Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Understanding and controlling asthma in Latin America: A review of recent research informed by the SCAALA programme.

Asthma is an important health concern in Latin America (LA) where it is associated with variable prevalence and disease burden between countries. High prevalence and morbidity have been observed in some regions, particularly marginalized urban populations. Research over the past 10 years from LA has shown that childhood disease is primarily non-atopic. The attenuation of atopy may be explained by enhanced immune regulation induced by intense exposures to environmental factors such as childhood infections and poor environmental conditions of the urban poor. Non-atopic symptoms are associated with environmental and lifestyle factors including poor living conditions, respiratory infections, psychosocial stress, obesity, and a diet of highly processed foods. Ancestry (particularly African) and genetic factors increase asthma risk, and some of these factors may be specific to LA settings. Asthma in LA tends to be poorly controlled and depends on access to health care and medications. There is a need to improve management and access to medication through primary health care. Future research should consider the heterogeneity of asthma to identify relevant endotypes and underlying causes. The outcome of such research will need to focus on implementable strategies relevant to populations living in resource-poor settings where the disease burden is greatest.

Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype.

OBJECTIVE: The objective of this study was to describe clinical features, [18 F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB). METHODS: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD). RESULTS: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD. INTERPRETATION: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: friend or foe?

Helicobacter pylori (H. pylori) is a flagellated, spiral-shaped, microaerophilic Gram-negative bacillus that colonises the gastric mucosa of more than 50% of the human population. Infection is a risk factor for gastritis, ulcer disease and stomach cancer. Immunity against H. pylori is mainly related to Th1/Th17 skewing, and the activation of regulatory T cells is the main strategy used to limit inflammatory responses, which can result in the pathogen persistence and can lead to chronic gastrointestinal diseases, including cancer. Furthermore, host genetic factors that affect cytokines may determine differences in the susceptibility to many diseases. In this review, we present the cytokine profiles and the main cytokine gene polymorphisms associated with resistance/susceptibility to H. pylori and discuss how such polymorphisms may influence infection/disease outcomes.

The pattern of atrophy in familial Alzheimer disease: volumetric MRI results from the DIAN study.

OBJECTIVE: To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers. METHODS: A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume. RESULTS: Significant differences in gray matter (p < 0.05, family-wise error-corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers. CONCLUSIONS: Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.

Cinética e parâmetros de fermentação ruminal in vitro de silagens de parte aérea e raízes de mandioca / Kinetic parameters and in vitro rumen fermentation of cassava foliage and roots silages

Foram avaliados os efeitos do emurchecimento e da inclusão de raízes 0, 15, 30 e 45% da matéria natural sobre a cinética e os parâmetros da fermentação ruminal de silagens da parte aérea da mandioca. A produção acumulada de gases (PAG) às 96 horas de incubação foi influenciada significativamente (P<0,05) pela interação emurchecimento versus inclusão de raízes. Para a PAG, houve elevação linear de 1,88mL a cada unidade percentual de raiz adicionada às silagens não emurchecidas e efeito quadrático nas silagens emurchecidas, com produção máxima de 226mL de gases, com a inclusão de 30,5% de raízes. A degradabilidade verdadeira in vitro da MS (DVIMS) das silagens apresentou significância (P<0,05) para o emurchecimento e para a interação inclusão de raízes versus tempo de incubação. O emurchecimento reduziu, aproximadamente, 2% da degradabilidade da silagem, enquanto a inclusão de raízes propiciou elevação linear dessa variável, que atingiu o valor máximo às 24 horas de incubação.

The effects of wilting and roots inclusion (0, 15, 30 and 45% fresh matter) on rumen fermentation kinetics and parameters of cassava foliage silages were evaluated. Total gas production (TGP) after 96 hours of incubation was significantly influenced (P <0.05) by the interaction between wilting and roots inclusion. TGP was linearly increased by 1.88 mL for each percent unit of root added to the wilted silage, whereas, for wilted ones, a quadratic effect was observed, with a maximum gas cumulative output of 226 mL for 30.5% roots addition. The true DM degradability of silages in vitro (IVTDMD) showed significance (P<0.05) to wilting and interaction between root inclusion and incubation time. Wilting reduced silage degradability in approximately 2%, while root inclusion led to linear increases in this variable, which reached its peak at 24h of incubation.

