Expanding the Spectrum of Movement Disorders Associated With C9orf72 Hexanucleotide Expansions.

OBJECTIVE: Hexanucleotide repeat expansions (HREs) in C9orf72 are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in C9orf72 through a retrospective review of patients' medical records. METHODS: We retrospectively reviewed the clinical records of patients carrying a C9orf72 HRE in the pathogenic range and compared the characteristics of patients with and without MD. RESULTS: Seventeen of 40 patients with a C9orf72 HRE had a documented MD. In 6 of 17, MD were the presenting symptom, and in 2 of 17, MD were the sole manifestation of the disease. FTD was present in 13 of 17 patients, ALS in 5 of 17 patients, and 2 of 17 patients did not develop FTD or ALS. Thirteen of 17 patients had more than one MD. The most common MD were parkinsonism and tremor (resembling essential tremor syndrome), each one present in 11 of 17 patients. Distal, stimulus-sensitive upper limbs myoclonus was present in 6 of 17 patients and cervical dystonia in 5 of 17 patients. Chorea was present in 5 of 17 patients, 4 of whom showed marked orofacial dyskinesias. The most frequent MD combination was tremor and parkinsonism, observed in 8 of 17 patients, 5 of whom also had myoclonus. C9orf72 patients without MD had shorter follow-up times and higher proportion of ALS, although these results did not survive the correction for multiple comparisons. CONCLUSIONS: MD are frequent in C9orf72. They may precede signs of ALS or FTD, or even be present in isolation. Parkinsonism, tremor, and myoclonus are most commonly observed.

MIND and Mediterranean Diets Associated with Later Onset of Parkinson's Disease.

BACKGROUND: The MIND diet has been linked with prevention of Alzheimer's disease and cognitive decline but has not been fully assessed in the context of Parkinson's disease (PD). The objective of the present study was to determine whether MIND diet adherence is associated with the age of Parkinson's disease onset in a manner superior to that of the Mediterranean diet. METHODS: Food Frequency Questionnaires from 167 participants with PD and 119 controls were scored for MIND and 2 versions of Mediterranean diet adherence. Scores were compared between sex and disease subgroups, and PD diet adherence was correlated with age at onset using univariate and multivariate linear models. RESULTS: The female subgroup adhered more closely to the MIND diet than the male subgroup, and diet scores were not modified by disease status. Later age of onset correlated most strongly with MIND diet adherence in the female subgroup, corresponding to differences of up to 17.4 years (P < 0.001) between low and high dietary tertiles. Greek Mediterranean adherence was also significantly associated with later PD onset across all models (P = 0.05-0.03). Conversely, only Greek Mediterranean diet adherence remained correlated with later onset across all models in men, with differences of up to 8.4 years (P = 0.002). CONCLUSIONS: This cross-sectional study found a strong correlation between age of onset of PD and dietary habits, suggesting that nutritional strategies may be an effective tool to delay PD onset. Further studies may help to elucidate potential nutrition-related sex-specific pathophysiological mechanisms and differential prevalence rates in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Isolated and combined genetic tremor syndromes: a critical appraisal based on the 2018 MDS criteria.

The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines "isolated" and "combined" tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired. Several genetic defects have been proven to cause tremor disorders, including autosomal dominant and recessive, X-linked, and mitochondrial diseases, as well as chromosomal abnormalities. Furthermore, some tremor syndromes are recognized in individuals with a positive family history, but their genetic confirmation is pending. Although most genetic tremor disorders show a combined clinical picture, there are some distinctive conditions in which tremor may precede the appearance of other neurological signs by years or remain the prominent manifestation throughout the disease course, previously leading to misdiagnosis as essential tremor (ET). Advances in the knowledge of genetically determined tremors may have been hampered by the inclusion of heterogeneous entities in previous studies on ET. The recent classification of tremors therefore aims to provide more consistent clinical data for deconstructing the genetic basis of tremor syndromes in the next-generation and long-read sequencing era. This review outlines the wide spectrum of tremor disorders with defined or presumed genetic etiology, both isolated and combined, unraveling diagnostic clues of these conditions and focusing mainly on ET-like phenotypes. Furthermore, we suggest a phenotype-to-genotype algorithm to support clinicians in identifying tremor syndromes and guiding genetic investigations.

Microbiota Composition and Metabolism Are Associated With Gut Function in Parkinson's Disease.

