Associations Between Vascular Risk Factors and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia.

BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (ß= 0.03/year, p < 0.0001), Hispanic ethnicity (ß= 0.29, p = 0.01), education (ß= 0.04/year, p = 0.04), and coronary bypass surgery (ß= 0.93, p = 0.02). CSO PVS only associated with age (ß= 0.03/year, p < 0.01). APOE4 and amyloid-ß were not associated with PVS. CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Poor sleep accelerates hippocampal and posterior cingulate volume loss in cognitively normal healthy older adults.

Poor sleep quality is a known risk factor for Alzheimer's disease. This longitudinal imaging study aimed to determine the acceleration in the rates of tissue loss in cognitively critical brain regions due to poor sleep in healthy elderly individuals. Cognitively-normal healthy individuals, aged ≥60 years, reported Pittsburgh Sleep Quality Index (PSQI) and underwent baseline and 2-year follow-up magnetic resonance imaging brain scans. The links between self-reported sleep quality, rates of tissue loss in cognitively-critical brain regions, and white matter hyperintensity load were assessed. A total of 48 subjects were classified into normal (n = 23; PSQI score <5) and poor sleepers (n = 25; PSQI score ≥5). The two groups were not significantly different in terms of age, gender, years of education, ethnicity, handedness, body mass index, and cognitive performance. Compared to normal sleepers, poor sleepers exhibited much faster rates of volume loss, over threefold in the right hippocampus and fivefold in the right posterior cingulate over 2 years. In contrast, there were no significant differences in the rates of volume loss in the cerebral and cerebellar grey and white matter between the two groups. Rates of volume loss in the right posterior cingulate were negatively associated with global PSQI scores. Poor sleep significantly accelerates volume loss in the right hippocampus and the right posterior cingulate cortex. These findings demonstrate that self-reported sleep quality explains inter-individual differences in the rates of volume loss in cognitively-critical brain regions in healthy older adults and provide a strong impetus to offer sleep interventions to cognitively normal older adults who are poor sleepers.

Vascular Cognitive Impairment (VCI).

Vascular cognitive impairment (VCI) is predominately caused by vascular risk factors and cerebrovascular disease. VCI includes a broad spectrum of cognitive disorders, from mild cognitive impairment to vascular dementia caused by ischemic or hemorrhagic stroke, and vascular factors alone or in a combination with neurodegeneration including Alzheimer's disease (AD) and AD-related dementia. VCI accounts for at least 20-40% of all dementia diagnosis. Growing evidence indicates that cerebrovascular pathology is the most important contributor to dementia, with additive or synergistic interactions with neurodegenerative pathology. The most common underlying mechanism of VCI is chronic age-related dysregulation of CBF, although other factors such as inflammation and cardiovascular dysfunction play a role. Vascular risk factors are prevalent in VCI and if measured in midlife they predict cognitive impairment and dementia in later life. Particularly, hypertension, high cholesterol, diabetes, and smoking at midlife are each associated with a 20 to 40% increased risk of dementia. Control of these risk factors including multimodality strategies with an inclusion of lifestyle modification is the most promising strategy for treatment and prevention of VCI. In this review, we present recent developments in age-related VCI, its mechanisms, diagnostic criteria, neuroimaging correlates, vascular risk determinants, and current intervention strategies for prevention and treatment of VCI. We have also summarized the most recent and relevant literature in the field of VCI.

Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease.

Mesenchymal stem cell (MSC) administration is a novel and promising therapeutic approach for Alzheimer's disease (AD). Focusing on an intervention easily translatable into clinical practice, we administered allogeneic bone marrow-derived MSCs intravenously in a mouse model of AD (3xTg-AD). We systematically evaluated the effects of a single-dose and multiple-doses of MSCs in young and old mice (5 or 10 months old), comparing the short-term and long-term effects after 1, 2, or 7 months of treatment. A single dose of MSCs in young mice attenuated neuroinflammation 1 and 7 months after injection, whereas multiple-doses did not show any effect. Multiple-doses of MSCs (administered at 5 to 12 mo, or 10 to 12 mo) reduced the ß-secretase cleavage of the amyloid precursor protein, although levels of Aß-42 did not change. Most interestingly, multiple doses of MSCs affected tau hyperphosphorylation. MSCs administered in young mice for 7 months decreased the pathological tau phosphorylation at T205, S214, and T231. MSCs administered in old mice for 2 months decreased tau phosphorylation at S396. Our findings show how different timing and frequency of MSC injections can affect and modulate several aspects of the AD-like neuropathology in the 3xTg-AD mouse model, strengthening the concept of fine-tuning MSC therapy for Alzheimer's disease.