Intensity of exercise recovery, blood lactate disappearance, and subsequent swimming performance.

The aim of this study was to examine the effects of active versus passive recovery on blood lactate disappearance and subsequent maximal performance in competitive swimmers. Fourteen male swimmers from the University of Virginia swim team (mean age 20.3 years, s= 4.1; stature 1.85 m, s= 2.2; body mass 81.1 kg, s= 5.6) completed a lactate profiling session during which the speed at the lactate threshold (V(LT)), the speed at 50% of the lactate threshold (V(LT.5)), and the speed at 150% of the lactate threshold (V(LT1.5)) were determined. Participants also completed four randomly assigned experimental sessions that consisted of a 200-yard maximal-effort swim followed by 10 min of recovery (passive, V(LT.5), V(LT), V(LT1.5)) and a subsequent 200-yard maximal effort swim. All active recovery sessions resulted in greater lactate disappearance than passive recovery (P < 0.0001 for all comparisons), with the greatest lactate disappearance associated with recovery at V(LT) (P= 0.006 and 0.007 vs. V(LT.5) and V(LT1.5) respectively) [blood lactate disappearance was 2.1 mmol l(-1) (s= 2.0), 6.0 mmol l(-1) (s=2.6), 8.5 mmol l(-1) (s= 1.8), and 6.1 mmol l(-1) (s= 2.5) for passive, V(LT.5), V(LT), and V(LT1.5) respectively]. Active recovery at VLT and V(LT1.5) resulted in faster performance on time trial 2 than passive recovery (P=0.005 and 0.03 respectively); however, only active recovery at V(LT) resulted in improved performance on time trial 2 (TT2) relative to time trial 1 (TT1) [TT2- TT1: passive +1.32 s (s= 0.64), V(LT.5) +1.01 s (s= 0.53), V(LT) -1.67 s (s= 0.26), V(LT1.5) -0.07 s (s = 0.51); P < 0.0001 for V(LT)). In conclusion, active recovery at the speed associated with the lactate threshold resulted in the greatest lactate disappearance and in improved subsequent performance in all 14 swimmers. Our results suggest that coaches should consider incorporating recovery at the speed at the lactate threshold during competition and perhaps during hard training sessions.

A case control study of dermatophagoides immunotherapy in children below 5 years of age.

BACKGROUND: In this study we investigate the effects of parenteral immunotherapy on children below 5 years of age in order to prove the safety and clinical efficacy of dust mite specific immunotherapy (SIT) in such young patients. In young children, allergy is often due to dermatophagoides and causes a persistent inflammation that leads to recurrent respiratory infections. This condition impairs the normal development of airways by inducing remodelling. Although many paediatric allergists are used to treating young allergic children with SIT, this method is still subject to discussion. The benefits versus risks of SIT must also be defined. METHODS: In a case control study, 28 patients with dermatophagoides induced asthma and rhinitis treated with subcutaneous immunotherapy were assessed alongside a comparable control group. Symptom and drugs scores were collected from diary cards. RESULTS AND DISCUSSION: Scores proved to be significantly lower in the immunotherapy group in respect to the control group (p = 0.001). In particular, asthma attacks in the case group decreased significantly during the first year of treatment (p = 0.001). SIT was well tolerated and compliance was good. CONCLUSIONS: Our results confirm the safety and the efficacy of SIT in children below 5 years of age and above all, they confirm that SIT can begin at a very early age.

Semiautomated ultrasonographic measurement of fetal nuchal translucency using a computer software tool.

Nuchal translucency (NT) thickness measurement has been recently proposed as a part of routine ultrasound scanning during the late first trimester of pregnancy, for the early screening of chromosomal abnormalities. Manual determination of NT is currently performed using electronic calipers placed by the operator in the middle of two echogenic lines displayed on the screen. Therefore, intraobserver and interobserver repeatability can be questioned. This paper presents a software tool that has been developed for achieving this goal in a semiautomatic way, improving the reproducibility of the method.