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Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ42 (all

BACKGROUND: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer’s disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown. OBJECTIVE: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD. METHOD: We prospectively followed cognitively normal drivers (aged 65 + years) with (n = 10) and without preclinical AD (n = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant’s vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded. RESULTS: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1–5 miles. CONCLUSION: Changes in driving occur even during the preclinical stage of AD.

Background Brain insulin resistance is a well-recognized abnormality in Alzheimer's disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. Objective This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Methods Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform. Results In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. Conclusion In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors.

Effective audiovisual sensory integration involves dynamic changes in functional connectivity between superior temporal sulcus and primary sensory areas. This study examined whether disrupted connectivity in early Alzheimer's disease (AD) produces impaired audiovisual integration under conditions requiring greater corticocortical interactions. Audiovisual speech integration was examined in healthy young adult controls (YC), healthy elderly controls (EC), and patients with amnestic mild cognitive impairment (MCI) using McGurk-type stimuli (providing either congruent or incongruent audiovisual speech information) under conditions differing in the strength of bottom-up support and the degree of top-down lexical asymmetry. All groups accurately identified auditory speech under congruent audiovisual conditions, and displayed high levels of visual bias under strong bottom-up incongruent conditions. Under weak bottom-up incongruent conditions, however, EC and amnestic MCI groups displayed opposite patterns of performance, with enhanced visual bias in the EC group and reduced visual bias in the MCI group relative to the YC group. Moreover, there was no overlap between the EC and MCI groups in individual visual bias scores reflecting the change in audiovisual integration from the strong to the weak stimulus conditions. Top-down lexicality influences on visual biasing were observed only in the MCI patients under weaker bottom-up conditions. Results support a deficit in bottom-up audiovisual integration in early AD attributable to disruptions in corticocortical connectivity. Given that this deficit is not simply an exacerbation of changes associated with healthy aging, tests of audiovisual speech integration may serve as sensitive and specific markers of the earliest cognitive change associated with AD.

The frequent co-occurrence of Alzheimer's disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-beta peptide (Abeta) in CSF in preclinical and early AD. CSF biomarker data (Abeta, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Abeta in APOE epsilon4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Abeta in epsilon4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Abeta in preclinical AD. The basis for the apparent effect of APOE epsilon4 genotype on the relationship of ventricular volume to Abeta and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease.

In the present study we examined cognitive function, radiographic features, and functional ability in individuals with vascular dementia (VaD). Subjects were subdivided into individuals with only white matter involvement (WM) and individuals with evidence of a cortical infarction in addition to white matter ischemic change (C+WM). Results revealed that both groups of subjects were impaired across cognitive functions. Cognitive performance was more severely impaired among the C+WM group, but the general pattern of deficits did not differ between the two groups. Hachinski scores were significantly higher and instrumental activities of daily living were more severely affected in the C+WM group compared to the WM group. No significant differences were evident between the two groups on overall dementia severity or the extent of white matter involvement. These findings indicate that cognitive function in VaD may be globally impaired, and that cortical infarction in addition to white matter ischemia results in greater impairment, but the differences are largely quantitative rather than qualitative.