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Objective To examine the effects of high-intensity laser therapy (HILT) on pain sensitivity and motor performance in patients with thumb carpometacarpal (CMC) osteoarthritis (OA). Design Prospective, triple-blinded, randomized, placebo-controlled trial. Setting Private practice, Malaga, Spain. Subjects Forty-three patients (mean ± SD age = 71 ± 12 years) with a diagnosis of thumb CMC OA grade 1–2 were randomized to the control group (N = 21) or experimental group (N = 22). Methods The experimental group (ExpG) received high-intensity laser therapy (HILT), and the control group (ConG) received a placebo treatment. The outcome measures were pain intensity (visual analog scale) and key pinch strength measurements (dynamometer). All outcome measures were collected at baseline, immediately following the intervention, at four weeks, and at 12 weeks following the intervention. Results Analysis of variance revealed a group × time interaction (F = 40.8, P  < 0.001) for pain intensity, with those patients receiving LT experiencing a greater reduction in pain compared with those receiving placebo therapy at the end of the intervention (P  < 0.001), as well as at 12 weeks after the intervention. Although mean values in the ExpG were higher than in the ConG for key pinch at assessment, these differences were not statistically significant. Conclusions HILT effectively diminishes pain intensity when used as an isolated treatment for patients with thumb CMC OA, but the effect of treatment decreases after 12 weeks. [ABSTRACT FROM AUTHOR]

Background: Conservative treatment for carpometacarpal (CMC) joint osteoarthritis (OA) may include orthotic fabrication to decrease pain. Different types of orthoses have been used as conservative interventions to improve symptoms, but there are no guidelines specifying if inclusion of the thumb metacarpophalangeal (MCP) in an orthosis is required in the treatment of thumb CMC joint OA. The main objective of this study is to determine the effectiveness of 2 different thumb CMC joint orthotic designs on pain reduction and improved hand function: one design immobilizes both the MCP joint and the CMC joint and the other design immobilizes only the CMC joint. Methods: A total of 66 patients were included in the study. One group of 33 patients received a short thumb orthosis with the MCP joint excluded, and the other group of 33 patients received a short thumb orthosis with the MCP joint included. Outcomes measures included the visual analog scale for pain and the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH; Spanish version) for function. Results: In both patient groups, the orthoses contributed to decreased pain levels and improved functional abilities (F1.0 = 315.467 and F1.0 = 72.419; both, P < .001). There was no significant difference between the 2 groups regarding pain or improvement in daily activities (F1.0 = 0.553 and F1.0 = 2.539; both, P > .05). Conclusion: There are benefits of either thumb orthotic design on pain reduction and functional improvement even after 1 week of using the orthoses as the sole conservative treatment. [ABSTRACT FROM AUTHOR]

Background: Patients with early‐onset dementia (EOD) often have a high genetic burden, and EOD kindreds with an autosomal dominant pattern of inheritance (ADPI) are particularly powerful for gene identification studies. Methods: We present the clinical phenotype and a whole‐exome sequencing (WES) study of a Spanish EOD family with ADPI, including five affected and two unaffected siblings. The proband case was negative for mutations in a Next Generation Sequencing panel of genes associated with neurodegenerative dementias. Candidate pathogenic mutations were prioritized according to frequency in population databases, impact/pathogenicity scores, and segregation (including a disease‐free second branch of the family). Final candidate genes were also examined in a set of Spanish‐origin FTD cases (n=583) and controls (n=493), plus in a Belgian WES dataset of AD (n=236) and FTD (n=269) cases. Results: Affected siblings had an average disease onset of 60.2 years (range 56‐63 years). Two had a behavioral rather than an amnestic phenotype, developing some psychotic features and significant parkinsonism after treatment with risperidone. However, CSF biomarkers in one patient were indicative of an AD pathology. WES was conducted in four affected and one unaffected siblings (all of them APOEε 4,4). Variant prioritization pointed to 16 candidate variants, including three loss of function variants, two in‐frame deletions, and 11 missense. Additional genetic analysis of another unaffected sibling, a fifth affected sibling with incipient disease, plus four unaffected relatives from the second branch narrowed the list to two candidate genes: TRIM25 (p.C186*, CADD score 36) and EEA1 (p.V693A, CADD 18.2). TRIM25 is a cytoplasmic protein that functions as an ubiquitin E3 ligase and is involved in the innate immune response, while EEA1 is an endosomal trafficking protein. Potentially pathogenic (CADD>20) rare variants were found in the studied populations in EEA1 (0,7‐3,8%; Spanish‐Belgian) and TRIM25 (0‐0,7%). All except one were missense variants of uncertain significance. Importantly, in TRIM25 which is highly intolerable for loss of function mutations, we identified one additional nonsense mutation in TRIM25 in a frontal‐type dementia case. Conclusion: We conclude that in this EOD family, the nonsense mutation in TRIM25 is the most likely causal mutation. [ABSTRACT FROM AUTHOR]

Plasma biomarkers represent promising tools for the screening and diagnosis of patients with neurodegenerative conditions. However, it is crucial to account for the effects of aging on biomarker profiles, especially in the oldest segments of the population. Additionally, biomarkers in this sample can offer in vivo insights into the physiological mechanisms underlying brain aging while concomitantly supporting cognitive preservation. In this study we analyzed plasma Alzheimer's disease (AD) core biomarkers, neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) using the Single Molecule Array (SIMOA) platform in 75 cognitively preserved nonagenarians, and compared with baseline samples of 153 volunteers who were cognitively unimpaired (CU) during six years (classified in ≤ 70, and 71 to 85 years of age), and with 108 AD patients. Nonagenarians almost lack the APOEε4 allele, and had significantly higher Aß40, Aß42, p-tau181, NfL, and GFAP, along with a significantly lower Aß42/40 ratio (P&;lt0.001) compared with the two CU groups. NfL and GFAP tripled concentrations in nonagenarians. No differences were noted in any plasma biomarker between the younger and older CU groups. Biomarkers correlated strongly with age only when analyzing together CU controls and nonagenarians. Compared with AD cases, nonagenarians showed lower p-tau181 (P=0.001), higher total tau (P=0.02), and much higher Aß40, Aß42 and NfL levels (P&;lt0.001). The levels of GFAP in nonagenarians were similar to those observed in AD patients. In conclusion, cognitively preserved nonagenarians do not develop the AD biomarker signature and exhibit higher levels of Aß42. However, their threefold increase in NfL and GFAP supports their aging brains are somehow resilient to neurodegeneration. These data support caution in the prognosis of clinical dementia based on NfL and GFAP values. Overall, plasma biomarkers in CU individuals remained quite stable till the eighties.

Introduction: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies., Methods: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate., Results: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism., Discussion: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases., Highlights: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)