Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized. To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD. Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred. A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female). Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed. All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall. Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.

Four-repeat (4R) tauopathies, such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), often exhibit considerable phenotypic overlap, which complicates invivo diagnosis. This report presents a 62-year-old woman who initially presented clinical features of corticobasal syndrome, such as asymmetric parkinsonism, fixed right limb dystonia, and orobuccal apraxia. The later development of supranuclear vertical gaze palsy and recurrent falls led to a revised diagnosis of probable PSP. Neuropsychological evaluation identified a non-amnestic major neurocognitive disorder with severe executive dysfunction, attentional deficits, and apraxia. Neuroimaging contributed critical diagnostic information: FDG-PET revealed severe asymmetric cortical hypometabolism in the left frontoparietal regions, and MRI demonstrated marked midbrain atrophy with the hummingbird sign. Volumetric analysis further confirmed asymmetric cortical atrophy, predominantly in the left frontoparietal areas, as well as reduced brainstem volume. Negative genetic testing supported a sporadic etiology. This case underscores the complex clinical overlap within the 4R tauopathy spectrum, illustrating that PSP may present with a CBS phenotype. The findings support the clinical value of categorizing these disorders as probable 4R-tauopathies to facilitate early recognition. Integration of clinical, radiological, and volumetric data is crucial for diagnostic precision.

Introduction: Restless legs syndrome (RLS) is a neurological sensorimotor disorder with both sporadic and familial forms, the latter frequently associated with a genetic basis. Materials and methods: Four members of a family from Yarumal, Antioquia, with symptoms suggestive of restless legs syndrome, underwent a neurological evaluation, including a workup for secondary causes. The diagnosis was established by applying the clinical criteria proposed by the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), thereby ensuring greater diagnostic certainty. Additionally, a narrative review was conducted using Medline to explore the genetic component of restless legs syndrome. Results: Genetic studies, including genome-wide association studies (GWAS) and whole-exome sequencing (WES), have identified several risk variants associated with restless legs syndrome. In vivo mouse and zebrafish models have elucidated the role of some variants in the neurobiology of this syndrome. Conclusion: This is the first case report of a Colombian family with four documented members and two deceased members affected by restless legs syndrome across three generations. The family exhibits an autosomal dominant inheritance pattern, although with significant clinical variability. Despite its complexity, restless legs syndrome demonstrates a significant genetic component contributing to its familial aggregation.

Alzheimer’s disease (AD), the leading cause of dementia, lacks an inexpensive and non-invasive method for early detection. Here, we investigate whether electrodermal activity (EDA), a measure of changes in electrical conductance at the skin’s surface, can offer a convenient avenue for AD screening by capturing the autonomic dysfunction associated with the disease’s pathology. As few studies have comprehensively examined EDA’s utility as a standalone biomarker for AD, we conducted a pilot study with 10 cognitively healthy controls and 20 patients with AD, evaluating EDA recordings collected during an orthostatic test and a Montreal Cognitive Assessment (MoCA). The AD group included both carriers from Colombian kindreds affected by autosomal-dominant AD and patients with sporadic late-onset AD. We compared EDA features between groups using statistical analysis and tested whether machine learning models could separate the two groups using these features. During the MoCA, phasic EDA measures, specifically the number of skin conductance responses (NSSCR) and mean time-variant sympathetic tone (TVSymp), were significantly lower in the AD group than in controls (NSSCR: $p=0.0083$, Cohen’s $d=-1.07$; mean TVSymp: $p=0.0166$, $d=-0.96$), suggesting a blunted sympathetic response to cognitive stress in AD. No significant between-group differences were observed during the orthostatic test (all $p\ge 0.60$). A random forest classifier trained on MoCA-derived EDA features achieved a balanced accuracy of 78% (95% CI 60 to 93%; 75% sensitivity, 80% specificity, AUROC 0.75), with phasic features contributing most to performance. Performance did not differ significantly from that of the support vector machine or logistic regression models. These results provide preliminary, hypothesis-generating evidence for the utility of EDA in screening for AD. The small sample size, unequal group allocation, sex imbalance, and substantial mean age disparity between groups (≈23.5 years) limit the strength of these conclusions and necessitate replication in larger, age- and sex-matched cohorts that include prodromal stages.