Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive impairment. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of FTD and parkinsonism linked to chromosome 17.

Human-correlated genetic models identify precision therapy for liver cancer.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations, with hepatocytes the most likely cell of origin.

Results of a modified Delphi consensus on the optimal testing pathway for oesophago-gastric cancer care in the UK.

Objective: To develop expert consensus on the optimal testing pathway for oesophago-gastric (OG) cancer care.

Methods And Analysis: The process followed a modified Delphi methodology to develop consensus on the optimal testing pathway for OG cancer care. In November 2023, a review of available literature on the topic of OG cancer was conducted.

Improving the Clinical Diagnostic Criteria for Genetically Confirmed Adult-Onset Huntington Disease: Considering Nonmotor Presentations.

Background: Huntington disease (HD) is a genetic neurodegenerative disorder. Given the focus on motor manifestations, nonmotor symptoms are frequently underappreciated in clinical evaluations, despite frequently contributing to primary functional impairment.

Recent Findings: A diagnosis of motor-onset as the definition of manifest symptoms misrepresents the complex nature of HD presentation.

Neuropathological correlates of vulnerability and resilience in the cerebellum in Alzheimer's disease.

Introduction: We investigated whether the cerebellum develops neuropathology that correlates with well-accepted Alzheimer's disease (AD) neuropathological markers and cognitive status.

Methods: We studied cerebellar cytoarchitecture in a cohort (N = 30) of brain donors. In a larger cohort (N = 605), we queried whether the weight of the contents of the posterior fossa (PF), which contains primarily cerebellum, correlated with dementia status.

Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure.

A novel multisite model to facilitate hepatitis C virus elimination in people experiencing homelessness.

Background & Aims: Only a handful of countries are on target to achieve elimination of HCV by 2030. People experiencing homelessness (PEH) remain an important HCV reservoir. The END C study evaluated clinical, patient reported, and health economic outcomes of a decentralised integrated model.

Hereditary spastic paraplegia with thin corpus callosum and SPG11 mutation: A neuropathological evaluation.

Hereditary spastic paraplegia (HSP) with thin corpus callosum can be due to a variety of genetic causes, the most common of which are biallelic variants in SPG11 (HSP11). Only six cases of neuropathologic examination of HSP11 have been reported. Here we present neuropathological findings in another case of HSP11 with novel mutation (homozygous c.

Team climate, job satsfaction and burnout: results from a national survey of staff in general practice in England.

Background: Measures are needed to address recruitment and retention problems in general practice. A good team climate (relational processes of team working) can mitigate the effects of pressured work environments, but little is known about it in British general practice.

Aim: To assess team climate, explore practice characteristics and workforce combinations associated with favourable team climates, and analyse associations between practice team climate and job satisfaction, intention to remain in post, burnout and measures of practice performance.

Evidence of mutant huntingtin and tau-related pathology within neuronal grafts in Huntington's disease cases.

A number of post-mortem studies conducted in transplanted Huntington's disease (HD) patients from various trials have reported the presence of pathological and misfolded proteins, in particular mutant huntingtin (mHtt) and phosphorylated tau neuropil threads, in the healthy grafted tissue. Here, we extended these observations with histological analysis of post-mortem tissue from three additional HD patients who had received similar striatal allografts from the fetal tissue transplantation trial conducted in Los Angeles in 1998. Immunohistochemical staining was performed using anti-mHtt antibodies, EM48 and MW7, as well as anti-hyperphosphorylated tau antibodies, AT8 and CP13.

Multi-scale in vivo imaging of tumour development using a germline conditional triple-reporter system.

Imaging reporter genes are indispensable for visualising biological processes in living subjects, particularly in cancer research where they have been used to observe tumour development, cancer cell dissemination, and treatment response. Engineering reporter genes into the germline frequently involves single imaging modality reporters operating over limited spatial scales. To address these limitations, we developed an inducible triple-reporter mouse model (Rosa26) that integrates reporters for complementary imaging modalities, flfluorescence, bioluminescence and positron emission tomography (PET), along with inducible Cre-lox functionality for precise spatiotemporal control of reporter expression.

A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring.

TREM2 variants that cause early dementia and increase Alzheimer's disease risk affect gene splicing.

Loss-of-function variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are responsible for a spectrum of neurodegenerative disorders. In the homozygous state, they cause severe pathologies with early onset dementia, such as Nasu-Hakola disease and behavioural variants of frontotemporal dementia (FTD), whereas heterozygous variants increase the risk of late-onset Alzheimer's disease (AD) and FTD. For over half of TREM2 variants found in families with recessive early onset dementia, the defect occurs at the transcript level via premature termination codons or aberrant splicing.

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons.

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs.

Assessing and Identifying Improvements for Lung Cancer Screening in a Rural Population: A Human-Centered Design and Systems Approach.

Although lung cancer claims more lives than any other cancer in the United States, screening is severely underutilized, with <6% of eligible patients screened nationally in 2021 versus 76% for breast cancer and 67% for colorectal cancer. This article describes an effort to identify key reasons for the underutilization of lung cancer screening in a rural population and to develop interventions to address these barriers suitable for both a large health system and local community clinics. Data were generated from 26 stakeholder interviews (clinicians, clinical staff, and eligible patients), a review of key systems (Electronic Health Record and billing records), and feedback on the feasibility of several potential interventions by health care system staff.

NOTCH3 C201R variant causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) that can be confused with early-onset Alzheimer's disease.

Background: NOTCH3 is the causative gene for autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) which is associated with both stroke and dementia. When CADASIL presents primarily as dementia it can be difficult to distinguish from Alzheimer's disease (AD) at both the clinical and neuropathological levels.

Methods: We performed exome sequencing of several affected individuals from a large family affected with AD.

A familial missense variant in the Alzheimer's Disease gene impairs its maturation and endosomal sorting.

The gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring.

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34).