Retinal Microvascular Alterations as the Biomarkers for Alzheimer Disease: Are We There Yet?

BACKGROUND: Alzheimer disease (AD) is a heterogeneous and multifactorial disorder with an insidious onset and slowly progressive disease course. To date, there are no effective treatments, but biomarkers for early diagnosis and monitoring of disease progression offer a promising first step in developing and testing potential interventions. Cerebral vascular imaging biomarkers to assess the contributions of vascular dysfunction to AD are strongly recommended to be integrated into the current amyloid-ß (Aß) [A], tau [T], and neurodegeneration [(N)]-the "AT(N)" biomarker system for clinical research. However, the methodology is expensive and often requires invasive procedures to document cerebral vascular dysfunction. The retina has been used as a surrogate to study cerebral vascular changes. There is growing interest in the identification of retinal microvascular changes as a safe, easily accessible, low cost, and time-efficient approach to enhancing our understanding of the vascular pathogenesis associated with AD. EVIDENCE ACQUISITION: A systemic review of the literature was performed regarding retinal vascular changes in AD and its prodromal stages, focusing on functional and structural changes of large retinal vessels (vessels visible on fundus photographs) and microvasculature (precapillary arterioles, capillary, and postcapillary venules) that are invisible on fundus photographs. RESULTS: Static and dynamic retinal microvascular alterations such as retinal arterial wall motion, blood flow rate, and microvascular network density were reported in AD, mild cognitive impairment, and even in the preclinical stages of the disease. The data are somewhat controversial and inconsistent among the articles reviewed and were obtained based on cross-sectional studies that used different patient cohorts, equipment, techniques, and analysis methods. CONCLUSIONS: Retinal microvascular alterations exist across the AD spectrum. Further large scale, within-subject longitudinal studies using standardized imaging and analytical methods may advance our knowledge concerning vascular contributions to the pathogenesis of AD.

Directed Polymers and Interfaces in Disordered Media.

We consider field theory formulation for directed polymers and interfaces in the presence of quenched disorder. We write a series representation for the averaged free energy, where all the integer moments of the partition function of the model contribute. The structure of field space is analysed for polymers and interfaces at finite temperature using the saddle-point equations derived from each integer moments of the partition function. For the case of an interface we obtain the wandering exponent ξ = ( 4 - d ) / 2 , also obtained by the conventional replica method for the replica symmetric scenario.

Neurogranin as a predictor of memory and executive function decline in MCI patients.

OBJECTIVE: To determine whether high CSF levels of neurogranin (Ng) predict longitudinal decline in memory and executive function during early-stage Alzheimer disease (AD). METHODS: Baseline levels of CSF Ng were studied in relation to cross-sectional and longitudinal cognitive performance over 8 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, and participants with normal cognition (n = 111) and mild cognitive impairment (MCI) (n = 193) were included. RESULTS: High levels of CSF Ng were associated with poor baseline memory scores (ß = -0.21, p < 0.0001). CSF Ng predicted both memory and executive function decline over time (ß = -0.0313, p = 0.0068 and ß = -0.0346, p = 0.0169, respectively) independently of age, sex, education, and APOE ε4 status. When the rate of decline by tertiles was examined, CSF Ng was a level-dependent predictor of memory function, whereby the group with highest levels of Ng showed the fastest rates of decline in both memory and executive function. When examined separately, elevated Ng was associated with cognitive decline in participants with MCI but not in those with normal cognition. The levels of CSF Ng were not associated with cognitive measures when tau and amyloid 42 (Aß42) were controlled for in these analyses. CONCLUSIONS: High CSF Ng associates with poor memory scores in participants with MCI cross-sectionally and with poor memory and executive function longitudinally. The association of Ng with cognitive measures disappears when tau and Aß42 are included in the statistical models. Our findings suggest that CSF Ng may serve as a biomarker of cognition. Synaptic dysfunction contributes to cognitive impairment in early-stage AD.