Commentary: Global Alzheimer's disease and Alzheimer's disease related dementia research funding organizations support and engage the research community throughout the COVID-19 pandemic.

The COVID-19 pandemic has disproportionately affected more vulnerable populations, including those living with dementia. Over 50 million individuals worldwide are living with Alzheimer's disease (AD) or other dementia, and it is crucial to continue the fight against the condition during the global pandemic. Since the start of mandated lockdowns in March 2020, charity and non-profit organizations that fund AD and related dementia research continue to respond to the needs of the AD research community, ensuring the momentum continues and accelerates. Members of the International Alzheimer's and Related Dementia Research Funder Consortium, a group of nearly 40 funding organizations that informally convene throughout the year to share updates and information, have taken a number of steps to ensure the continued support of the research community. Even during times of uncertainty, it is essential that the field moves forward to uncover preventions, diagnoses, and treatments for these diseases that affect many millions globally.

ALS/FTD-associated FUS activates GSK-3ß to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations.

Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca(2+) uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca(2+) levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3ß (GSK-3ß), a kinase already strongly associated with ALS/FTD.

Guidelines to improve animal study design and reproducibility for Alzheimer's disease and related dementias: For funders and researchers.

The reproducibility of laboratory experiments is fundamental to the scientific process. There have been increasing reports regarding challenges in reproducing and translating preclinical experiments in animal models. In Alzheimer's disease and related dementias, there have been similar reports and growing interest from funding organizations, researchers, and the broader scientific community to set parameters around experimental design, statistical power, and reporting requirements. A number of efforts in recent years have attempted to develop standard guidelines; however, these have not yet been widely implemented by researchers or by funding agencies. A workgroup of the International Alzheimer's disease Research Funder Consortium, a group of over 30 research funding agencies from around the world, worked to compile the best practices identified in these prior efforts for preclinical biomedical research. This article represents a consensus of this work group's review and includes recommendations for researchers and funding agencies on designing, performing, reviewing, and funding preclinical research studies.

A direct interaction between leucine-rich repeat kinase 2 and specific ß-tubulin isoforms regulates tubulin acetylation.

Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2 (LRRK2), are a common cause of Parkinson disease. LRRK2 has been suggested to influence the cytoskeleton as LRRK2 mutants reduce neurite outgrowth and cause an accumulation of hyperphosphorylated Tau. This might cause alterations in the dynamic instability of microtubules suggested to contribute to the pathogenesis of Parkinson disease. Here, we describe a direct interaction between LRRK2 and ß-tubulin. This interaction is conferred by the LRRK2 Roc domain and is disrupted by the familial R1441G mutation and artificial Roc domain mutations that mimic autophosphorylation. LRRK2 selectively interacts with three ß-tubulin isoforms: TUBB, TUBB4, and TUBB6, one of which (TUBB4) is mutated in the movement disorder dystonia type 4 (DYT4). Binding specificity is determined by lysine 362 and alanine 364 of ß-tubulin. Molecular modeling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine 40 acetylation site in α-tubulin. This location is predicted to be poorly accessible within mature stabilized microtubules, but exposed in dynamic microtubule populations. Consistent with this finding, endogenous LRRK2 displays a preferential localization to dynamic microtubules within growth cones, rather than adjacent axonal microtubule bundles. This interaction is functionally relevant to microtubule dynamics, as mouse embryonic fibroblasts derived from LRRK2 knock-out mice display increased microtubule acetylation. Taken together, our data shed light on the nature of the LRRK2-tubulin interaction, and indicate that alterations in microtubule stability caused by changes in LRRK2 might contribute to the pathogenesis of Parkinson disease.

The dementia research career pipeline: Gender disparities in publication authorships and grant funding outcomes at different career stages.

Background: Multiple studies have analysed gender disparities in academic research. Here we study the gender composition of the dementia research field at different stages in the career pipeline. Methods: We use various data sources to gain insights about the gender ratio across career stages: conference attendance data as a proxy for the field as a whole; bibliometric data to know who publishes, and who occupies positions of seniority among the listed authors; and Alzheimer's Research UK's (ARUK) internal grant funding data to understand who obtains funding. We also analyse the scoring of grant applications based on the gender of the reviewers. Results: Our results confirm that female researchers leave dementia academic research at higher rates than men, before transitioning into senior positions. In 2020, they comprised over 60% of the field, produced 54% of first authorships, but only accounted for 38% of last authorships. Overall, women received 37% of ARUK's competitive grants, with significant differences between grant schemes awarded for early career researchers (64% female awardees) compared to grant schemes aimed at senior researchers (33% female awardees). Men and women applied for and obtained grants at significantly different rates depending on the career stage at which the grant was aimed.Finally, we also observed that male and female reviewers apply evaluation criteria differently, with men giving better scores than women on average. Conclusions: Our study adds to the evidence that shows that women get published less, receive less funding, and transition into senior academic positions at disproportionally lower rates than men do. We briefly discuss potential reasons why gender disparities arise as researchers progress into senior positions, and offer interventions ARUK can implement in its application and evaluation process to address those disparities.