BACKGROUND: Parkinson's disease is characterized by a high burden of gastrointestinal comorbidities, especially constipation and reduced colonic transit time, and by gut microbiota alterations. The diverse metabolites produced by the microbiota are broadly relevant to host health. How microbiota composition and metabolism relate to gastrointestinal function in Parkinson's disease is largely unknown. The objectives of the current study were to assesses associations between microbiota composition, stool consistency, constipation, and systemic microbial metabolites in Parkinson's disease to better understand how intestinal microbes contribute to gastrointestinal disturbances commonly observed in patients. METHODS: Three hundred participants (197 Parkinson's patients and 103 controls) were recruited for this cross-sectional cohort study. Participants supplied fecal samples for microbiota sequencing (n = 300) and serum for untargeted metabolomics (n = 125). Data were collected on motor and nonmotor Parkinson's symptoms, medications, diet, and demographics. RESULTS: Significant microbiota taxonomic differences were observed in Parkinson's patients, even when controlling for gastrointestinal function. Parkinson's microbiota was characterized by reduced carbohydrate fermentation and butyrate synthesis capacity and increased proteolytic fermentation and production of deleterious amino acid metabolites, including p-cresol and phenylacetylglutamine. Taxonomic shifts and elevated proteolytic metabolites were strongly associated with stool consistency (a proxy for colonic transit time) and constipation among patients. CONCLUSIONS: Compositional and metabolic alterations in the Parkinson's microbiota are highly associated with gut function, suggesting plausible mechanistic links between altered bacterial metabolism and reduced gut health in this disease. The systemic detection of elevated deleterious proteolytic microbial metabolites in Parkinson's serum suggests a mechanism whereby microbiota dysbiosis contributes to disease etiology and pathophysiology. © 2020 International Parkinson and Movement Disorder Society.

PET Molecular Imaging in Familial Parkinson's Disease.

Most cases of Parkinson's disease (PD) are idiopathic, but some characteristics, such as early onset or a positive family history, raise suspicions of an inherited form of the disease. In the last decades several genes have been linked to parkinsonism, with different patterns of inheritance and different clinical phenotypes. Positron emission tomography (PET) imaging has helped to characterize genetic-linked parkinsonism, thanks to the availability of dopaminergic and nondopaminergic tracers. On the other hand, investigation of molecular changes in mutation carriers, even at preclinical stages, has provided a deeper comprehension of the pathogenesis of PD and of the compensatory mechanisms that take place in the very early stages of the disease.

Effect of adverse storage conditions on performance of glucometer test strips.

OBJECTIVE: A study was conducted to assess the impact of adverse storage environments, i.e., not manufacturer recommended, on the performance of reagent test strips used with a point of care testing (POCT) glucometer to measure whole blood glucose levels. DESIGN/SETTING: Glucose reagent test strips were placed in open, i.e., uncapped, and closed, i.e., capped vials. These vials were those used by the manufacturer to package and store the reagent test strips. One of each type of vial was placed in the manufacturer-recommended storage environment at room temperature and the adverse environments (incubator, direct light to mimic sunlight exposure, humidity, and refrigerated). The Accu-Chek Easy glucometer and reagent test strips as well as Accu-Chek Easy high and low glucose control solutions, manufactured by Roche, were used for this study. MAIN OUTCOME MEASURES: On day-3, day-7, and then once every 7 days, one strip from each vial in each environment was tested with the same glucometer using both a high and a low glucose control. The strip was considered failed for a type of vial and storage environment when either control was out of the reference range on a regular testing day and still out of range when tested the subsequent day. Testing continued up to 50 days. RESULTS: For the tested environments it was found that, overall, test strip stability lasted longer for closed vials than open vials. For open vials in adverse storage conditions, the refrigerator environment offered the longest stability at 35 to 50 days and direct light and humidity offered the shortest periods of stability at 3 to 14 days. CONCLUSIONS: The results of this study support the manufacturer's recommendations to store POCT glucose test strips in their original vial, capped, and at room temperature, though refrigeration may offer an alternative storage environment with acceptable stability. As compliance with testing, quality control, and storage instructions is often an issue with POCT, the manufacturers of these systems for blood glucose measurement should design storage systems that allow the patient to store the glucose meter and the reagent strips in the same location. Manufacturers may also need to consider designing storage systems that are more portable, knowing that patients must take the glucose meters and test strips with them when they travel. Roche's Accu-Chek Compact system is an example of such a design. The glucose test strips are incorporated into a drum that is stored in the Accu-Chek meter itself. When a patient performs a fingerstick blood glucose measurement, the drum advances to move a test strip outside the meter. When the test is complete, the test strip is ejected for disposal. Future studies to clarify the effect of adverse storage conditions, particularly refrigeration, on the integrity of POCT test systems and reagent strips is warranted with currently marketed brands.