Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and heterozygous HTRA1 mutation-related cerebral small vessel disease (CSVD) are the two types of dominant hereditary CSVD. Blood–brain barrier (BBB) failure has been hypothesized in the pathophysiology of CSVD. However, it is unclear whether there is BBB damage in the two types of hereditary CSVD, especially in heterozygous HTRA1 mutation-related CSVD. In this study, a case-control design was used with two disease groups including CADASIL (n = 24), heterozygous HTRA1 mutation-related CSVD (n = 9) and healthy controls (n = 24). All participants underwent clinical cognitive assessments and brain MRI. Diffusion-prepared pseudo-continuous arterial spin labelling was used to estimate the water exchange rate across the BBB (k_w). Correlation and multiple linear regression analyses were used to examine the association between k_w and disease burden and neuropsychological performance, respectively. Compared with the healthy controls, k_w in the whole brain and multiple brain regions was decreased in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients (Bonferroni-corrected P < 0.007). In the CADASIL group, decreased k_w in the whole brain (β = −0.634, P = 0.001), normal-appearing white matter (β = −0.599, P = 0.002) and temporal lobe (β = −0.654, P = 0.001) was significantly associated with higher CSVD score after adjusting for age and sex. Reduced k_w in the whole brain was significantly associated with poorer neuropsychological performance after adjusting for age, sex and education in both CADASIL and heterozygous HTRA1 mutation-related CSVD groups (β = 0.458, P = 0.001; β = 0.884, P = 0.008). This study showed that there was decreased water exchange rate across the BBB in both CADASIL and heterozygous HTRA1 mutation-related CSVD patients, suggesting a common pathophysiological mechanism underlying the two types of hereditary CSVD. These results highlight the potential use of k_w for monitoring the course of CADASIL and heterozygous HTRA1 mutation-related CSVD, a possibility which should be tested in future research.

INTRODUCTION: We explored how blood‐brain barrier (BBB) leakage rate of gadolinium chelates (K^trans) and BBB water exchange rate (k_w) varied in cerebral small vessel disease (cSVD) subtypes.METHODS: Thirty sporadic cSVD, 40 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 13 high‐temperature requirement factor A serine peptidase 1 (HTRA) ‐related cSVD subjects were investigated parallel to 40 healthy individuals. Subjects underwent clinical, cognitive, and MRI assessment.RESULTS: In CADASIL, no difference in K^trans, but lower k_w was observed in multiple brain regions. In sporadic cSVD, no difference in k_w, but higher K^trans was found in the whole brain and normal‐appearing white matter. In HTRA1‐related cSVD, both higher K^trans in the whole brain and lower k_w in multiple brain regions were observed. In each patient group, the altered BBB measures were correlated with lesion burden or clinical severity.DISCUSSION: In cSVD subtypes, distinct alterations of k_w and K^trans were observed. The combination of K^trans and k_w can depict the heterogeneous BBB dysfunction.Highlights: We measured BBB leakage to gadolinium‐based contrast agent (K^trans) and water exchange rate (k_w) across BBB in three subtypes of cSVD. CADASIL is characterized by lower k_w, HTRA1‐related cSVD exhibits both higher K^trans and lower k_w, while sporadic cSVD is distinguished by higher K^trans. There are distinct alterations in k_w and K^trans among subtypes of cSVD, indicating the heterogeneous nature of BBB dysfunction.

