CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.

Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10^-09 and 95%CI:-7.28 to -4.44, p = 5.87×10^-16, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS.

Background: The emerging evidence of the role of the glymphatic system (GS) in Alzheimer’s disease (AD) provides new opportunities for intervention from the earliest stages of the disease. The aim of the study is to evaluate the efficacy of GS in AD to identify new disease biomarkers. Methods: We performed a two-stage proteomic study to evaluate the GS health using intravenous gadolinium-based contrast agent (GBCA) with serial T1 3T magnetic resonance imaging (MRI) in individuals with amnestic mild cognitive impairment (aMCI). In Stage 1 (evaluated in the Cohort 1 of aMCI participants (n = 11)), we correlated the levels of 7K cerebrospinal fluid (CSF) proteins (estimated by SOMAscan) with GS health in 78 Freesurfer-segmented brain regions of interest (ROIs). Results: A total of seven different proteins were significantly associated with GS health (p-value < 6.4 × 10^–4). The stronger correlations were identified for NSUN6, GRAAK, OLFML3, ACTN2, RUXF, SHPS1 and TIM-4. A pathway enrichment analysis revealed that the proteins associated with GS health were mainly implicated in neurodegenerative processes, immunity and inflammation. In Stage 2, we validated these proteomic results in a new cohort of aMCI participants (with and without evidence of AD pathology in CSF (aMCI(-) and aMCI/AD( +); n = 22 and 7, respectively) and healthy controls (n = 10). Proteomic prediction models were generated in each ROI. These were compared with demographic-only models for identifying participants with aMCI(-) and aMCI/AD( +) vs controls. This analysis was repeated to determine if the models could identify those with aMCI/AD( +) from both aMCI(-) and controls. The proteomic models were found to outperform the demographic-only models. Conclusions: Our study identifies proteins linked with GS health and involved the immune system in aMCI participants.

Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (q-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and p-value = 9.6 × 10⁻⁶) and non-lobar ICH (z-score = −4.8 and p-value = 1.58 × 10⁻⁶) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (p-value = 3.66 × 10⁻⁵) and non-lobar ICH (p-value = 1.81 × 10⁻⁵). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.

Decades of pharmacogenetic research have revealed genetic biomarkers of clinical response to antipsychotics. Genetic variants in antipsychotic targets, dopamine and serotonin receptors in particular, and in metabolic enzymes have been associated with the efficacy and toxicity of antipsychotic treatments. However, genetic prediction of antipsychotic response based on these biomarkers is far from accurate. Despite the clinical validity of these findings, the clinical utility remains unclear. Nevertheless, genetic information on CYP metabolic enzymes responsible for the biotransformation of most commercially available antipsychotics has proven to be effective for the personalisation of clinical dosing, resulting in a reduction of induced side effects and in an increase in efficacy. However, pharmacogenetic information is rarely used in psychiatric settings as a prescription aid. Lack of studies on cost-effectiveness, absence of clinical guidelines based on pharmacogenetic biomarkers for several commonly used antipsychotics, the cost of genetic testing and the delay in results delivery hamper the implementation of pharmacogenetic interventions in clinical settings. This narrative review will comment on the existing pharmacogenetic information, the clinical utility of pharmacogenetic findings, and their current and future implementations.

Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.