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.

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.

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 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.

Blood-Based Cardiac Biomarkers and the Risk of Cognitive Decline, Cerebrovascular Disease, and Clinical Events.

Background and Purpose: Cardiac biomarkers, NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15) have been proposed as important biomarkers of early vascular pathology. However, little is known of the longitudinal associations of these cardiac biomarkers with cerebrovascular disease and clinical events. We examine the association of blood-based cardiac biomarkers (NT-proBNP, hs-cTnT, and GDF-15) with cognitive decline, incident cerebrovascular disease, vascular events, and mortality. Methods: Four hundred thirty-four memory-clinic patients provided blood samples at baseline, underwent 3 annual neuropsychological assessments and brain magnetic resonance imaging scans at baseline and follow-up. NT-proBNP and hs-cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF-15 by quantitative sandwich immunoassay. Baseline and follow-up magnetic resonance imagings were graded for white matter hyperintensities, lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Data on incident vascular events and mortality were obtained. Results: Patients with higher levels of NT-proBNP, hs-cTnT, and GDF-15 showed greater decline in memory domain. Additionally, hs-cTnT was associated with decline in global cognition, executive function, and visuomotor speed. Higher levels of NT-proBNP were associated with incident cerebral microbleeds and hs-cTnT with incident cortical infarcts. During a mean follow-up of 3 years, 26 (5.9%) patients died and 35 (8.1%) developed vascular events. Patients with higher levels of NTpro-BNP and hs-cTnT were at increased risk of vascular events whereas those with higher levels of NT-proBNP and GDF-15 were at risk of mortality. Conclusions: Higher levels of blood-based cardiac biomarkers were associated with decline in memory and risk of vascular events and mortality. Moreover, NT-proBNP and hs-cTnT were associated with incident cerebral microbleeds and cortical infarcts. Thus, these biomarkers are potentially useful in identifying patients at risk of adverse vascular events and death.

Improved amyloid burden quantification with nonspecific estimates using deep learning.

PURPOSE: Standardized uptake value ratio (SUVr) used to quantify amyloid-ß burden from amyloid-PET scans can be biased by variations in the tracer's nonspecific (NS) binding caused by the presence of cerebrovascular disease (CeVD). In this work, we propose a novel amyloid-PET quantification approach that harnesses the intermodal image translation capability of convolutional networks to remove this undesirable source of variability. METHODS: Paired MR and PET images exhibiting very low specific uptake were selected from a Singaporean amyloid-PET study involving 172 participants with different severities of CeVD. Two convolutional neural networks (CNN), ScaleNet and HighRes3DNet, and one conditional generative adversarial network (cGAN) were trained to map structural MR to NS PET images. NS estimates generated for all subjects using the most promising network were then subtracted from SUVr images to determine specific amyloid load only (SAßL). Associations of SAßL with various cognitive and functional test scores were then computed and compared to results using conventional SUVr. RESULTS: Multimodal ScaleNet outperformed other networks in predicting the NS content in cortical gray matter with a mean relative error below 2%. Compared to SUVr, SAßL showed increased association with cognitive and functional test scores by up to 67%. CONCLUSION: Removing the undesirable NS uptake from the amyloid load measurement is possible using deep learning and substantially improves its accuracy. This novel analysis approach opens a new window of opportunity for improved data modeling in Alzheimer's disease and for other neurodegenerative diseases that utilize PET imaging.

The effect of intracranial stenosis on cognitive decline in a memory clinic cohort.

BACKGROUND AND PURPOSE: Intracranial stenosis (ICS) is a risk factor for cognitive impairment and dementia in cross-sectional studies. However, data examining the effect of ICS on cognitive decline are limited. We investigated the effect of ICS on cognition over a period of 3 years in a memory clinic cohort. METHODS: Patients were recruited from the National University Hospital in Singapore. Data were collected using a standardised questionnaire, physical examination, and 3-T magnetic resonance imaging (MRI) at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any intracranial vessel. Cognition was measured at baseline and annually for 3 years using the Mini-Mental State Examination, the Montreal Cognitive Assessment, and a detailed neuropsychological test battery. The association between ICS and cognitive decline was analysed using generalised estimating equations. RESULTS: A total of 364 patients were included in the analysis. The mean (±SD) age was 71.9 (±8.0) years, and 164 (45.1%) patients were male. A total of 66 (18.1%) patients had ICS. ICS was associated with worse executive function (ß = -0.37, 95% confidence interval = -0.68 to -0.05, p = 0.022) and modified the effect of follow-up time on memory (p = 0.005) and visuomotor speed (p = 0.047). These results remained significant after controlling for demographics, overall diagnosis, cardiovascular risk factors, and MRI markers of cerebrovascular disease. CONCLUSIONS: Intracranial stenosis was independently associated with worse executive function across all time points, and cognitive decline in memory and visuomotor speed over 3 years of follow-up. This suggests that ICS may be a useful indicator of vascular brain damage leading to cognitive decline and may warrant consideration of antiatherosclerotic treatment in clinical trials.

