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Essential tremor (ET) is one of the most common movement disorders, with a reported >60 million affected individuals worldwide. The definition and underlying pathophysiology of ET are contentious. Patients present primarily with motor features such as postural and action tremors, but may also have other non-motor features, including cognitive impairment and neuropsychiatric symptoms. Genetics account for most of the ET risk but environmental factors may also be involved. However, the variable penetrance and challenges in validating data make gene–environment analysis difficult. Structural changes in cerebellar Purkinje cells and neighbouring neuronal populations have been observed in post-mortem studies, and other studies have found GABAergic dysfunction and dysregulation of the cerebellar–thalamic–cortical circuitry. Commonly prescribed medications include propranolol and primidone. Deep brain stimulation and ultrasound thalamotomy are surgical options in patients with medically intractable ET. Further research in post-mortem studies, and animal and cell-based models may help identify new pathophysiological clues and therapeutic targets and, together with advances in omics and machine learning, may facilitate the development of precision medicine for patients with ET. This Primer summarizes the epidemiology, diagnosis, treatment and pathophysiology of essential tremor, a movement disorder that is typically characterized by upper limb action tremor in the absence of other neurological signs.

Parkinson's disease (PD) is a well-known neurodegenerative disease with a strong association established with systemic inflammation. Recently, the role of the gingipain protease group from was implicated in Alzheimer's disease and here we present evidence, using a fluorescent antibody to detect gingipain R1 (RgpA), of its presence in a PD population. To further elucidate the action of this gingipain, as well as the action of the lipopolysaccharide (LPS) from , low concentrations of recombinant RgpA and LPS were added to purified fluorescent fibrinogen. We also substantiate previous findings regarding PD by emphasizing the presence of systemic inflammation via multiplex cytokine analysis, and demonstrate hypercoagulation using thromboelastography (TEG), confocal and electron microscopy. Biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. In our PD and control blood analysis, our results show increased hypercoagulation, the presence of amyloid formation in plasma, and profound ultrastructural changes to platelets. Our laboratory analysis of purified fibrinogen with added RgpA, and/or LPS, showed preliminary data with regards to the actions of the protease and the bacterial membrane inflammagen on plasma proteins, to better understand the nature of established PD.

Abnormalities on CT imaging may contribute to the diagnosis of tuberculous meningitis (TBM). Recently, an expert consensus case definition (CCD) and set of imaging criteria for diagnosing basal meningeal enhancement (BME) have been proposed. This study aimed to evaluate the sensitivity, specificity and reliability of these in a prospective cohort of adult meningitis patients. Initial diagnoses were based on the CCD, classifying patients into: 'Definite TBM' (microbiological confirmation), 'Probable TBM' (diagnostic score ≥10), 'Possible TBM' (diagnostic score 6-9), 'Not TBM' (confirmation of an alternative diagnosis) or 'Uncertain' (diagnostic score of <6). CT images were evaluated independently on two occasions by four experienced reviewers. Intra-rater and inter-rater agreement were calculated using the kappa statistic. Sensitivities and specificities were calculated using both 'Definite TBM' and either 'Definite TBM' or 'Probable TBM' as gold standards. CT scan criteria for BME had good intra-rater agreement (κ range 0.35-0.78) and fair to moderate inter-rater agreement (κ range 0.20-0.52). Intra- and inter-rater agreement on the CCD components were good to fair (κ  =  ranges 0.47-0.81 and 0.21-0.63). Using 'Definite TBM' as a gold standard, the criteria for BME were very specific (61.5%-100%), but insensitive (5.9%-29.4%). Similarly, the imaging components of the CCD were highly specific (69.2-100%) but lacked sensitivity (0-56.7%). Similar values were found when using 'Definite TBM' or 'Probable TBM' as a gold standard. The fair to moderate inter-rater agreement and poor sensitivities of the criteria for BME suggest that little reliance should be placed in these features in isolation. While the presence of the CCD criteria of acute infarction or tuberculoma(s) appears useful as rule-in criteria, their absence is of little help in excluding TBM. The CCD and criteria for BME, as well as any new criteria, need to be standardized and validated in prospective cohort studies.

