REKOVER study protocol: a pRospective patient treatment rEgistry of tramadol and dexKetoprofen trometamol oral fixed-dose combination (SKUDEXA) in mOderate to seVere acutE pain in Real-world setting in Asia.

INTRODUCTION: Satisfactory management of acute pain remains a major medical challenge despite the availability of multiple therapeutic options including the fixed-dose combination (FDC) drugs. Tramadol and dexketoprofen trometamol (TRAM/DKP) 75/25 mg FDC was launched in 2018 in Asia and is widely used in the management of moderate to severe acute pain. There are limited data on its effectiveness and safety in Asian patients, and therefore, a need to better understand its usage patterns in clinical practice. We aim to understand the usage pattern of TRAM/DKP FDC, its effectiveness and tolerability in patients with moderate to severe acute pain in Asia. METHODS AND ANALYSIS: REKOVER is a phase-IV, multicountry, multicentre, prospective, real-world observational study. A total of 750 postsurgical and non-surgical patients (male and female, aged 18-80 years) will be recruited from 13 tertiary-care hospitals (15 sites) in Singapore, Thailand, the Philippines and Malaysia. All patients prescribed with TRAM/DKP FDC and willing to participate in the study will be enrolled. The recruitment duration for each site will be 6 months. The severity of pain will be collected using Numeric Pain Rating Scale through the treatment period from day 1 to day 5, while satisfaction with the treatment will be evaluated using Patient Global Evaluation Scale at the end of treatment. Any adverse event reported during the study duration will be recorded for safety analysis (up to day 6). The study data will be entered into the ClaimIt portal and mobile application (app) (ObvioHealth, USA). All the inpatient data will be entered into the portal by the study site and for outpatient it will be done by patients through an app. ETHICS AND DISSEMINATION: The study has been approved by the local ethics committee from each study sites in Singapore, Thailand, the Philippines and Malaysia. Findings will be disseminated through local and global conference presentations, publications in peer-reviewed scientific journals and continuing medical education.

CT-based volumetric measures obtained through deep learning: Association with biomarkers of neurodegeneration.

INTRODUCTION: Cranial computed tomography (CT) is an affordable and widely available imaging modality that is used to assess structural abnormalities, but not to quantify neurodegeneration. Previously we developed a deep-learning-based model that produced accurate and robust cranial CT tissue classification. MATERIALS AND METHODS: We analyzed 917 CT and 744 magnetic resonance (MR) scans from the Gothenburg H70 Birth Cohort, and 204 CT and 241 MR scans from participants of the Memory Clinic Cohort, Singapore. We tested associations between six CT-based volumetric measures (CTVMs) and existing clinical diagnoses, fluid and imaging biomarkers, and measures of cognition. RESULTS: CTVMs differentiated cognitively healthy individuals from dementia and prodromal dementia patients with high accuracy levels comparable to MR-based measures. CTVMs were significantly associated with measures of cognition and biochemical markers of neurodegeneration. DISCUSSION: These findings suggest the potential future use of CT-based volumetric measures as an informative first-line examination tool for neurodegenerative disease diagnostics after further validation. HIGHLIGHTS: Computed tomography (CT)-based volumetric measures can distinguish between patients with neurodegenerative disease and healthy controls, as well as between patients with prodromal dementia and controls. CT-based volumetric measures associate well with relevant cognitive, biochemical, and neuroimaging markers of neurodegenerative diseases. Model performance, in terms of brain tissue classification, was consistent across two cohorts of diverse nature. Intermodality agreement between our automated CT-based and established magnetic resonance (MR)-based image segmentations was stronger than the agreement between visual CT and MR imaging assessment.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

The association of diffusion tensor MRI measures of normal appearing white matter and cognition.