Head-to-head comparison of amplified plasmonic exosome Aß42 platform and single-molecule array immunoassay in a memory clinic cohort.

BACKGROUND AND PURPOSE: Various blood biomarkers reflecting brain amyloid-ß (Aß) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. METHODS: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aß40, Aß42, Aß42/Aß40 and the amplified plasmonic exosome (APEX) Aß42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aß+) participants. RESULTS: Compared to Simoa biomarkers, APEX-Aß42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aß42 and 48.6% for Simoa-Aß42/Aß40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aß42 pre-screening does not increase the required number of initial participants. CONCLUSIONS: With its high diagnostic performance, APEX is an ideal candidate for Aß+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aß+ participants whilst halving recruitment costs.

Improved quantification of amyloid burden and associated biomarker cut-off points: results from the first amyloid Singaporean cohort with overlapping cerebrovascular disease.

PURPOSE: The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases raised the question about the validity of current standards for amyloid quantification under abnormal conditions. In this work, we implemented a novel pipeline for improved amyloid PET quantification of this atypical cohort. METHODS: The investigated data correction and amyloid quantification methods included motion correction, standardized uptake value ratio (SUVr) quantification using the parcellated MRI (standard method) and SUVr quantification without MRI. We introduced a novel amyloid analysis method yielding 2 biomarkers: AßL which quantifies the global Aß burden and ns that characterizes the non-specific uptake. Cut-off points were first determined using visual assessment as ground truth and then using unsupervised classification techniques. RESULTS: Subject's motion impacts the accuracy of the measurement outcome but has however a limited effect on the visual rating and cut-off point determination. SUVr computation can be reliably performed for all the subjects without MRI parcellation while, when required, the parcellation failed or was of mediocre quality in 10% of the cases. The novel biomarker AßL showed an association increase of 29.5% with the cognitive tests and increased effect size between positive and negative scans compared with SUVr. ns was found sensitive to cerebral microbleeds, white matter hyperintensity, volume, and age. The cut-off points for SUVr using parcellated MRI, SUVr without parcellation, and AßL were 1.56, 1.39, and 25.5. Finally, k-means produced valid cut-off points without the requirement of visual assessment. CONCLUSION: The optimal processing for the amyloid quantification of this atypical cohort allows the quantification of all the subjects, producing SUVr values and two novel biomarkers: AßL, showing important increased in their association with various cognitive tests, and ns, a parameter sensitive to non-specific retention variations caused by age and cerebrovascular diseases.

Hearing handicap in Asian patients with dementia.

BACKGROUND: Hearing loss and hearing handicap may contribute to cognitive impairment and dementia. The purpose of this study was to analyze the association between hearing loss and hearing handicap with dementia in an Asian memory clinic parents. METHODS: This study includes the data obtained from patients with mild dementia who attended the National University hospital memory clinic and non-demented healthy subjects among spouses and caregivers who are non-genetically related to our patients. All participants underwent comprehensive physical, medical, neuropsychological and audiological assessments (i.e. pure tone audiometry - PTA). Disabling hearing loss was defined as a hearing loss of >40 dB in the better ear on PTA. Amsterdam Inventory for Auditory Disability and Handicap (AIADH) questionnaire was administered through the verbal interview to measure their hearing handicap score. Linear regression models were used to investigate the association between hearing loss and hearing handicap with dementia. Mean differences (ß) with 95% confidence intervals (CI) were calculated. RESULTS: 91 participants (65-90 years old) were recruited for this study; 39 of them were patients with dementia and 52 were non-demented healthy controls. 48.7% of the patients with dementia had disabling hearing loss, which is higher than the non-demented controls (25.0%) (p = 0.019). The significant association between hearing handicap (as measured by AIADH) and dementia was observed, which was independent of demographic factors and audiology related history and PTA average (ß = -6.40; 95% CI =0.11.99, -0.81, p = 0.025). There was no independent association between hearing loss and dementia (p > 0.05). CONCLUSION: A significant association between hearing handicap and dementia was found. The mechanism of this association requires further research and may involve higher order central processing disorder.