Alpha‐synuclein (αsyn) aggregates are pathological features of several neurodegenerative conditions including Parkinson disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). Accumulating evidence suggests that mitochondrial dysfunction and impairments of the autophagic‐lysosomal system can contribute to the deposition of αsyn, which in turn may interfere with health and function of these organelles in a potentially vicious cycle. Here we investigated a potential convergence of αsyn with the PINK1‐PRKN‐mediated mitochondrial autophagy pathway in cell models, αsyn transgenic mice, and human autopsy brain. PINK1 and PRKN identify and selectively label damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) to mark them for degradation (mitophagy). We found that disease‐causing multiplications of αsyn resulted in accumulation of the ubiquitin ligase PRKN in cells. This effect could be normalized by starvation‐induced autophagy activation and by CRISPR/Cas9‐mediated αsyn knockout. Upon acute mitochondrial damage, the increased levels of PRKN protein contributed to an enhanced pS65‐Ub response. We further confirmed increased pS65‐Ub‐immunopositive signals in mouse brain with αsyn overexpression and in postmortem human disease brain. Of note, increased pS65‐Ub was associated with neuronal Lewy body‐type αsyn pathology, but not glial cytoplasmic inclusions of αsyn as seen in MSA. While our results add another layer of complexity to the crosstalk between αsyn and the PINK1‐PRKN pathway, distinct mechanisms may underlie in cells and brain tissue despite similar outcomes. Notwithstanding, our finding suggests that pS65‐Ub may be useful as a biomarker to discriminate different synucleinopathies and may serve as a potential therapeutic target for Lewy body disease. The increase of the selective mitophagy marker pS65‐Ub in human autopsy brain is associated with neuronal Lewy body‐type, but not glial cytoplasmic inclusions of alpha‐synuclein pathology.

Parkinson’s disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants in CFAP65 , RTF1 , NRXN2 , TEP1 and CCNF . The variant in NRXN2 was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. If NRXN2 is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD.

Background Acoustic telemetry is increasingly being used as a tool to measure survival, migration timing and behaviour of fish. Tagged fish may fall prey to other animals with the tag continuing to be detected whilst it remains in the gastrointestinal tract of the predator. Failure to identify post-predation detections introduces “predation bias” into the data. We employed a new predator tag technology in the first known field trial to understand the extent these tags could reduce predation bias in Atlantic salmon ( Salmo salar L.) smolt migration through a 65-km zone beginning in freshwater and extending through an estuary. These tags signal predation by detecting a pH change in the predators’ gut during digestion of a tagged prey. We quantified survival and timing bias by comparing measurements from non- and post-predated detections of tagged individuals’ to only those detections where predation was not signalled. Results Of the 50 fish tagged, 41 were detected with 24 of these signalling as predated. Predation bias was greatest in the upper estuary and decreased towards the bay. Survival bias peaked at 11.6% at river km 54. Minimum and maximum migration time were both biased long and were 16% and 4% greater than bias corrected timing at river km 66 and 54, respectively. After correcting for bias, the apparent survival from release through freshwater and estuary was 19% and minimum and maximum migration timing was 6.6 and 7.0 days, respectively. Conclusions Using this tag, we identified a high proportion of predation events that may have otherwise gone unnoticed using conventional acoustic tags. Estimated survival presented the greatest predation bias in the upper estuary which gradually declined to nearly no apparent bias in the lower estuary as predated tags failed through time to be detected. This is most likely due to tag expulsion from the predator between or upstream of receiver arrays. Whilst we have demonstrated that predation can bias telemetry results, it appears to be rather short-lived given the apparent retention times of these tags within the predators introducing the bias.

Predation and mortality are often difficult to estimate in the ocean, which hampers the management and conservation of marine fishes. We used data from pop-up satellite archival tags to investigate the ocean predation and mortality of adult Atlantic salmon ( Salmo salar ) released from 12 rivers flowing into the North Atlantic Ocean. Data from 156 tagged fish revealed 22 definite predation events (14%) and 38 undetermined mortalities (24%). Endothermic fish were the most common predators (n = 13), with most of these predation events occurring in the Gulf of St. Lawrence and from the Bay of Biscay to the Irish Shelf. Predation by marine mammals, most likely large deep-diving toothed whales (n = 5), and large ectothermic fish (n = 4) were less frequent. Both the estimated predation rates (Z P ) and total mortality rates (Z M ) where higher for Atlantic salmon from Canada, Ireland, and Spain (Z P  = 0.60–1.32 y −1 , Z M  = 1.73–3.08 y −1 ) than from Denmark and Norway (Z P  = 0–0.13 y −1 , Z M  = 0.19–1.03 y −1 ). This geographical variation in ocean mortality correlates with ongoing population declines, which are more profound for southern populations, indicating that low ocean survival of adults may act as an additional stressor to already vulnerable populations.

Background The leucine-rich repeat kinase 2 gene ( LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab–Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab–Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15–1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35–3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab–Berber series (combined odds ratio 0·82, 0·72–0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20–2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36–1·07; p=0·087). In the Arab–Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33–15·09; p=0·012). The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Michael J Fox Foundation and National Institutes of Health.

BackgroundRecent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture.MethodsWe studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers.ResultsTendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells.ConclusionsTissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.