The longitudinal association between cognitive impairment and incident visual impairment in a multiethnic Asian population: a prospective cohort study.

BACKGROUND: The relationship between baseline cognitive impairment (CI) and incident visual impairment (VI) in Asians is unclear. OBJECTIVE: To determine the associations between baseline CI with incident VI and visual acuity (VA) at 6-year follow-up in multiethnic Asians. DESIGN: Cohort. SETTING: Population-based. SUBJECTS: Two thousand three hundred and twenty-four adults aged ≥60 years from the Singapore Epidemiology of Eye Diseases Study (response rate 64%). METHODS: CI was defined using the validated Abbreviated Mental Test (AMT). VA was objectively measured using a LogMAR chart. Any incident VI was defined as having no VI (Snellen's VA better than or equal to 20/40) at baseline but present (VA worse than 20/40) at 6-year follow-up. VI severity was defined according to the International Classification of Diseases, 11th Revision. Associations were assessed using logistic and linear regression models. RESULTS: Of the 2,324 participants, 248 had CI at baseline. Presence of baseline CI was associated with more than twice the odds of any incident VI, incident mild and moderate-severe VI (OR [95% confidence interval]: 2.48 [1.55-3.90], 2.07 [1.17-3.55], and 2.61 [1.36-4.93], respectively) and worse VA (ß [95% confidence interval]: 0.026 [0.006-0.046]) at 6-year follow-up. The leading causes of incident VI were cataract and under-corrected refractive error. CONCLUSIONS: Older adults with CI had more than double the odds of VI development and poorer VA than their cognitively intact counterparts, and most causes of incident VI were correctable. Strategies such as targeted vision screening and early intervention for early detection and management of vision loss in patients with cognitive decline are warranted.

The Bidirectional Relationship between Vision and Cognition: A Systematic Review and Meta-analysis.

TOPIC: Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. CLINICAL RELEVANCE: Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. METHODS: PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. RESULTS: Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84-3.07]; longitudinal: OR, 1.66 [95% CI, 1.46-1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48-4.01]; longitudinal: OR, 2.09 [95% CI, 1.37-3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. DISCUSSION: Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences.

Longitudinal trajectory of Amyloid-related hippocampal subfield atrophy in nondemented elderly.

Hippocampal atrophy and abnormal ß-Amyloid (Aß) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aß-associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aß correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET-Aß in AD-vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto-segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aß-related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aß correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal-to-widespread trajectory of Aß-associated hippocampal subfield atrophy over disease progression in nondemented elderly.

Frequency and Clinical Impact of Serious Adverse Events on Post-Stroke Recovery with NeuroAiD (MLC601) versus Placebo: The CHInese Medicine Neuroaid Efficacy on Stroke Recovery Study.

BACKGROUND: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke. METHODS: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution. RESULTS: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01). CONCLUSIONS: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs.

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies.

BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study.

BACKGROUND: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. METHODS: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6-14, pre-stroke modified Rankin Scale (mRS) score ≤1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. RESULTS: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0-1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. CONCLUSIONS: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies.

Comparison Between the Original and Shortened Versions of the National Institutes of Health Stroke Scale in Ischemic Stroke Patients of Intermediate Severity.

BACKGROUND AND PURPOSE: The 15-item National Institutes of Health Stroke Scale (NIHSS) has been critiqued for its complexity and variability, and shortened versions have been proposed. This study aimed to compare the measurement properties of the original version with 3 shortened versions with 11, 8, and 5 items, respectively. METHODS: Analyses were performed using data from an international, double-blind randomized controlled trial investigating the efficacy of MLC601 on stroke recovery in patients with ischemic stroke of intermediate severity (Chinese Medicine Neuroaid Efficacy on Stroke recovery [CHIMES]). To compare discriminative ability and responsiveness to change, the effect sizes of the NIHSS scores in relation to modified Rankin Scale, mini-mental status examination, and Barthel index were estimated using regression analysis. RESULTS: For both discriminative ability and responsiveness to change, the original version exhibited a larger effect size (0.55 and 0.84) in relation to modified Rankin Scale than the other 3 shortened versions (0.35-0.46 and 0.74-0.78). CONCLUSIONS: The original 15-item NIHSS retained information that made it more discriminative and responsive to change than the shortened versions. We recommend future clinical researchers to use the full version NIHSS to evaluate patients' stroke severity. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Prognostic factors and treatment effect in the CHIMES study.