Objective: Median and peak height of fractional anisotropy (FA) and mean diffusivity (MD) are diffusion tensor imaging (DTI) markers used to quantify white matter microstructure changes. We examine the association of DTI histogram-derived measures in global normal appearing white matter (NAWM) and cognitive decline in patients with normal cognition and cognitive impairment no dementia from a memory clinic in Singapore. Methods: A total of 252 patients (mean age: 71.1 ± 7.6 years, 53.2% women) were included. All patients underwent clinical assessments, a brain MRI scan at baseline, and neuropsychological assessments annually for 2 years. DTI scans were processed to obtain MD and FA histogram-derived measures. The National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network harmonization neuropsychological battery were used to assess cognitive function. Linear regression models with generalised estimating equation (GEE) and logistic regression models were used to examine the association between DTI histogram measures and cognitive decline. Results: When compared to baseline, MD and FA measures at Year 2 were associated with an accelerated worsening in global cognition (all p for interaction <0.001; Year 0 vs 2, MD median: -0.29 (95%CI: -0.49, -0.09) vs -0.45 (95%CI: -0.65,-0.25); MD peak height: 0.22 (95%CI: 0.07, 0.37) vs 0.37 (95%CI: 0.21, 0.53); FA median: 0.11 (95%CI: -0.05, 0.26) vs 0.22 (95%CI: 0.07, 0.37); FA peak height: -0.14 (95%CI: -0.28, 0.00) vs -0.24 (95%CI: -0.38, -0.10);). Similar findings were observed for executive function and visuomotor speed while only MD measures predicted worsening in memory domain. Interpretation: This study shows that DTI histogram measures are associated with accelerated cognitive decline suggesting the utility of DTI as a pre-clinical marker in predicting the worsening of cognition in clinical trials.

The potential benefits of assessing post-cardiopulmonary exercise testing (CPET) in aging: a narrative review.

Cardiopulmonary exercise testing (CPET) is an important tool to measure the cardiopulmonary fitness of an individual and has been widely used in athletic, clinical and research settings. Most CPET focus on analyzing physiological responses during exercise. We contend that the post-CPET recovery physiological responses offer further diagnostic and prognostic information about the health of the cardiopulmonary and metabolic systems, especially when testing apparently healthy middle-aged and older adults. However, there are limited studies that investigate physiological responses during the post-CPET recovery, and even less so in middle-aged and older adults. Therefore, this current review is aimed at discussing the contribution of post-CPET recovery parameters to cardiopulmonary health and their potential applications in aging populations. In addition to the existing methods, we propose to examine the aerobic and anaerobic recovery threshold post-CPET as novel potential diagnostic and/or prognostic tools.

Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease.

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral sTNF-R1 have been reported in both Alzheimer's disease (AD) dementia and vascular dementia (VaD). However, the status of sTNF-R1 in predementia subjects (cognitive impairment, no dementia, CIND) is unknown, and putative associations with cerebral small vessel disease (CSVD), as well as with longitudinal changes in cognitive functions are unclear. We measured baseline serum sTNF-R1 in a longitudinally assessed cohort of 93 controls and 103 CIND, along with neuropsychological evaluations and neuroimaging assessments. Serum sTNF-R1 levels were increased in CIND compared with controls (p < 0.001). Higher baseline sTNF-R1 levels were specifically associated with lacunar infarcts (rate ratio = 6.91, 95% CI 3.19-14.96, p < 0.001), as well as lower rates of cognitive decline in the CIND subgroup. Our data suggest that sTNF-R1 interacts with vascular cognitive impairment in a complex manner at predementia stages, with elevated levels associated with more severe CSVD at baseline, but which may subsequently be protective against cognitive decline.

Association of Interleukin-6 and Interleukin-8 with Cognitive Decline in an Asian Memory Clinic Population.

BACKGROUND: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. OBJECTIVE: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. METHODS: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. RESULTS: Among the 387 (mean age = 72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend< 0.001), attention (p-trend = 0.005), executive function (p-trend< 0.001), and visuospatial function (p-trend = 0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. CONCLUSION: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.

The Associations Between Intracranial Stenosis, Brain Amyloid-beta, and Cognition in a Memory Clinic Sample.

