The global burden of cerebral small vessel disease in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. Previous studies on the prevalence of cSVD are mostly based on single geographically defined cohorts in high-income countries. Studies investigating the prevalence of cSVD in low- and middle-income countries (LMICs) are expanding but have not been systematically assessed. AIM: This study aims to systematically review the prevalence of cSVD in LMICs. RESULTS: Articles were searched from the Ovid MEDLINE and EMBASE databases from 1 January 2000 to 31 March 2022, without language restrictions. Title/abstract screening, full-text review, and data extraction were performed by two to seven independent reviewers. The prevalence of cSVD and study sample size were extracted by pre-defined world regions and health status. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). A meta-analysis of proportion was performed to assess the prevalence of different magnetic resonance imaging markers of cSVD, and a meta-regression was performed to investigate associations between cSVD prevalence and type of study, age, and male: female ratio. Of 2743 studies identified, 42 studies spanning 12 global regions were included in the systematic review. Most of the identified studies were from China (n = 23). The median prevalence of moderate-to-severe white matter hyperintensities (WMHs) was 20.5%, 40.5%, and 58.4% in the community, stroke, and dementia groups, respectively. The median prevalence of lacunes was 0.8% and 33.5% in the community and stroke groups. The median prevalence of cerebral microbleeds (CMBs) was 10.7% and 22.4% in the community and stroke groups. The median prevalence of moderate-to-severe perivascular spaces was 25.0% in the community. Meta-regression analyses showed that the weighted median age (51.4 ± 0.0 years old; range: 36.3-80.2) was a significant predictor of the prevalence of moderate-to-severe WMH and lacunes, while the type of study was a significant predictor of the prevalence of CMB. The heterogeneity of studies was high (>95%). Male participants were overrepresented. CONCLUSIONS: This systematic review and meta-analysis provide data on cSVD prevalence in LMICs and demonstrated the high prevalence of the condition. cSVD research in LMICs is being published at an increasing rate, especially between 2010 and 2022. More data are particularly needed from Sub-Saharan Africa and Central Europe, Eastern Europe, and Central Asia.

Resveratrol: A "miracle" drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis.

BACKGROUND: Over the last decade resveratrol has been trialled for the prevention and treatment of cognitive decline; however, the results have shown a conflict between human studies compared with animal studies, especially on cognition, blood pressure, neuroimaging, and mood. METHODS: Human clinical trials and animal studies published prior to January 2020, were identified searching across major electronic databases. PRISMA guidelines were used for data extraction, which was independently performed by two authors. Pooled standard mean difference (SMD, random effect model) and odds ratios (ORs) were calculated. RESULTS: Most publications on animal models reported positive outcomes on cognition and brain function following exposure to resveratrol or grape seed extracts. By contrast, 11 meta-analyses of data from human placebo vs resveratrol, grape or wine treatment trials identified no statistically significant effect on a variety of measures, including cognitive and mood assessments, grey matter volume and blood pressure. CONCLUSIONS: Based on currently available data, the promising effects of resveratrol in animal models is not replicated in human clinical trials. The effects, if any, of resveratrol on human cognition are likely to be small. This work may be useful for the design and implementation of future pre-clinical and clinical studies using resveratrol in a neurological setting.

Interrupting the trajectory of frailty in dementia with Lewy bodies with anabolic exercise, dietary intervention and deprescribing of hazardous medications.

An 87-year-old man with dementia with Lewy bodies, living in residential aged care, exhibited rapid functional decline and weight loss associated with injurious falls over 9 months. Independent clinicians (geriatrician and exercise physiologist) assessed him during an extended wait-list period prior to his commencement of a pilot exercise trial. The highly significant role of treatable factors including polypharmacy, sarcopenia and malnutrition as contributors to frailty and rapid functional decline in this patient are described. The results of a targeted intervention of deprescribing, robust exercise and increased caloric intake on his physical and neuropsychological health status are presented. This case highlights the need to aggressively identify and robustly treat reversible contributors to frailty, irrespective of advanced age, progressive 'untreatable' neurodegenerative disease and rapidly deteriorating health in such individuals. Frailty is not a contraindication to robust exercise; it is, in fact, one of the most important reasons to prescribe it.