Global cerebrovascular burden and long-term clinical outcomes in Asian elderly across the spectrum of cognitive impairment.

ABSTRACTBackground/Aim:To investigate the predictive ability of the previously established global cerebrovascular disease (CeVD) burden scale on long-term clinical outcomes in a longitudinal study of Asian elderly participants across the spectrum of cognitive impairment. METHODS: A case-control study was conducted over a 2-year period involving participants with no cognitive impairment, cognitive impairment-no dementia (CIND), and Alzheimer's disease (AD). Annually, cognitive function was assessed with a comprehensive neuropsychological battery and the clinical dementia rating (CDR) scale was used to stage disease severity. RESULTS: Of 314 participants, 102 had none/very mild CeVD, 31 mild CeVD, 94 moderate CeVD, and 87 severe CeVD at baseline. There was a 1.14 and 1.42 units decline per year on global cognitive z-scores in moderate and severe CeVD groups, respectively, compared to none/very mild CeVD. Moderate-severe CeVD predicted significant functional deterioration at year 2 (HR = 2.0, 95% CI = 1.2-3.4), and conversion to AD (HR = 6.3, 95% CI = 1.7-22.5), independent of medial temporal atrophy. CONCLUSION: The global CeVD burden scale predicts poor long-term clinical outcome independent of neurodegenerative markers. Furthermore, CeVD severity affects the rate of cognitive and functional deterioration. Hence, cerebrovascular burden, which is potentially preventable, is a strong prognostic indicator, both at preclinical and clinical stages of AD, independent of neurodegenerative processes.

Auditory brainstem responses after electrolytic lesions in bilateral subdivisions of the medial geniculate body of tree shrews.

This study aimed to establish a tree shrew model of bilateral electrolytic lesions in the medial geniculate body (MGB) to determine the advantages of using a tree shrew model and to assess the pattern of sound processing in tree shrews after bilateral electrolytic damage in different parts of the MGB. The auditory brainstem responses (ABRs) of a normal control group (n = 30) and an electrical damage group (n = 30) were tested at 0 h, 24 h, 48 h, 72 h, 7 days, 15 days, and 30 days after surgery. (1) The bilateral ablations group exhibited a significant increase in the ABR threshold of the electrolytic damage group between pre- and post-operation. (2) There were significant increases in the I-VI latencies at 0 h after MGBd and MGBm lesions and at 24 h after MGBv lesion. (3) The amplitudes of wave VI were significantly decreased at 24 h and 48 h after MGBd lesion, at 72 h and 7 days after MGBm lesion, and at 24 h, 48 h, 72 h, and 7 days after MGBv lesion. (1) The electrolytic damage group suffered hearing loss that did not recover and appeared to be difficult to fully repair after bilateral ablation. (2) The latencies and amplitudes of responses in the MGB following bilateral electrolytic lesion were restored to pre-operation levels after 15-30 days, suggesting that a portion of the central nuclei lesion was reversible. (3) The tree shrew auditory animal model has many advantages compared to other animal models, such as greater complexity of brain structure and auditory nuclei fiber connections, which make the results of this experiment more useful for clinical diagnoses compared with studies using rats and guinea pigs.

The effects of the auditory brainstem response before and after fluoro-gold injection in medial geniculate body.

OBJECTIVE: This study aimed to use the tree shrew as an otological model, not only to verify the location of the auditory pathway in tree shrews by fluoro-gold (FG) but also to elucidate the effects of the auditory brainstem response (ABR) before and after FG injection. METHODS: FG was injected into the medial geniculate body (MGB) of experimental group (n=10).The normal group (n=10) was inserted the microsyringe, which was not perfused FG. Hearing was assessed by testing ABRs before and after the operation. RESULTS: FG-labelled neurons were primarily distributed in the ipsilateral MGB, the ipsilateral and contralateral nuclei of the inferior colliculus (NIC), the superior olivary nucleus (SON), the dorsal cochlear nucleus (DCN), and the ventral cochlear nucleus (VCN). The ABR after FG injection caused a significant decrease in the wave amplitudes at 24 h that recovered by 72 h. However, the wave I-VI interpeak latencies in the right ear were shortened at 0 and 24 h post-surgery, whereas after 48 h, the interpeak latencies were prolonged. CONCLUSIONS: The FG retrograde tracing technique accurately displays the anatomical location of the auditory pathway in the tree shrew. The change in ABR waves suggested that there was a functional abnormality in the central auditory pathway after FG injection. The auditory thalamus may have self-regulating properties.

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.

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.

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.

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.

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.

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.