BACKGROUND: Intracranial stenosis (ICS) and brain amyloid-beta (Aß) have been associated with cognition and dementia. We aimed to investigate the association between ICS and brain Aß and their independent and joint associations with cognition. METHODS: We conducted a cross-sectional study of 185 patients recruited from a memory clinic. ICS was measured on 3-dimensional time-of-flight magnetic resonance angiography and defined as stenosis ≥50%. Brain Aß was measured with [ 11 C] Pittsburgh compound B-positron emission tomography imaging. Cognition was assessed with a locally validated neuropsychological battery. RESULTS: A total of 17 (9.2%) patients had ICS, and the mean standardized uptake value ratio was 1.4 (±0.4 SD). ICS was not significantly associated with brain Aß deposition. ICS was significantly associated with worse global cognition (ß: -1.26, 95% CI: -2.25; -0.28, P =0.013), executive function (ß: -1.04, 95% CI: -1.86; -0.22, P =0.015) and visuospatial function (ß: -1.29, 95% CI: -2.30; -0.27, P =0.015). Moreover, in ICS patients without dementia (n=8), the presence of Aß was associated with worse performance on visuomotor speed. CONCLUSIONS: ICS was significantly associated with worse cognition and showed interaction with brain Aß such that patients with both pathologies performed worse on visuomotor speed specifically in those without dementia. Further studies may clarify if ICS and brain Aß deposition indeed have a synergistic association with cognition.

Effects of Carotid Artery Stiffness on Cerebral Small-Vessel Disease and Cognition.

Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small-vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess ß-index, pressure-strain elastic modulus, and pulse-wave velocity-ß. Brain magnetic resonance images were graded for cerebral small-vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that ß-index (ß=0.69; P=0.002), elastic modulus (ß=0.78; P<0.001), and pulse-wave velocity-ß (ß=0.80; P<0.001) were associated with white matter hyperintensities, and elastic modulus (odds ratio [OR], 1.39 [95% CI, 1.04-1.85]) and pulse-wave velocity-ß (OR, 1.47 [95% CI, 1.10-1.98]) were independently associated with lacunes. Similarly, ß-index (OR, 2.04 [95% CI, 1.14-4.13]), elastic modulus (OR, 2.22 [95% CI, 1.25-4.42]), and pulse-wave velocity-ß (OR, 2.50 [95% CI, 1.36-5.18]) were independently associated with vascular dementia. Carotid stiffness measures were independently associated with worse performance in global cognition, visuomotor speed, visuospatial function, and executive function. These associations became largely nonsignificant after further adjusting for cerebral small-vessel disease markers. Conclusions In memory clinic patients, carotid artery stiffness was associated with white matter hyperintensities and lacunes, impairment in global and domain-specific cognition, and causative subtypes of dementia, particularly vascular. The effects of carotid stiffness on cognition were not independent of, and were partially mediated by, cerebral small-vessel disease.

Deep-learning retinal vessel calibre measurements and risk of cognitive decline and dementia.

Previous studies have explored the associations of retinal vessel calibre, measured from retinal photographs or fundus images using semi-automated computer programs, with cognitive impairment and dementia, supporting the concept that retinal blood vessels reflect microvascular changes in the brain. Recently, artificial intelligence deep-learning algorithms have been developed for the fully automated assessment of retinal vessel calibres. Therefore, we aimed to determine whether deep-learning-based retinal vessel calibre measurements are predictive of risk of cognitive decline and dementia. We conducted a prospective study recruiting participants from memory clinics at the National University Hospital and St. Luke's Hospital in Singapore; all participants had comprehensive clinical and neuropsychological examinations at baseline and annually for up to 5 years. Fully automated measurements of retinal arteriolar and venular calibres from retinal fundus images were estimated using a deep-learning system. Cox regression models were then used to assess the relationship between baseline retinal vessel calibre and the risk of cognitive decline and developing dementia, adjusting for age, gender, ethnicity, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes, and smoking. A total of 491 participants were included in this study, of whom 254 developed cognitive decline over 5 years. In multivariable models, narrower retinal arteriolar calibre (hazard ratio per standard deviation decrease = 1.258, P = 0.008) and wider retinal venular calibre (hazard ratio per standard deviation increase = 1.204, P = 0.037) were associated with increased risk of cognitive decline. Among participants with cognitive impairment but no dementia at baseline (n = 212), 44 progressed to have incident dementia; narrower retinal arteriolar calibre was also associated with incident dementia (hazard ratio per standard deviation decrease = 1.624, P = 0.021). In summary, deep-learning-based measurement of retinal vessel calibre was associated with risk of cognitive decline and dementia.