BACKGROUND: Stroke trials often analyze patients with heterogeneous prognoses using a single definition of outcome, which may not be applicable to all subgroups. We aimed to evaluate the treatment effects of MCL601 among patients stratified by prognosis in the Chinese Medicine Neuroaid Efficacy on Stroke Recovery (CHIMES) study. METHODS: Analyses were performed using data from the CHIMES study, an international, randomized, placebo-controlled, double-blind trial comparing MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. All subjects with baseline data and the modified Rankin Scale (mRS) score at 3 months were included. RESULTS: Data from 1006 subjects were analyzed. The predictive variables for mRS score greater than 1 at month 3 were age older than 60 years (P < .001), baseline National Institutes of Health Stroke Scale score 10-14 (P < .001), stroke onset to initiation of study treatment of more than 48 hours (P < .001), and female sex (P = .026). A higher number of predictors was associated with poorer mRS score at month 3 for both placebo (P < .001) and treatment (P < .001) groups. The odds ratio (OR) for achieving a good outcome increased with the number of predictors and reached statistical significance in favor of MLC601 among patients with 2 to 4 predictors combined (unadjusted OR = 1.44, 95% confidence interval, 1.02-2.03; adjusted OR = 1.60, 95% confidence interval, 1.10-2.34). CONCLUSIONS: Age, sex, baseline National Institutes of Health Stroke Scale score, and time to first dose are predictors of functional outcome in the CHIMES study. Stratification by prognosis showed that patients with 2 or more predictors of poorer outcome have better treatment effect with MLC601 than patients with single or no prognostic factor. These results have implications on designing future stroke trials.

Effects of MLC601 on early vascular events in patients after stroke: the CHIMES study.

BACKGROUND AND PURPOSE: Early vascular events are an important cause of morbidity and mortality in the first 3 months after a stroke. We aimed to investigate the effects of MLC601 on the occurrence of early vascular events within 3 months of stroke onset. METHODS: Post hoc analysis was performed on data from subjects included in the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study, a randomized, placebo-controlled, double-blinded trial that compared MLC601 with placebo in 1099 subjects with ischemic stroke of intermediate severity in the preceding 72 hours. Early vascular events were defined as a composite of recurrent stroke, acute coronary syndrome, and vascular death occurring within 3 months of stroke onset. RESULTS: The frequency of early vascular events during the 3-month follow-up was significantly less in the MLC601 group than in the placebo group (16 [2.9%] versus 31 events [5.6%]; risk difference=-2.7%; 95% confidence interval, -5.1% to -0.4%; P=0.025) without an increase in nonvascular deaths. Kaplan-Meier survival analysis showed a difference in the risk of vascular outcomes between the 2 groups as early as the first month after stroke (Log-rank P=0.024; hazard ratio, 0.51; 95% confidence interval, 0.28-0.93). CONCLUSIONS: Treatment with MLC601 was associated with reduced early vascular events among subjects in the CHIMES study. The mechanisms for this effect require further study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study.

BACKGROUND AND PURPOSE: Previous clinical studies suggested benefit for poststroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. METHODS: This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. RESULTS: The modified Rankin Scale shift analysis-adjusted odds ratio was 1.09 (95% confidence interval, 0.86-1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups. CONCLUSIONS: MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

The NeuroAiD II (MLC901) in vascular cognitive impairment study (NEURITES).

