Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer's Disease.

BACKGROUND: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. OBJECTIVE: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. METHODS: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. RESULTS: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. CONCLUSIONS: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility.

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.

Age-Related Eye Diseases in Individuals With Mild Cognitive Impairment and Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) and age-related eye diseases pose an increasing burden as the world's population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases. Methods: In this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases. Results: Over half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15-7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45-1.24). Conclusion: Patients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases.

Plasma osteopontin as a biomarker of Alzheimer's disease and vascular cognitive impairment.

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer's disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

Primary Care Prognostic (PCP) Index of 11-Year Mortality Risk: Development and Validation of a Brief Prognostic Tool.

BACKGROUND: Healthcare providers use a life expectancy of at least 5 to 10 years in shared clinical decision-making with older adults about cancer screening, major surgeries, and disease prevention interventions. At present, few prognostic indexes predict long-term mortality beyond 10 years or are suited for use in primary care settings. OBJECTIVE: We developed and validated an 8-item multidimensional index predicting 11-year mortality for use in primary care. DESIGN, SETTING, AND PARTICIPANTS: Using data from the Singapore Longitudinal Ageing Studies (SLAS), we developed a Primary Care Prognostic (PCP) Index for predicting 11-year mortality risk in a development cohort (n = 1550) and validated it in a geographically different cohort (n = 928). MAIN MEASURES: The PCP Index was derived from eight indicators (body mass loss, weakness, slow gait, comorbidity, polypharmacy, IADL/BADL dependency, low albumin, low total cholesterol, out of 25 candidate indicators) using stepwise Cox proportional hazard models. KEY RESULTS: In the developmental cohort, the mortality hazard ratio increased by 53% per PCP point score increase, independent of age and sex. Across risk categories, absolute risks of mortality increased from 5% (score 0) to 67.9% (scores 7-9), with area under curve (AUC = 0.77 (95% CI 0.73-0.80)). The PCP Index also predicted mortality in the validation cohort, with AUC = 0.70 (95% CI 0.64-0.75). CONCLUSIONS: The PCP Index using simple clinical assessments and point scoring is a potentially useful prognostic tool for predicting long-term mortality and is well suited for risk stratification and shared clinical decision-making with older adults in primary care.

The Alzheimer's disease THErapy with NEuroaid (ATHENE) study protocol: Assessing the safety and efficacy of Neuroaid II (MLC901) in patients with mild-to-moderate Alzheimer's disease stable on cholinesterase inhibitors or memantine-A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Dementia is a large and growing health care burden globally, and its major cause is Alzheimer's disease (AD). MLC901 (Neuroaid II) is a simplified form of MLC601 (Neuroaid), a Traditional Chinese Medicine with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury. MLC601 has been shown to modulate amyloid precursor protein (APP) processing in human neuroblastoma cell cultures and increase the levels of soluble APPα. In addition, MLC901 has been shown to reduce tau phosphorylation in vitro. Hence, MLC901 may have possible multimodal actions and a disease-modifying effect in AD. In previous clinical studies, MLC601 has shown promising effects in AD. OBJECTIVE: To investigate the safety and efficacy of MLC901 add-on therapy to standard treatment in mild-to-moderate probable AD patients stable on standard treatment and to evaluate if MLC901 has a disease-modifying effect in AD. METHODS: This is a 6-month randomized, double-blind, placebo-controlled trial in mild-to-moderate probable AD where MLC901 will be given as an add-on therapy to standard AD treatment, followed by an extension study for another 6 months, where all subjects will be treated with open-label MLC901 in addition to standard treatment. The primary outcome is safety as measured by adverse events, vital signs, electrocardiogram, laboratory tests, and physical and neurological examinations. Secondary outcomes evaluating cognition, behavior, and activities of daily living at various time points include the Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Mini-Mental State Examination. CONCLUSION: MLC901 has the potential to improve cognition in AD patients. It may also have a role in delaying disease progression. This study will be the first to provide safety and efficacy data for MLC901 in mild-to-moderate probable AD patients already receiving standard therapy.

The Diagnostic Utility of the NINDS-CSN Neuropsychological Battery in Memory Clinics.

AIMS: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. METHODS: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. RESULTS: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5-min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). CONCLUSION: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment.

Trends in length of stay, functional outcomes, and discharge destination stratified by disease type for inpatient rehabilitation in Singapore community hospitals from 1996 to 2005.

OBJECTIVE: To determine the trends in length of stay (LOS), rehabilitation functional outcome, and discharge destination of patients admitted for inpatient rehabilitation from 1996 to 2005 and stratified by disease in Singapore. DESIGN: Retrospective national data were extracted from medical records of community-based inpatient rehabilitation admissions in Singapore from 1996 to 2005. SETTING: Four community hospitals. PARTICIPANTS: There were 12,506 first admissions for rehabilitation; 40.6% were for stroke, 30.4% for fracture, 2.9% for lower limb (LL) joint replacement, 2.3% for LL amputation, 1.9% for cancer, 1.8% for falls, 1.6% for pneumonia, and 18.5% for other illnesses. The overall mean age ± SD was 73.2±11.5 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: LOS, rehabilitation outcomes (rehabilitation effectiveness [R-effectiveness], rehabilitation efficiency [R-efficiency], relative functional efficiency [Relative-FE]), and discharge destination. RESULTS: The overall median LOS for all disease groups decreased by 16.2% (37 to 31d) from 1996 to 2005. The sharpest decline in LOS among the 8 disease groups was observed in the LL amputation group. The overall mean ± SD admission and discharge activities of daily living scores were 45.6±25.7 and 60.3±28.9, respectively; median R-effectiveness was 28.8%, median R-efficiency was 12.9/30d, and median Relative-FE was 27.7%/30d. From 1996 to 2005, mean R-effectiveness increased by 184% (14% to 40%), R-efficiency increased by 104% (9 to 19 units/30d), and Relative-FE increased by 145% (21% to 51%/30d). Among all inpatient admissions, most were discharged home (78.2%), 10.9% were discharged to an acute hospital, and 9.8% were discharged to nursing or sheltered homes, with no significant change during the 10-year period. CONCLUSIONS: Rehabilitation outcomes of patients admitted to Singapore's community hospitals have improved between 1996 and 2005 despite a decreasing LOS. Discharge destinations have largely remained unchanged over this period.