To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, Pcombined = 2.35 × 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.

Abnormal structures in the cortical and subcortical regions have been identified in subcortical vascular cognition impairment (SVCI). However, little is known about the functional alterations in SVCI, and no study refers to the functional connectivity in the prefrontal and subcortical regions in this context. The medial prefrontal cortex (MPFC) is an important region of the executive network and default mode network, and the subcortical thalamus plays vital roles in mediating or modulating these two networks. To investigate both thalamus- and MPFC-related functional connectivity as well as its relationship with cognition in SVCI, 32 SVCI patients and 23 control individuals were administered neuropsychological assessments. They also underwent structural and functional magnetic resonance imaging scans. Voxel-based morphometry and functional connectivity analysis were performed to detect gray matter (GM) atrophy and to characterize the functional alterations in the thalamus and the MPFC. For structural data, we observed that GM atrophy was distributed in both cortical regions and subcortical areas. For functional data, we observed that the thalamus functional connectivity in SVCI was significantly decreased in several cortical regions [i.e., the orbitofrontal lobe (OFL)], which are mainly involved in executive function and memory function. However, connectivity was increased in several frontal regions (i.e., the inferior frontal gyrus), which may be induced by the compensatory recruitment of the decreased functional connectivity. The MPFC functional connectivity was also decreased in executive- and memory-related regions (i.e., the anterior cingulate cortex) along with a motor region (i.e., the supplementary motor area). In addition, the cognitive performance was closely correlated with functional connectivity between the left thalamus and the left OFL in SVCI. The present study, thus, provides evidence for an association between structural and functional alterations, and sheds light on the underlying neural mechanisms of executive dysfunction in SVCI.

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Gait disturbances are important clinical features of cerebral small vessel disease (CSVD) that increase the risk of falls and disability. Brain structural alterations and gait disturbances in CSVD patients have been well demonstrated. However, intrinsic resting cerebral function patterns in CSVD patients with gait disorders remain largely unknown. Fifty-eight CSVD patients were enrolled in our studies and categorized into the gait disorder group (CSVD-GD, n = 29) and no-gait disorder group (CSVD-NGD, n = 29) based on a gait examination. Gait was quantitatively assessed with the Timed Up and Go test and the intelligent device for energy expenditure and activity (IDEEA). Functional MRI and fractional amplitude of low-frequency fluctuation (fALFF) analyses were employed to explore local intrinsic neural oscillation alterations. Functional connectivity based on fALFF results was calculated to detect the potential changes in remote connectivity. Compared with the CSVD-NGD group, the CSVD-GD group showed decreased fALFF in regions mainly located in the sensorimotor network and frontoparietal network, such as the left supplementary motor area (SMA.L) and the left superior parietal gyrus, and increased fALFF in the right inferior frontal gyrus (orbital part), the left caudate, and the left precuneus. Moreover, the CSVD-GD patients exhibited lower connectivity between the SMA.L and temporal lobe, which was related to gait speed. The fALFF value of the SMA.L was associated with cadence. This study highlights the regional and network interaction abnormalities of the SMA in CSVD patients with gait disturbances. These findings could provide further insight into the neural mechanisms of gait disturbances in CSVD.

The aim of this study was to investigate the changes in cerebral blood flow velocity (CBFV) and its relation to apolipoprotein E (apoE) epsilon4 allele in mild cognitive impairment (MCI). Thirty MCI and 30 controls were assessed using Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C), and then insonated in the anterior (ACA), middle (MCA) and basilar (BA) cerebral arteries using transcranial Doppler ultrasonography. Compared with controls, MCI showed significant decreases in the mean (V(m)), systolic (V(s)) and diastolic (V(d)) CBFV, bilaterally in MCA and ACA (P < 0.05-0.001), but not in BA. Compared with 17 apoE epsilon4 allele non-carriers, 13 carriers in MCI showed significant CBFV decreases, bilaterally in MCA (P < 0.05-0.001). Our findings, the decreased CBFV in apoE epsilon4 allele carriers with MCI, suggest that a large sample and longitudinal study in CBFV and cognitive changes may have the implications on early diagnosis of Alzheimer's disease.