BACKGROUND: A substantial proportion of patients after nondisabling stroke are cognitively impaired compared to age- and education-matched community-dwelling controls. Moreover, poststroke patients who have 'vascular cognitive impairment no dementia' (VCIND) of moderate severity have a high risk of incident dementia, dependency and death. Further studies are urgently needed to demonstrate effective cognition-enhancing therapies in VCIND given the scarcity of evidence-based treatment options. NeuroAiD is a traditional Chinese medicine that has been shown to induce neuroplasticity, promote cell proliferation and stimulate the development of dense axonal and dendritic networks in animal stroke models. NeuroAiD may improve cerebral blood flow and functional recovery after stroke in patients. OBJECTIVE: To investigate the effects and tolerability of NeuroAiD II in patients with VCIND. METHODS: The NeuroAiD II (MLC901) in Vascular Cognitive Impairment Study (NEURITES) is a 24-week, double-blind, randomized, placebo-controlled phase II study of NeuroAiD II in patients with VCIND. The primary outcome is executive function as measured by the Verbal Fluency test. Secondary outcomes include cognitive assessments such as the ADAS-Cog, MoCA, MMSE and Cognitive Battery: activities of daily living as measured by the Alzhei-mer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale for mild cognitive impairment, behavior as measured by the Neuropsychiatric Inventory, and depression as measured by the Geriatric Depression Scale and the Beck Depression Scale. In addition, there will be novel exploratory outcomes: (a) magnetic resonance imaging of lesion location (structural imaging), structural integrity of white matter pathways (diffusion tensor imaging), neuronal function (resting studies) and perfusion (arterial spin labeling and MR angiography), and (b) retinal and optic nerve imaging. Safety and tolerability will be assessed using adverse events, laboratory tests and vital signs. CONCLUSIONS: NEURITES has the potential to set new standards for the systematic evaluation of Asian traditional medicine for integration into standard medicine practice and establishing a novel therapeutic approach for improving cognition after stroke.

The Association Between Standard Electrocardiography and Cerebral Small Vessel Disease in a Memory Clinic Study.

BACKGROUND: P-wave terminal force in lead V1 (PTFV1) on electrocardiography has been associated with atrial fibrillation and ischemic stroke. OBJECTIVE: To investigate whether PTFV1 is associated with cerebral small vessel disease (CSVD) markers and etiological subtypes of cognitive impairment and dementia. METHODS: Participants were recruited from ongoing memory clinic study between August 2010 to January 2019. All participants underwent physical and medical evaluation along with an electrocardiography and 3 T brain magnetic resonance imaging. Participants were classified as no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, and dementia subtypes (Alzheimer's disease and vascular dementia). Elevated PTFV1 was defined as > 4,000µV×ms and measured manually on ECG. RESULTS: Of 408 participants, 78 (19.1%) had elevated PTFV1 (37 women [47%]; mean [SD] age, 73.8 [7.2] years). The participants with elevated PTFV1 had higher burden of lacunes, cerebral microbleeds (CMB), and cortical microinfarcts. As for the CMB location, persons with strictly deep CMB and mixed CMB had significantly higher PTFV1 than those with no CMB (p = 0.005, p = 0.007). Regardless of adjustment for cardiovascular risk factors and/or heart diseases, elevated PTFV1 was significantly associated with presence of CMB (odds ratio, 2.26; 95% CI,1.33-3.91). CONCLUSION: Elevated PTFV1 was associated with CSVD, especially deep CMB. PTFV1 in vascular dementia was also higher compared to Alzheimer's disease. Thus, PTFV1 might be a potential surrogate marker of brain-heart connection and vascular brain damage.

Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.

OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression. DESIGN: Randomized double-blind placebo-controlled delayed-start study. SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035). METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales. RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences. CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.

NEURoaid II (MLC901) in cognitively Impaired not demenTEd patientS (NEURITES): A pilot double blind, placebo-controlled randomized trial.

OBJECTIVE: To investigate the efficacy and safety of MLC901 in vascular cognitive impairment no dementia (VCIND) patients. DESIGN: This was a multi-center, double-blind, randomized, placebo-controlled pilot study. SETTING AND PARTICIPANT: VCIND patients from hospitals in Singapore (67), Vietnam (19), and the Philippines (17) were recruited and followed-up from March 2013 to April 2018. METHODS: The primary outcome was executive function as measured by the Verbal Fluency (VF) and 2-part Color Trails Test (CTT). The mean difference in the scores between baseline and week 12, and baseline and week 24, was compared between MLC901 and placebo using a two-sample t-test. RESULTS: The trial randomized 103 subjects: MLC901 (n = 57) and placebo (n = 46). The mean age of participants was 68.3 ± 8.4 years and 38.8% were female. Improvement in executive function with MLC901 was not significantly better than placebo at week 12 (CTT1 mean difference [md] 3.8 seconds, 95% confidence interval [CI]: -9.0 to 16.5, CTT2 md 10.9 seconds, 95% CI: -0.2 to 22.0), and at week 24 (CTT1 md 2.8 seconds, 95% CI: -8.4 to 14.0, CTT2 md = 4.4 seconds, 95% CI: -8.2 to 16.9). Improvement in VF from baseline was not significantly different between MLC901 and placebo at weeks 12 and 24. There were no significant differences in adverse events (43.5% vs. 56.1%) or serious adverse events (13% vs. 22.8%) in placebo versus MLC901 groups. In post hoc exploratory analysis, the treatment effect of MLC901 on cognitive function appears more apparent in subjects with existing impairment in executive function: CTT2 (md 14.4 seconds [P = .05] and 9.9 seconds [P = .3] at week 12 and week 24, respectively). CONCLUSIONS: Whilst MLC901 appears to be safe, there was no significant cognitive benefit from MLC901 in the study population. Post hoc hypotheses generating analyses suggest that VCIND patients with existing impairment in executive function may show benefit.

