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Background: Widespread white matter (WM) injury is a hallmark feature of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, controversies about the mechanism of WM tract injury exist persistently. Excessive iron accumulation, frequently reported in CADASIL patients, might cause WM tract injury. Purpose: To test the association between iron accumulation and WM tract injury in CADASIL patients. Study Type: Retrospective. Population: A total of 35 CADASIL patients (age = 50.4 ± 6.4, 62.9% female) and 48 healthy controls (age = 55.7 ± 8.0, 68.8% female). Field Strength/Sequence: Diffusion‐weighted spin‐echo echo‐planar sequence; enhanced susceptibility‐weighted angiography (ESWAN) gradient echo sequence on a 3 T scanner. Assessment: The phase images acquired by ESWAN were used to calculate quantitative susceptibility mapping (QSM). Iron accumulation was evaluated in deep gray matters using QSM. WM tract injury was quantified by diffusion metrics based on WM major tracts skeleton. We compared iron deposition between groups and analyzed the correlation between WM tract injury and iron deposition in regions showing significant differences from healthy controls. Exploratory analysis was carried out to investigate whether WM tract injury mediated the relationship between iron deposition and cognitive impairment evaluated by Mini‐Mental State Examination (MMSE). Statistical Tests: General linear model (GLM), partial correlation, stepwise linear regression and mediation analysis were used. The threshold of statistical significance was set as p < 0.05. Results: Compared with healthy controls, CADASIL patients had significantly increased iron deposition in the caudate and putamen. Aberrant iron deposition in these two regions was significantly associated with decreased WM fractional anisotropy (FA) (caudate, r = −0.373； putamen, r = − 0.421), and increased radial diffusivity (RD) (caudate, r = 0.372; putamen, r = 0.386). Furthermore, WM tract injury mediated the relationship between iron deposition and cognitive impairment. Data Conclusion: Patients with CADASIL show increased iron deposition in the caudate and putamen that is correlated to WM tract injury, which may in turn mediate the association with cognitive impairment. Evidence Level: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). Methods: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD‐risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3‐year follow‐up, 60 PD patients were screened and assigned to the low‐PRS group (n = 30) and high‐PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross‐sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = −0.190, p = 0.003; PRS2, Spearman ρ = −0.189, p = 0.003). The high‐PRS group showed more extensive WM microstructural degeneration compared with the low‐PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior fronto‐occipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = −0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = −0.405, p = 0.030). Conclusions: These findings suggest that PD‐associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients. [ABSTRACT FROM AUTHOR]

Brain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease ( AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β-amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5-month-old APPswe/ PS1dE9 ( APP/ PS1) mice. Furthermore, c-Jun N-terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein ( APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/ PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

Aims: To analyze the NOTCH3 gene mutations in patients from mainland China clinically suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and evaluate large intracranial arteries in CADASIL patients. Methods: We performed clinical, neuroimaging and NOTCH3 gene (exons 2–23) examinations in 47 subjects from 34 families. Large intracranial arteries were assessed using magnetic resonance angiography (MRA) in 19 cases with NOTCH3 gene variants. Results: Screening of exons 3 and 4 identified six different known mutations in eight families and two novel mutations in two families. Further screening of the remaining exons identified p.R1175W, a variant of unknown significance. The incidence of NOTCH3 mutations was 29.4% (10/34). Five cases with NOTCH3 mutations showed intracranial atherosclerosis. One patient developed cerebral infarction due to left middle cerebral artery occlusion (M2 segment). Conclusions: The NOTCH3 mutation spectrum in our group was diverse and consistent with those in Caucasians but differed from those in Korea and Taiwan. The screening strategy used in Caucasian populations can be applied to mainland Chinese patients. Atherosclerosis of the large intracranial arteries involvement does not exclude CADASIL diagnosis. [ABSTRACT FROM AUTHOR]

Objective: Transient ischemic attacks (TIAs) are divided into anterior and posterior circulation types (AC-TIA, PC-TIA, respectively). In the present study, we sought to evaluate the ABCD2 score for predicting stroke in either AC-TIA or PC-TIA. Methods: We prospectively studied 369 consecutive patients who presented with TIA between June 2009 and December 2012. The 7 d occurrence of stroke after TIA was recorded and correlated with the ABCD2 score with regards to AC-TIA or PC-TIA. Results: Overall, 273 AC-TIA and 96 PC-TIA patients were recruited. Twenty-one patients with AC-TIA and seven with PC-TIA developed a stroke within the subsequent 7 d (7.7% vs. 7.3%, p = 0.899). The ABCD2 score had a higher predictive value of stroke occurrence in AC-TIA (the AUC was 0.790; 95% CI, 0.677-0.903) than in PC-TIA (the AUC was 0.535; 95% CI, 0.350-0.727) and the z-value of two receiver operating characteristic (ROC) curves was 2.24 ( p = 0.025). AC-TIA resulted in a higher incidence of both unilateral weakness and speech disturbance and longer durations of the symptoms. Inversely, PC-TIA was associated with a higher incidence of diabetes mellitus (19.8% vs. 10.6%, p = 0.022). Evaluating each component of scores, age ≥ 60 yr (OR = 7.010, 95% CI 1.599-30.743), unilateral weakness (OR = 3.455, 95% CI 1.131-10.559), and blood pressure (OR = 9.652, 95% CI 2.202-42.308) were associated with stroke in AC-TIA, while in PC-TIA, diabetes mellitus (OR = 9.990, 95% CI 1.895-52.650) was associated with stroke. Conclusion: In our study, the ABCD2 score could predict the short-term risk of stroke after AC-TIA, but might have limitation for PC-TIA. [ABSTRACT FROM AUTHOR]

This study aimed to develop a cell culture model of Huntington disease and observe the effect of sodium butyrate on this cell culture model. Exon 1 of both a wild type and a mutant IT15 gene from the genomic DNA of a healthy adult and a patient with Huntington disease was amplified and cloned into the eukaryotic expression vector pEGFP-C1. Human neuroblastoma SH-SY5Y cells were transiently transfected with these recombinant plasmids in the absence and presence of sodium butyrate (0. 1, 0. 2, 0. 5, 1 . 0 mmol/L). The MTT assay was used to measure cell viability. The results indicated that the N-terminal fragment of mutant huntingtin formed perinuclear and intranuclear aggregates and caused a decrease of SH-SY5Y cell viability. Sodium butyrate inhibited the decrease of SH-SY5Y cell viability caused by the N-terminal fragment of mutant huntingtin. This suggests that sodium butyrate has a protective effect on this cell culture model of Huntington disease. [ABSTRACT FROM AUTHOR]