Design and Development of the Brain Training System for the Digital "Maintain Your Brain" Dementia Prevention Trial.

BACKGROUND: Dementia is the leading cause of disability worldwide, and interventions aimed at reducing the prevalence and burden of the disease are urgently needed. Maintain Your Brain (MYB) is a randomized controlled trial of a multimodal digital health intervention targeting modifiable dementia risk factors to combat cognitive decline and potentially prevent dementia. In addition to behavioral modules targeting mood, nutrition, and physical exercise, a new Brain Training System (BTS) will deliver computerized cognitive training (CCT) throughout the trial to provide systematic, challenging, and personally adaptive cognitive activity. OBJECTIVE: This paper aimed to describe the design and development of BTS. METHODS: BTS has been designed with a central focus on the end user. Raw training content is provided by our partner NeuroNation and delivered in several innovative ways. A baseline cognitive profile directs selection and sequencing of exercises within and between sessions and is updated during the 10-week 30-session module. Online trainers are available to provide supervision at different levels of engagement, including face-to-face share-screen coaching, a key implementation resource that is triaged by a "red flag" system for automatic tracking of user adherence and engagement, or through user-initiated help requests. Individualized and comparative feedback is provided to aid motivation and, for the first time, establish a social support network for the user based on their real-world circle of friends and family. RESULTS: The MYB pilot was performed from November 2017 to March 2018. We are currently analyzing data from this pilot trial (n=100), which will make up a separate research paper. The main trial was launched in June 2018. Process and implementation data from the first training module (September to November 2018) are expected to be reported in 2019 and final trial outcomes are anticipated in 2022. CONCLUSIONS: The BTS implemented in MYB is focused on maximizing adherence and engagement with CCT over the short and long term in the setting of a fully digital trial, which, if successful, could be delivered economically at scale. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000851268; https://www.anzctr.org.au /Trial/Registration/TrialReview.aspx?id=370631&isReview=true.

Comparison of Single Phase and Biphasic Extraction Protocols for Lipidomic Studies Using Human Plasma.

Lipidomic profiling of plasma is an emerging field, given the importance of lipids in major cellular pathways, and is dependent on efficient lipid extraction protocols. Recent attention has turned to plasma lipidomics as a means to identify potential diagnostic and prognostic biomarkers related to dementia, neuropsychiatric health and disease. Although several solvent-based lipid extraction protocols have been developed and are currently in use, novel and more efficient methods could greatly simplify lipid analysis in plasma and warrant investigation. Human plasma from normolipidemic adult volunteers was collected to evaluate three different solvent extraction protocols, including the classical Folch method, the methanol/tert-butyl methyl ether (MTBE) (Matyash) method, and a recent single-phase methanol/1-butanol (Alshehry) method. Extracted lipids were analyzed using liquid chromatography mass spectrometry (LC-MS) in positive and negative ion mode. Overall, more than 500 different lipids were identified in positive and negative ion mode combined. Our data show that the single phase Alshehry method was as effective as the Folch and Matyash methods in extracting most lipid classes and was more effective in extraction of polar lipids. Normalized peak areas of the Alshehry method were highly and positively correlated with both the Folch and Matyash methods (r 2 = 0.99 and 0.97, respectively). Within- and between- subject correlations were r = 0.99 and 0.96, respectively. Median intra-assay coefficient of variation (CV%) in positive mode was 14.1, 15.1, and 21.8 for the Alshehry, Folch and Matyash methods, respectively. Median Alshehry inter-assay CV (collected over 5 separate days) was 14.4%. In conclusion, the novel Alshehry method was at least as good as, if not better than the established biphasic extraction methods in detecting a wide range of lipid classes, using as little as 10 µL of plasma, and was highly reproducible, safer and more environmentally-friendly as it doesn't require chloroform.

Quantifying the cellular NAD+ metabolome using a tandem liquid chromatography mass spectrometry approach.