Background: The comprehensive geriatric assessment (CGA) has been proposed as a supplementary tool to reduce perioperative complications of geriatric patients, however there is no universally accepted standardization of CGA for orthopedic surgery. In this study, a novel CGA strategy was applied to evaluate the conditions of older patients undergoing orthopedic surgery from a broad view and to identify potential risk factors for postoperative complications. Methods: A prospective cohort study was conducted from March 2019 to December 2020.The study enrolled patients (age > 75 years) for elective or confined orthopedic surgery. All patients were treated by a multidisciplinary team. A structured CGA was conducted to identify high-risk older patients and to facilitate coordinated multidisciplinary team care by a geriatric team. The basic patient characteristics, CGA results, postoperative complication and mortality rates were collected. Multivariate logistic regression analysis was used to identify risk factors for postoperative complications. Results: A total of 214 patients with an age of 81.07 ± 4.78 (range, 75–100) years were prospectively enrolled in this study. In total, 66 (30.8%) complications were registered, including one death from myocardial infarction (mortality rate, 0.5%). Poor Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) were accompanied by frailty, worse perioperative risk, pain, and nutritional status. Poor ADL was also associated with higher risks of falling, polypharmacy, and cardiac and respiration complications. Poor IADL was associated with a higher risk of cardiac and respiration complications. Higher stroke risk was accompanied by higher risks of cardiac complications, delirium, and hemorrhage. Worse American Society of Anesthesiologists (ASA) score was associated with worse ADL, IADL, frailty, and higher delirium risk. Multivariate logistic regression analysis showed that spinal fusion (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.65 to 0.83; p = 0.0214), blood loss(OR, 1.68; 95% CI, 1.31 to 2.01; p = 0.0168), ADL (severe dysfunction or worse) (OR, 1.45; 95% CI, 1.16 to 1.81; p = 0.0413), IADL (serious dependence) (OR, 1.08; 95% CI, 1.33 to 1.63; p = 0.0436), renal function (chronic kidney disease (CKD) ≥ stage 3a) (OR, 2.01; 95% CI, 1.54 to 2.55; p = 0.0133), and malnutrition(OR, 2.11; 95% CI, 1.74 to 2.56; p = 0.0101) were independent risk factors for postoperative complications. Conclusion: The CGA process reduces patient mortality and increases safety in older orthopedic surgery patients. Spinal fusion, blood loss, ADL (severe dysfunction or worse), IADL (serious dependence), renal function (CKD ≥ stage 3a) and nutrition mini nutritional assessment (MNA) (malnourished) were independent risk factors of postoperative complications following orthopaedic surgery in older patients.

Parkinson’s disease (PD) is characterized by α-synuclein aggregation in dopaminergic (DA) neurons, which are sensitive to oxidative stress. Mitochondria aconitase 2 (ACO2) is an essential enzyme in the tricarboxylic acid cycle that orchestrates mitochondrial and autophagic functions to energy metabolism. Though widely linked to diseases, its relation to PD has not been fully clarified. Here we revealed that the peripheral ACO2 activity was significantly decreased in PD patients and associated with their onset age and disease durations. The knock-in mouse and Drosophila models with the A252T variant displayed aggravated motor deficits and DA neuron degeneration after 6-OHDA and rotenone-induction, and the ACO2 knockdown or blockade cells showed features of mitochondrial and autophagic dysfunction. Moreover, the transcription of autophagy-related genes LC3 and Atg5 was significantly downregulated via inhibited histone acetylation at the H3K9 and H4K5 sites. These data provided multi-dimensional evidences supporting the essential roles of ACO2, and as a potential early biomarker to be used in clinical trials for assessing the effects of antioxidants in PD. Moreover, ameliorating energy metabolism by targeting ACO2 could be considered as a potential therapeutic strategy for PD and other neurodegenerative disorders.

The importance of late-onset cobalamin C (cblC) disorder is underestimated in adults. Improved awareness on its clinical and neuroimaging features helps timely diagnosis and appropriate treatment. Totally 16 late-onset cblC cases were diagnosed based on clinical, biochemical findings and MMAHC gene mutation analysis. Clinical presentations, neuroimaging features and mutational spectrum were reviewed. The case series included 10 males and 6 females, with average age of 22 (range 13–40) years. All the 16 patients displayed bilateral pyramidal tract signs, and most of the cases (13) had cognitive impairment. Other symptoms included psychiatric symptoms (6), epilepsy (6), peripheral nerve damage (5), ocular symptoms (4) and lower-limb thrombosis (1). The neuroimaging findings were dominated by cerebral atrophy (11/16), followed by white matter lesions (4), cerebellar lesions/atrophy (2) and spinal cord lesions (1). There were also 2 patients with normal imaging. All the MMACHC mutations were compound heterozygous, of which the most and second frequent was c.482G > A (p.R161Q; 15/16 case; allele frequency: 46.88%) and c.609G > A(p.W203X; 6/16 case; allele frequency: 18.75%). In addition, patients carrying frameshift mutations (deletion/duplication) presented more frequently with psychiatric symptoms (57.1%) and optic nerve damages (42.9%) than those carrying point mutations (22.2 and 11.1%, respectively). In contrast, peripheral nerve (44.4%) and white matter lesions (33.3%) were more frequently identified in point mutation- carriers. However, the differences did not achieve statistical significance (all p > 0.05). Compared to the early-onset form, late-onset cblC displayed some clinical, neuroimaging and mutational profiles, which warrants particular attention in adult neurologic practice. These findings not only broaden our insights into the genotypes and phenotypes of the disease, but highlight the importance of early diagnosis and initiation of appropriate treatments.