Auditory brainstem response after electrolytic lesions in the unilateral medial geniculate body of tree shrews.

OBJECTIVES: This study aimed to assess the processing of clicks and tone pips in the auditory brainstem of tree shrews and analyze the long-term evolution of postlesion plasticity in the auditory system and its ability to self-repair. METHODS: The auditory brainstem response (ABR) was measured in the normal control group (n=10) and the electrolytic damage group (n=10) before and 0 h, 24 h, 48 h, 72 h, and 25 d after electrolytic damage. Recordings were performed under closed-field conditions using clicks and tone pips, followed by statistical analysis of the ABR threshold, amplitude and latency. RESULTS: The results were as follows: (1) After electrolytic damage to the tree shrew medial geniculate body (MGB), the latency and amplitude of ABR waveforms from the left ear changed from 0 h to 25 d. All parameters were lower at 25 d than they were preoperatively. The amplitude of ABR wave VI (using click sound stimulation) decreased or disappeared in both ears. (2) The ABR threshold was significantly different in both ears at 72 h postoperatively compared with preoperatively (0 h) (P < 0.05) but recovered by 25 d. CONCLUSION: Based on these results, we conclude the following: (1) The origin of wave VI in tree shrews may be associated with the MGB. After electrolytic damage to the MGB, the changes in the ABR waveforms at different frequencies indicated that the MGB nucleus had a certain characteristic frequency. (2) Unilateral injury to the MGB can lead to similar levels of hearing impairment in both ears.

Association of Arterial Spin Labeling Parameters With Cognitive Decline, Vascular Events, and Mortality in a Memory-Clinic Sample.

BACKGROUND: Cognitive decline in older adults has been attributed to reduced cerebral blood flow (CBF). Recently, the spatial coefficient of variation (sCoV) of ASL has been proposed as a proxy marker of cerebrovascular insufficiency. We investigated the association between baseline ASL parameters with cognitive decline, incident cerebrovascular disease, and risk of vascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS: About 368 memory-clinic patients underwent three-annual neuropsychological assessments and brain MRI scans at baseline and follow-up. MRIs were graded for white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), cortical infarcts, and intracranial stenosis. Baseline gray (GM) and white matter (WM) CBF and GM-sCoV were obtained with ExploreASL from 2D-EPI pseudo-continuous ASL images. Cognitive assessment was done using a validated neuropsychological battery. Data on incident vascular events (heart disease, stroke, transient ischemic attack) and mortality were obtained. RESULTS: Higher baseline GM-sCoV was associated with decline in the memory domain over 3 years of follow-up. Furthermore, higher GM-sCoV was associated with a decline in the memory domain only in participants without dementia. Higher baseline GM-sCoV was associated with progression of WMH and incident CMBs. During a mean follow-up of 3 years, 29 (7.8%) participants developed vascular events and 18 (4.8%) died. Participants with higher baseline mean GM-sCoV were at increased risk of vascular events. CONCLUSIONS: Higher baseline GM-sCoV of ASL was associated with a decline in memory and risk of cerebrovascular disease and vascular events, suggesting that cerebrovascular insufficiency may contribute to accelerated cognitive decline and worse clinical outcomes in memory clinic participants.

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

BACKGROUND: The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS: A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. RESULTS: Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (p = 0.042). CONCLUSIONS: These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

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.

Alpha-Ketoglutarate dietary supplementation to improve health in humans.

