Background: Carriers of small cytosine‐adenine‐guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied.Objective: To study the phenotype of CAG_36‐38 repeat carriers.Methods: We included 35 patients and premanifest carriers of CAG_36‐38 repeats. We compared clinical and neuropsychological profiles of 11 CAG_36‐38 patients with 11 matched CAG_40‐42 patients. In addition, we analyzed 243 CAG_36‐38 individuals from the ENROLL study to complete the phenotype description.Results: Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG_36‐38 and typically CAG_40‐42 expanded individuals. Chorea as the first symptom was significantly less frequent for CAG_36‐38 patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG_36‐38 carriers (P = 0.003). The similar cognitive and different motor profile of CAG_36‐38 (n = 243) and CAG_40‐42 (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e−8) and diagnosis happened significantly later in CAG_36‐38 (P = 2.2e−6) despite a similar age at symptom onset (P = 0.29).Conclusions: We showed that small CAG_36‐38 expansion carriers had a similar cognitive profile to those with the more common CAG_40‐42 expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Primary care is often the first point of contact for patients with cognitive complaints, making initial cognitive screening an essential step to avoid delays in diagnosing Alzheimer's disease (AD) at an early stage. We developed MemScreen, a self-administered smartphone application that assesses overall cognition and verbal memory, and evaluated its ability to detect mild cognitive impairment (MCI) in both general and clinical populations. We conducted two validation cohort studies: (1) UK-based Whitehall II cohort study (13th wave, 2018-2022) involving a general population (MCI defined by poor performance on a global cognitive score), and (2) five French memory clinics involving patients without dementia (amnestic MCI defined by the Free and Cued Selective Reminding Test). MemScreen, MMSE, and TMT-A effectiveness was assessed using Area Under the Curve (AUC) values from unadjusted and adjusted logistic regression models. In Whitehall II (n = 2118, mean age 75.9 years, 23.9 % women, 14.5 % MCI), median MemScreen completion time was 4 min 18 s. MemScreen had the highest AUC (0.87; 95 % CI: 0.82-0.89) for distinguishing MCI, outperforming MMSE (AUC = 0.79; 0.76-0.82; p = 0.018) and TMT-A (AUC = 0.77; 0.74-0.80; p = 0.023). MemScreen sensitivity and specificity were 78.6 % and 78.7 %, respectively. In memory clinics (n = 303, mean age 70.5 years, 53 % women, 46.9 % amnestic MCI), median completion time was 5 min 17 s. MemScreen showed superior performance (AUC = 0.87; 0.83-0.91) compared to MMSE (AUC = 0.72; 0.67-0.78; p < 0.001) and TMT-A (AUC = 0.63; 0.56-0.69; p < 0.001), with 93.0 % sensitivity and 54.0 % specificity for amnestic MCI. MemScreen outperformed traditional tests in identifying MCI in both general and clinical populations. Its self-administration and short completion time suggest potential as an effective screening tool to optimize memory clinic referrals for AD diagnosis and treatment.

Transcranial direct current stimulation (tDCS) has generated some promising outcomes in primary progressive aphasia (PPA). The logopenic variant (lv-PPA), one of the most frequent PPA phenotypes, erodes the temporal-parietal junction (TPJ) generating impaired lexical processing, rapidly extending to semantic deficits. Positive tDCS effects have been reported in several small-cohort studies but there is need for rigorous sham-controlled double-blind investigations to substantiate, or not, beneficial effects. We used a sham-controlled double-blind counter-balanced crossover design with 12 clinically and imaging-characterized lv-PPA patients applying, according to the principle of interhemispheric rivalry, anodal and cathodal tDCS over the left and right TPJ, respectively, as compared to sham. A letter fluency (lexical access), a picture-naming (lexical/semantic access), and a semantic-matching task (semantic access) were applied before and after tDCS. Computational modeling was used to characterize predicted cortical tDCS current distribution. Comparisons of post/pre-tDCS results did not show language improvement in any task. Finite element models showed impact for both tDCS modalities on the TPJ, but with lower radial field-strength when atrophy was implemented in the model. Correlation analyses on individual data, uncorrected for multiples comparisons, suggested that lesser aphasia severity and shorter disease duration are associated with more efficient tDCS effects. Our results showing the absence of significant tDCS outcomes in lv-PPA mitigate previous reports of positive tDCS effects with similar or smaller patient sample sizes, and they demonstrate the need for exploring factors influencing stimulation effects. Findings from computational modelling combined with our uncorrected correlation results suggest that tDCS use might be most appropriate in PPA patients having slight atrophy and aphasia severity. Future studies on larger patient populations are required for robust proof-of-concept regarding therapy use of tDCS in PPA.

The nonfluent/agrammatic variant of primary progressive aphasia (nfav-PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes that raise diagnostic challenges related to several issues. First, there are two divergent conceptions, one stipulating that (i) nfav-APP and PPAOS are distinct entities, and the other (ii) that PPAOS has to be integrated into the nfav-APP spectrum. A second related issue concerns the consideration of phonological dimensions, lying at the language interface with speech, which could potentially help overcome the nfva-PPA/PPAOS controversy. Third, there is a lack of internationally validated clinical tests assessing apraxia of speech and syntactic abilities with sufficient specificity and sensitivity. This narrative review discusses these issues taking into account clinical, neurocognitive and neurobiological dimensions. It proposes a conceptual-integrative framework conciliating competing nfav-APP/PPAOS accounts while suggesting a graded continuum with subdivisions, related to neurodegenerative expansion throughout language/speech production systems, ranging from syntactic to phonological to phonetic-articulatory impairments. A second controversy in the field of PPA arises from divergent conceptions of semantic PPA (sv-PPA), defined by primary damage to verbal semantics, and of semantic dementia (SD) characterized by multimodal semantic impairments. The current consensus criteria of PPA have deconstructed the initial SD conception by absorbing it into sv-PPA, hence leaving mixed and some non-verbal semantic phenotypes nosologically orphaned. Again, the article proposes a conceptual and integrative model, built on findings from clinical research and cognitive neuroscience, suggesting a graded continuum with subdivisions spanning from verbal to different non-verbal semantic impairments including social-semantic/behavioral phenotypes.