polarity on reaction times, significant effects of group on reaction times and errors as well as a marginally significant interaction of group×color on errors. All participants benefited from positive contrast polarity as indicated by increased performance speed. Furthermore, ADD patients reacted slower and less accurate than healthy controls, but showed higher accuracy at black-white and red-yellow than at blue-green color combinations.

The authors' findings suggest the implementation of signs with positive contrast polarity to ensure faster reactions. In addition, certain color combinations may enhance accuracy, particularly in patients with ADD.

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Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial.

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Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.

The scientists objective was to assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).

Mevidalen resulted in significant, dose-dependent improvements of MDS-UPDRS total score. The 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores compared to placebo.

Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose.

Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with Lewy body dementia on top of standard of care while improving or not worsening non-motor symptoms associated with traditional dopaminergic therapy.

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