Brain clocks capture diversity and disparities in aging and dementia across geographically diverse populations

Peer reviewe

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

The Genetics of Monogenic Frontotemporal Dementia

ABSTRACT Around 10-15% of patients diagnosed with frontotemporal dementia (FTD) have a positive family history for FTD with an autosomal dominant pattern of inheritance. Since the identification of mutations in MAPT(microtubuleassociated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review. Along with MAPT, mutations in GRN(progranulin) and C9orf72(chromosome 9 open reading frame 72) are the most commonly identified in FTD cohorts. The association of FTD and motor neuron disease (MND) can be caused by mutations in C9orf72and other genes, such as TARDBP(TAR DNA-binding protein), FUS(fused in sarcoma), UBQLN2(ubiquilin 2). Multisystem proteinopathy is a complex phenotype that includes FTD, Paget disease of the bone, inclusion body myopathy and MND, and can be due to mutations in VCP(valosing containing protein) and other recently identified genes

Prion diseases.

Prion diseases are a group of diseases caused by abnormally conformed infectious proteins, called prions. They can be sporadic (Jakob-Creutzfeldt disease [JCD]), genetic (genetic JCD, Gerstmann-Sträussler-Scheinker, and familial fatal insomnia), or acquired (kuru, variant JCD, and iatrogenic JCD). The clinical features associated with each form of prion disease, the neuroimaging findings, cerebrospinal fluid markers, and neuropathological findings are reviewed. Sporadic JCD is the most common form of human prion disease, and will be discussed in detail. Genetic prion diseases are caused by mutations in the prion-related protein gene (PRNP), and they are classified based on the mutation, clinical phenotype, and neuropathological features. Acquired prion diseases fortunately are becoming rarer, as awareness of transmission risk has led to implementation of measures to prevent such occurrences, but continued surveillance is necessary to prevent future cases. Treatment and management issues are also discussed