INTRODUCTION: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as a key hydride transfer coenzyme for several oxidoreductases. It is also the substrate for intracellular secondary messenger signalling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase, and epigenetic regulation of gene expression by a class of histone deacetylase enzymes known as sirtuins. The measurement of NAD+ and its related metabolites (hereafter, the NAD+ metabolome) represents an important indicator of cellular function. OBJECTIVES: A study was performed to develop a sensitive, selective, robust, reproducible, and rapid method for the concurrent quantitative determination of intracellular levels of the NAD+ metabolome in glial and oocyte cell extracts using liquid chromatography coupled to mass spectrometry (LC/MS/MS). METHODS: The metabolites were separated on a versatile amino column using a dual HILIC-RP gradient with heated electrospray (HESI) tandem mass spectrometry detection in mixed polarity multiple reaction monitoring mode. RESULTS: Quantification of 17 metabolites in the NAD+ metabolome in U251 human astroglioma cells could be achieved. Changes in NAD+ metabolism in U251 cell line, and murine oocytes under different culture conditions were also investigated. CONCLUSION: This method can be used as a sensitive profiling tool, tailoring chromatography for metabolites that express significant pathophysiological changes in several disease conditions and is indispensable for targeted analysis.

Severe depression masquerading as Creutzfeldt-Jakob disease.

We report a case of melancholic depression with catatonic features presenting as a rapidly progressive organic brain syndrome, initially thought to be probable Creutzfeldt-Jakob disease. The case highlights the fundamental importance of thorough exclusion of treatable pathology masquerading as an irreversible syndrome.

Improving screening for vascular cognitive impairment at three to six months after mild ischemic stroke and transient ischemic attack.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were compared with and without the addition of a brief processing speed test, the symbol digit modalities test (SDMT), for vascular cognitive impairment (VCI) screening at three to six months after stroke. METHODS: Patients with ischemic stroke and transient ischemic attack were assessed with MoCA and MMSE, as well as a formal neuropsychological battery three to six months after stroke. VCI was defined by impairment in any cognitive domain on neuropsychological testing. The area under the receiver operating characteristic curve (AUC) was used to compare test discriminatory ability. RESULTS: One hundred and eighty-nine patients out of 327 (58%) had VCI, of whom 180 (95%) had vascular mild cognitive impairment (VaMCI), and nine (5%) had dementia. The overall AUCs of the MoCA and MMSE scores and performance at their respective cut-off points were equivalent in detecting VCI (AUCs: 0.87 (95% CI 0.83-0.91) vs. 0.84 (95% CI 0.80-0.88), p = 0.13; cut-offs: MoCA (≤23) vs. MMSE (≤26), sensitivity: 0.78 vs. 0.71; specificity: 0.80 vs. 0.82; positive predictive value: 0.84 vs. 0.84; negative predictive value: 0.72 vs. 0.67; and correctly classified 78.6% vs. 75.5%; p = 0.42). The AUCs of MMSE and MoCA were improved significantly by the SDMT (AUCs: MMSE+SDMT 0.90 (95% CI 0.87-0.93), p <0.001; MoCA+SDMT 0.91 (95% CI 0.88-0.94), p < 0.02). CONCLUSIONS: The MoCA and MMSE are equivalent and moderately sensitive, and can be supplemented with the SDMT to improve their accuracy in VCI screening.

Bilateral deep brain stimulation of the nucleus accumbens for comorbid obsessive compulsive disorder and Tourette's syndrome.

We present the case of a 32-year-old Caucasian woman with severe treatment-refractory obsessive compulsive disorder (OCD) and Tourette's syndrome. Both conditions were present prior to age 5 and impacted significantly on the patient's functioning. Multiple trials of evidence-based pharmacological and behavioural therapies had not achieved remission of symptoms. Bilateral deep brain stimulation of the nucleus accumbens was undertaken to treat both illnesses but with a particular focus on OCD, as the patient identified this as the more debilitating of the two disorders. Following surgery there was an immediate improvement in OCD and tic severity. At follow-up 8 months later, there was a 90% improvement in OCD symptoms and a 57% improvement in tic severity. No intraoperative or postoperative complications or adverse events occurred and there were no undesired effects of stimulation.