Alzheimer's Research UK has conducted work to identify and address gender disparities along the career pipeline in dementia research. We used a mix of data from scientific publications (from more than 180,000 dementia research papers published between the years 2000 and 2020) and internal funding data (from more than 2,000 grant applications) to show that female researchers leave academia at higher rates than men before transitioning into senior positions. Women occupy fewer senior positions in authors list, despite being the majority of junior authors; they apply in lower numbers to senior grants schemes, despite being the majority of applicants to early career schemes; and they have lower success rates in obtaining funding for senior grant schemes, despite having higher success rate in junior calls. Moreover, our analysis shows that while the overall gender gap has been closing, the rate of change at senior positions has been slower than at junior positions, which indicates that women disproportionately face barriers that make their career progression more difficult. Alzheimer's Research UK is using this information to inform programmes that will help brilliant researchers succeed in their careers without being hindered by external factors. This will allow us to for people with dementia.

Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.

Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson's disease. The LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an intramolecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3), key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1 DEP domain were necessary and sufficient for LRRK2-DVL1 interaction. Co-expression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2-DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations at residues R1441 and R1728 strengthened LRRK2-DVL1 interactions. Co-expression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-COR domain mutations segregating with Parkinson's disease. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity, and (ii) Roc-COR domain mutations modulating LRRK2-DVL interactions indirectly influence kinase activity. Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new targets for genetic analysis in Parkinson's disease.

The role of parental social class, education and unemployment on child cognitive development.

OBJECTIVE: Assessing the association between socioeconomic gradient and cognitive development among children of a Spanish birth cohort aged 5-6 years from a gender perspective. METHOD: Cognitive development was assessed on 525 children aged 5-6 years in the INMA-Valencia cohort, with the Global Cognitive Score (GCS) from McCarthy Scales of Children's Abilities. Information on social class, education level and employment was collected for both parents in addition to other sociodemographic factors, parental, family and child characteristics. The relationship between maternal and paternal socioeconomic gradient and cognitive development was assessed by linear regressions and comparing the variance explained by each indicator measured in the mother and father. RESULTS: Maternal socioeconomic gradient indicators explained more variance on GCS than paternal. Maternal education and paternal social class had an important individual effect that stayed after adjusting by other parental, child and family determinants. In the multivariable analysis, maternal education, age and intelligence, paternal social class and the child's age and sex were significantly associated with cognitive development. CONCLUSIONS: Diverse socioeconomic gradient factors have an important influence on cognitive development, maternal education being the strongest determinant. Policies should be implemented to mitigate the negative effects of this gradient on child development.

Low antimicrobial resistance rates of Mycobacterium tuberculosis complex between 2000 and 2015 in Gipuzkoa, northern Spain.

OBJECTIVE: Although the incidence of tuberculosis (TB) has declined, TB drug resistance remains a major problem. The TB rate in Gipuzkoa (northern Spain) is higher than the European average. The objective of this study was to determine the antimicrobial susceptibility of 1855 Mycobacterium tuberculosis complex isolates (94.5% of confirmed cases between 2000 and 2015). METHODS: Susceptibility testing was performed using the agar proportion method and a commercial broth system (MGIT 960). In isoniazid- or rifampicin-resistant strains, we studied genetic determinants of drug resistance and genotype (MIRU-VNTR). RESULTS: The annual mean incidence of TB was 24.5 cases per 100,000 population on average, and tended to decrease. The multidrug-resistant TB rate was 0.5% (9/1855), and no extensively drug-resistant TB strains were detected. Rates of resistance to isoniazid and rifampicin were 3.9% (range, 3.4-4.3%) and 0.6% (range, 0.4-1.4%), respectively. TB resistance was more common among foreign-born individuals and those who had received previous TB treatment. Genotyping of 102 resistant strains showed predominance of the Euro-American lineage, although 4/9 multidrug-resistant strains had Eastern lineages (2 East African-Indian, and 2 East Asian [Beijing]). CONCLUSIONS: In Gipuzkoa, with a moderate incidence of TB, resistance was very low, mostly being detected among individuals who were born abroad or who had a history of TB treatment.