Cortisol response to individualised graded insulin infusions: a reproducible biomarker for CNS compounds inhibiting HPA activation.

AIM: To determine the potential of cortisol secretion, in response to a physiological stressor, as a biomarker for centrally active compounds targeting the hypothalamic-pituitary-adrenocortical (HPA) axis. METHODS: Cortisol response to hypoglycaemia was measured in 26 healthy males in two stages: firstly to derive an algorithm for individualized, graded insulin infusion rates to achieve defined hypoglycaemic targets over 3 h and secondly to determine the inter- and intra-subject variability of cortisol response to hypoglycaemia over two identical periods by measuring the maximum (t(max) ), time to maximum (C(max) ) response and cortisol area under the response curve (AUC). RESULTS: Hypoglycaemia induced a consistent cortisol response starting at approximately 1 h, corresponding to blood glucose concentrations of approximately 3.3 mmol l⁻¹, and peaking approximately 3 h after the start of infusion. The inter- and intra-subject coefficients of variation (CVs) of cortisol response were approximately 19 and 19% (AUC), 15 and 19 % (C(max) ) and 10 and 14% (t(max) ), respectively. The intra-subject CVs for the ratio of maximum cortisol response to baseline concentration and rate of initial cortisol response between study days were more variable (32.8% and 59.0%, respectively). The blood glucose-cortisol response model derived from the study was predictive of the individual observed cortisol responses, and estimated a blood glucose EC(50) associated with onset of the cortisol response of 3.3 mmol l⁻¹. CONCLUSIONS: Gradual hypoglycaemia is an effective, reproducible and well-tolerated method of stimulating a cortisol response and may therefore be useful in assessing the neuroendocrine response to HPA axis inhibitors, such as corticotropin-releasing hormone-1 (CRH-1) antagonists.

Psychometric Properties of the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network Neuropsychological Battery in an Asian Older Adult Sample.

OBJECTIVE: Despite the wide usage of the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network (NINDS-CSN) neuropsychological battery for the detection of vascular cognitive impairment, its reliability and validity have not been established. Therefore, the present study established the psychometric properties of the battery in cognitively normal older adults in a clinical setting in Singapore. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: A total of 105 cognitively normal older adults age 50 years and older were assessed in a memory clinic setting. METHODS: The 60-minute NINDS-CSN and 5-minute protocol were administered to participants at baseline and 3-month follow-up. Raw scores were transformed into standardized z scores. Test-retest reliability, concurrent validity and construct (convergent and discriminant) validity were reported. RESULTS: Moderate-to-excellent test-retest reliability (r = 0.36-0.87), concurrent validity, and construct validity (r = 0.41-0.83) were found in both protocols over 3 months (all Ps < 0.01). Although the 5-minute protocol showed moderate validity (r = 0.41), the 60-minute protocol had excellent concurrent validity against a locally validated neuropsychological battery (r = 0.83). CONCLUSION AND IMPLICATIONS: The NINDS-CSN is reliable and valid in assessing cognitive function. The 60-minute protocol demonstrates great utility beyond its current usage in vascular cognitive impairment populations to the general older adult population. The 5-minute protocol can be used as a brief cognitive screening tool in primary healthcare and the community, due to its brevity and accuracy. Future research should further examine the generalizability of the NINDS-CSN battery in other dementias and cognitive disorders.