Abstract-Recently, a genome-wide screen has shown a major quantitative trait locus (QTL) for a stroke-associated phenotype on rat chromosome 1 (RNO1) independent of QTL for blood pressure (BP) in the stroke-prone spontaneously hypertensive rat (SHRSP) of a Heidelberg colony. However, it remains to be elucidated whether these observations reflect the existence of different genes predisposing to each of the disorders. To address this issue, we performed comprehensive approaches in a Japanese colony, Izm, as follows. First, we undertook genome-wide searches in F 1 (SHRSP/IzmϫWKY/Izm)ϫSHRSP/Izm back-cross (nϭ63) to pursue a causal relation between hypertension and stroke. Although the strongest linkage to BP (LOD score of 3.4) was identified on RNO1, its relevance to stroke was not supported in the F 1 back-cross studied. Second, we also investigated linkage to BP in F 2 progeny (nϭ175) involving the stroke-resistant (or normal) spontaneously hypertensive rat (SHR). In F 2 studies of SHR/Izm, this locus did not appear to constitute a principal BP QTL. Third, we constructed congenic animals with detailed phenotype characterization. Transfer of a chromosomal fragment between markers Klk1 and D1Rat116 from WKY/Izm onto the SHRSP/Izm background lowered systolic BP by 20 to 80 mm Hg, prevented development of apparent stroke, and exaggerated impaired glucose tolerance. In conclusion, we have successfully isolated an RNO1 region affecting BP, stroke, and glucose tolerance in SHRSP/Izm-derived congenic rats. The size of the introgressed region is large, but our novel congenic strain should help delineate complex, genetic impairments underlying BP and associated vascular disease phenotypes.

Background/ObjectiveThe CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.MethodsIn Cdkal1-deficient (Cdkal1 −/−) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.Principal FindingsOn a standard diet, Cdkal1 −/− mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1 −/− mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1 −/− mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1 −/− mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1 −/− mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI.Conclusions Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.

Tremor is one of the core symptoms of Parkinson’s disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

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Background: Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness.Methods: PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate < 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated.Results: Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length. Conclusion:PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

Objective To identify risk factors for early neurological deterioration (END) in acute lacunar stroke patients, and its influence on functional outcome. Methods Consecutive acute lacunar stroke patients defined by MRI between January 2018 and June 2020 were included in the study. END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ≥2 points post admission, and favorable outcome was defined as a modified Rankin Scale (mRS) of 0-2 at discharge. Univariable and multivariable logistic regression were performed to identify risk factors related to END, as well as the influence of END on functional outcome. Results Among a total of 638 lacunar stroke patients (420 males (65.8%), median age 66 years (IQR:56-74)), 108 (16.9%) developed END, and 94.4% (102/108) of the END occurred within 72 h post admission. Admission NIHSS score (aOR 1.132, 95%CI 1.046-1.225, p=0.002), female (aOR 2.752, 95%CI 1.277-5.933, p=0.010), admission systolic blood pressure (SBP) (160-179mmHg) (aOR 9.395, 95%CI 4.310-20.479, p<0.001) and admission SBP (≥180mmHg) (aOR 16.030, 95%CI 5.991-42.891, p<0.001) were significantly associated with END. Delay time from onset to admission (aOR 0.995, 95%CI 0.990-1.000, p=0.031) , SBP dropping (≥20mmHg) within 3 days or when END occurred (aOR 0.037, 95%CI 0.016-0.086, p<0.001) and thalamic lacunar infarction (aOR 0.098, 95%CI 0.012-0.827, p=0.033) were inversely associated with END. END (aOR 12.374, 95%CI 6.881-22.254, p<0.001) and higher admission NIHSS score (aOR 1.488, 95%CI 1.359-1.629, p<0.001) predicted unfavorable outcome at discharge. Conclusion END in lacunar stroke patients is common and is associated with unfavorable outcome. Admission high SBP is a potentially modifiable risk factor for prevention of END, but this needs further investigation.

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