New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Polygenic risk and hazard scores for Alzheimer's disease prediction

OBJECTIVE: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. // METHODS: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. // RESULTS: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. // INTERPRETATION: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study)

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Bihemispheric tDCS enhances language recovery but does not alter BDNF levels in chronic aphasic patients

none6Marangolo P; Gelfo F; Shofany J; Razzano C; Caltagirone C; Angelucci CMarangolo, Paola; Gelfo, F; Shofany, J; Razzano, C; Caltagirone, C; Angelucci, C

The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson’s disease subjects

Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30-T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III - Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action

Moving Beyond the Brain: Transcutaneous Spinal Direct Current Stimulation in Post-Stroke Aphasia.

Over the last 20 years, major advances in cognitive neuroscience have clearly shown that the language function is not restricted into the classical language areas but it involves brain regions, which had never previously considered. Indeed, recent lines of evidence have suggested that the processing of words associated to motor schemata, such as action verbs, modulates the activity of the sensorimotor cortex, which, in turn, facilitates its retrieval. To date, no studies have investigated whether the spinal cord, which is functionally connected to the sensorimotor system, might also work as an auxiliary support for language processing. We explored the combined effect of transcutaneous spinal direct current stimulation (tsDCS) and language treatment in a randomized double-blind design for the recovery of verbs and nouns in 14 chronic aphasics. During each treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (10th vertebra) in three different conditions: (1) anodic, (2) cathodic and (3) sham, while performing a verb and noun naming tasks. Each experimental condition was run in five consecutive daily sessions over 3 weeks. Overall, a significant greater improvement in verb naming was found during the anodic condition with respect to the other two conditions, which persisted at 1 week after the end of the treatment. No significant differences were present for noun naming among the three conditions. The hypothesis is advanced that anodic tsDCS might have influenced activity along the ascending somatosensory pathways, ultimately eliciting neurophysiological changes into the sensorimotor areas which, in turn, supported the retrieval of verbs. These results further support the evidence that action words, due to their sensorimotor semantic properties, are partly represented into the sensorimotor cortex. Moreover, they also document, for the first time, that tsDCS enhances verb recovery in chronic aphasia and it may represent a promising new tool for language treatment

Bihemispheric tDCS enhances language recovery but does not alter BDNF levels in chronic aphasic patients

Several studies have shown that transcranial direct current stimulation (tDCS) is a useful tool to enhance language recovery in aphasia. It has also been suggested that modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) might be part of the mechanisms involved in tDCS effects on synaptic connectivity. However, all language studies have previously investigated the effects using unihemispheric stimulation. The purpose of the present study is to investigate the role of bihemispheric tDCS on language recovery and BDNF serum levels

The Efficacy of Balance Training with Video Game-Based Therapy in Subacute Stroke Patients: A Randomized Controlled Trial

The video game-based therapy emerged as a potential valid tool in improving balance in several neurological conditions with controversial results, whereas little information is available regarding the use of this therapy in subacute stroke patients. The aim of this study was to investigate the efficacy of balance training using video game-based intervention on functional balance and disability in individuals with hemiparesis due to stroke in subacute phase. Fifty adult stroke patients participated to the study: 25 subjects were randomly assigned to balance training with Wii Fit, and the other 25 subjects were assigned to usual balance therapy. Both groups were also treated with conventional physical therapy (40 min 2 times/day). The main outcome was functional balance (Berg Balance Scale-BBS), and secondary outcomes were disability (Barthel Index-BI), walking ability (Functional Ambulation Category), and walking speed (10-meters walking test). Wii Fit training was more effective than usual balance therapy in improving balance (BBS: 53 versus 48, P = 0.004) and independency in activity of daily living (BI: 98 versus 93,P = 0.021). A balance training performed with a Wii Fit as an add on to the conventional therapy was found to be more effective than conventional therapy alone in improving balance and reducing disability in patients with subacute stroke

The efficacy of balance training with video game-based therapy in subacute stroke patients: a randomized controlled trial

The video game-based therapy emerged as a potential valid tool in improving balance in several neurological conditions with controversial results, whereas little information is available regarding the use of this therapy in subacute stroke patients. The aim of this study was to investigate the efficacy of balance training using video game-based intervention on functional balance and disability in individuals with hemiparesis due to stroke in subacute phase. Fifty adult stroke patients participated to the study: 25 subjects were randomly assigned to balance training with Wii Fit, and the other 25 subjects were assigned to usual balance therapy. Both groups were also treated with conventional physical therapy (40 min 2 times/day). The main outcome was functional balance (Berg Balance Scale-BBS), and secondary outcomes were disability (Barthel Index-BI), walking ability (Functional Ambulation Category), and walking speed (10-meters walking test). Wii Fit training was more effective than usual balance therapy in improving balance (BBS: 53 versus 48, P = 0.004) and independency in activity of daily living (BI: 98 versus 93, P = 0.021). A balance training performed with a Wii Fit as an add on to the conventional therapy was found to be more effective than conventional therapy alone in improving balance and reducing disability in patients with subacute stroke