Alzheimer's Research UK 2016 Conference report.

The annual Alzheimer's Research UK (ARUK) Conference was hosted by the Manchester and North West Network Centre on March 8-9, 2016. In this report, we provide a summary of the research presented.

Report from the Alzheimer's Research UK Conference 2015.

On 10-11 March 2015 University College London hosted the annual Alzheimer's Research UK Conference. This report provides an overview of the presentations and discussions that took place.

Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

BACKGROUND: First-order relatives of persons with Autism Spectrum Disorder (ASD) exhibit a cognitive pattern which is part of a broader autism phenotype. METHOD: The purpose of the present study was to evaluate whether some neuropsychological features related to the autism phenotype are present in parents of ASD children. To this end, the exploration included a dichotic listening task, handedness and the Empathy Quotient (EQ-60). RESULTS: The scores obtained by the total sample (fathers plus mothers) were similar to those of the general population, although there were differences in some parameters of the dichotic listening task depending on the gender. Contrary to expectations, only in fathers, the negative correlation between data from both ears was not statistically significant, which could be evidence of a lack of hemispheric interdependence. CONCLUSIONS: These results support the possible existence of a genetic susceptibility to an aberrant language asymmetry pattern. Moreover, possible unknown epigenetic factors could act on a vulnerable genotype in some ASD subjects. Nevertheless, due to the small sample size, the present research must be considered a pilot study.

Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson's disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson's disease.

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca(2+) homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3ß (GSK-3ß) and that GSK-3ß regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

[Characterization of tuberculosis cases in the foreign- and native-born population in Guipúzcoa (Spain) from 2003-2007]. / Caracterización de los casos de tuberculosis en población autóctona y extranjera de Guipúzcoa en el período 2003-2007.

OBJECTIVE: To describe the sociodemographic and clinical characteristics of tuberculosis cases registered in Guipúzcoa and their management and to investigate possible differences depending on the country of origin of affected individuals. MATERIAL AND METHODS: We performed a population-based descriptive analysis of cases diagnosed from 2003 to 2007. Cases were drawn from the surveillance system, which incorporates an active information search in distinct sources. Incidences were calculated with the populations obtained from the Basque Institute of Statistics and the Ikuspegi-Basque Immigration Observatory. Chi-squared and Fisher's exact tests were used to compare categorical variables and the Mann-Whitney U-test was used to compare means. RESULTS: A total of 903 cases were registered, of which 94 corresponded to foreigners. During the study period, the mean incidence per 100,000 inhabitants was 86.3 for foreigners and 24.4 for native-born residents. No significant differences were found by gender, prior treatment, diagnostic delay, the microbiological tests performed or their results. Differences were found in age (foreigners were younger), contact tracing recommendation and its completion (less frequent in foreigners), treatment adherence (worse among foreigners), site of infection (more common in lymph nodes in foreigners) and risk factors (fewer chronic diseases in foreigners). CONCLUSIONS: Foreigners with tuberculosis were younger and had fewer chronic diseases than native-born individuals with tuberculosis. Study of contacts and treatment adherence were less successful among foreigners. Providing the most suitable care for each patients is essential.

Indicadores de colaboración científica inter-centros en los países de América Latina / Indicators of inter-center scientific co-operation in Latin American countries

Se presentan indicadores de colaboración científica de 24 países de América Latina y el Caribe, obtenidos a través de sus publicaciones en revistas científicas de difusión internacional firmadas por autores de dos o más instituciones diferentes durante el periodo 1999-2002, empleando técnicas de análisis bibliométrico de coautoría. Para cada país se establecieron tres tipos de colaboración: nacional, regional e internacional, diferenciando las colaboraciones bi y trilaterales de las grandes redes formadas por 6 o más países. Se destacan las áreas científicas de mayor presencia en relación con el tipo de colaboración y tamaño de las redes. Los trabajos en colaboración representan el 65 por ciento del total de los publicados y aumentan cada año, correspondiendo la mayor proporción a la colaboración internacional, mientras que la regional es muy escasa. Los países más productivos en ciencia presentan una colaboración relativamente menor que los pequeños productores. Se analiza la evolución de los hábitos de colaboración internacional entre los periodos 1991-1995 y 1999-2002