Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis.

BACKGROUND: Cerebral small vessel disease, a common cause of vascular dementia, is often considered clinically silent before dementia or stroke become apparent. However, some individuals have subtle symptoms associated with acute MRI lesions. We aimed to determine whether neuropsychiatric and cognitive symptoms vary according to small vessel disease burden. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and PsycINFO for articles published in any language from database inception to Jan 24, 2020. We searched for studies assessing anxiety, apathy, delirium, emotional lability, fatigue, personality change, psychosis, dementia-related behavioural symptoms or cognitive symptoms (including subjective memory complaints), and radiological features of cerebral small vessel disease. We extracted reported odds ratios (OR), standardised mean differences (SMD), and correlations, stratified outcomes by disease severity or symptom presence or absence, and pooled data using random-effects meta-analyses, reporting adjusted findings when possible. We assessed the bias on included studies using the Risk of Bias for Non-randomized Studies tool. This study is registered with PROSPERO, CRD42018096673. FINDINGS: Of 7119 papers identified, 81 studies including 79 cohorts in total were eligible for inclusion (n=21 730 participants, mean age 69·2 years). Of these 81 studies, 45 (8120 participants) reported effect estimates. We found associations between worse white matter hyperintensity (WMH) severity and apathy (OR 1·41, 95% CI 1·05-1·89) and the adjusted SMD in apathy score between WMH severities was 0·38 (95% CI 0·15-0·61). Worse WMH severity was also associated with delirium (adjusted OR 2·9, 95% CI 1·12-7·55) and fatigue (unadjusted OR 1·63, 95% CI 1·20-2·22). WMHs were not consistently associated with subjective memory complaints (OR 1·34, 95% CI 0·61-2·94) and unadjusted SMD for WMH severity between these groups was 0·08 (95% CI -0·31 to 0·47). Anxiety, dementia-related behaviours, emotional lability, and psychosis were too varied or sparse for meta-analysis; these factors were reviewed narratively. Overall heterogeneity varied from 0% to 79%. Only five studies had a low risk of bias across all domains. INTERPRETATION: Apathy, fatigue, and delirium associated independently with worse WMH, whereas subjective cognitive complaints did not. The association of anxiety, dementia-related behaviours, emotional lability, and psychosis with cerebral small vessel disease require further investigation. These symptoms should be assessed longitudinally to improve early clinical detection of small vessel disease and enable prevention trials to happen early in the disease course, long before cognition declines. FUNDING: Chief Scientist Office of the Scottish Government, UK Dementia Research Institute, Fondation Leducq, Stroke Association Garfield-Weston Foundation, Alzheimer's Society, and National Health Service Research Scotland.

Sustained Release of Cx43 Antisense Oligodeoxynucleotides from Coated Collagen Scaffolds Promotes Wound Healing.

Antisense oligodeoxynucleotides targeting the mRNA of the gap junction protein Cx43 promote tissue repair in a variety of different wounds. Delivery of the antisense drug has most often been achieved by a thermoreversible hydrogel, Pluronic F-127, which is very effective in the short term but does not allow for sustained delivery over several days. For chronic wounds that take a long time to heal, repeated dosing with the drug may be desirable but is not always compatible with conventional treatments such as the weekly changing of compression bandages on venous leg ulcers. Here the coating of collagen scaffolds with antisense oligonucleotides is investigated and a way to provide protection of the oligodeoxynucleotide drug is found in conjunction with sustained release over a 7 d period. This approach significantly reduces the normal foreign body reaction to the scaffold, which induces an increase of Cx43 protein and an inhibition of healing. As a result of the antisense integration into the scaffold, inflammation is reduced with the rate of wound healing and contracture is significantly improved. This coated scaffold approach may be very useful for treating venous leg ulcers and also for providing a sustained release of any other types of oligonucleotide drugs that are being developed.

Integration of scaffolds into full-thickness skin wounds: the connexin response.

Scaffolds have been reported to promote healing of hard-to-heal wounds such as burns and chronic ulcers. However, there has been little investigation into the cell biology of wound edge tissues in response to the scaffolds. Here, we assess the impact of collagen scaffolds on mouse full-thickness wound re-epithelialisation during the first 5 days of healing. We find that scaffolds impede wound re-epithelialisation, inducing a bulbous thickening of the wound edge epidermis as opposed to the thin tongue of migratory keratinocytes seen in normal wound healing. Scaffolds also increase the inflammatory response and the numbers of neutrophils in and around the wound. These effects were also produced by scaffolds made of alginate in the form of fibers and microspheres, but not as an alginate hydrogel. In addition, we find the gap junction protein connexin 43, which normally down-regulates at the wound edge during re-epithelialisation, to be up-regulated in the bulbous epidermal wound edge. Incorporation of connexin 43 antisense oligodeoxynucleotides into the scaffold can be performed to reduce inflammation whilst promoting scaffold biocompatibility.

Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration.

Poor healing of DFUs (diabetic foot ulcers) is a major clinical problem that can be extremely debilitating and lead to lower limb amputation. In the normal acute wound, the Cx43 (connexin 43) gap junction protein is down-regulated at the wound edge as a precursor to cell migration and healing. In fibroblasts from the human chronic DFU wound edge there was a striking and significant 10-fold elevation of Cx43 protein, as well as a 6-fold increase in N-cadherin and a 2-fold increase in ZO-1 (zonular occludin-1), compared with unwounded skin. In streptozotocin diabetic rats, Cx43 was found to be up-regulated in intact dermal fibroblasts in direct proportion to blood glucose levels and increased 2-fold further in response to wounding of the skin. To mimic diabetes, NIH 3T3 fibroblasts were cultured under different concentrations of glucose or mannitol and Cx43 protein intercellular communication and migration rates were determined. Cultures of fibroblasts in very high (40 mM) glucose conditions showed significantly elevated Cx43 protein levels, as shown by immunostaining and Western blotting, and significantly increasing gap junctional communication, as shown by dye transfer. In scratch wound-healing assays, increased levels of Cx43 from high glucose resulted in repressed filopodial extensions and significantly slower migration rates than in either standard conditions (5.5 mM glucose) or the osmotic control of mannitol. Conversely, when glucose-induced Cx43 up-regulation was prevented with Cx43shRNA (Cx43 short-hairpin RNA) transduction, the fibroblasts extended long filopodia and migrated significantly faster. Cx43 protein was up-regulated in fibroblasts in DFUs as well as after high glucose exposure in culture which correlated with inhibition of fibroblast migration and is likely to contribute to impaired wound healing.