Alpha-ketoglutarate (AKG) is an intermediate in the Krebs cycle involved in various metabolic and cellular pathways. As an antioxidant, AKG interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. These pleiotropic functions of AKG suggest it may also extend human healthspan. Recent studies in worms and mice support this concept. A few studies published in the 1980s and 1990s in humans suggested the potential benefits of AKG in muscle growth, wound healing, and in promoting faster recovery after surgery. So far there are no recently published studies demonstrating the role of AKG in treating aging and age-related diseases; hence, further clinical studies are required to better understand the role of AKG in humans. This review will discuss the regulatory role of AKG in aging, as well as its potential therapeutic use in humans to treat age-related diseases.

The prognostic utility of CSF neurogranin in predicting future cognitive decline in the Alzheimer's disease continuum: A systematic review and meta-analysis with narrative synthesis.

Core cerebrospinal fluid (CSF) biomarkers (Aß42, T-tau, P-tau) were included as supporting diagnostic criteria for Alzheimer's Disease (AD), but they lack the power to predict AD progression. On the other hand, a new biomarker CSF Neurogranin (Ng) has been shown to predict cognitive decline. This systematic review aims to synthesise the prognostic utility of CSF Ng in predicting cognitive decline in the AD continuum. Seven databases were searched systematically from inception to 30 September 2020. Participants were 55 years or older, who had baseline and at least one follow-up cognitive assessments. Risk of bias was assessed using the Quality in Prognosis Studies tool. Meta-analysis was conducted by pooling standardised beta coefficients and adjusted hazard ratios. Thirteen studies were included and high-quality evidence suggests that CSF Ng predicts Mini-Mental State Examination (MMSE) decline in Aß+ mild cognitive impairment (MCI). Moderate quality evidence showed that CSF Ng could predict the decline of memory and executive function in MCI. Narrative synthesis found that CSF Ng/Aß42 was also likely to predict cognitive decline. More studies are required to validate the use of CSF Ng as an AD prognostic marker and its application in future development of drug treatment and diagnosis.

Cerebral Microbleeds and White Matter Hyperintensities are Associated with Cognitive Decline in an Asian Memory Clinic Study.

BACKGROUND: Cerebral Small Vessel Disease (SVD); lacunes, Cerebral Microbleeds (CMBs), and White Matter Hyperintensities (WMH) have a vital role in cognitive impairment and dementia. SVD in lobar location is related to cerebral amyloid angiopathy, whereas SVD in a deep location with hypertensive arteriopathy. It remains unclear how different locations of SVD affect long-term cognitive decline. The present study aimed to analyse the association between different locations and severity of SVD with global and domain-specific cognitive decline over the follow-up interval of 3 years. METHODS: We studied 428 participants who had performed MRI scans at baseline and at least 3 neuropsychological assessments. Locations of lacunes and CMBs were categorized into strictly lobar, strictly deep and mixed-location, WMH volume into anterior and posterior. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Neuropsychological Battery was used to assess cognitive function. To analyse the association between baseline location and severity of SVD with cognitive decline, linear regression models with generalized estimated equations were constructed to calculate the mean difference, 95% confidence interval and two-way interaction factor between time and SVD. RESULTS: Increased numbers of baseline CMBs were associated with a decline in global cognition as well as a decline in executive function and memory domains. Location-specific analysis showed similar results with strictly lobar CMBs. There was no association with strictly deep and mixed-location CMBs with cognitive decline. Baseline WMH volume was associated with a decline in global cognition, executive function and memory. Similar results were obtained with anterior and posterior WMH volumes. Lacunes and their locations were not associated with cognitive decline. CONCLUSION: Strictly lobar CMBs, as well as WMH volume in anterior and posterior regions, were associated with cognitive decline. Future research focuses are warranted to evaluate interventions that may prevent cognitive decline related to SVD.

The Effects of Mean of Visit-to-Visit Blood Pressure on Incident Brain Vascular Lesions and Functional-Cognitive Decline.

BACKGROUND: Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear. OBJECTIVE: To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up. METHODS: 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95%confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline. RESULTS: Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline. CONCLUSION: These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD.