Siobhan M. Hoscheidt

Cerebrospinal Fluid Markers of Alzheimer’s Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer’s Disease

BACKGROUND The immune response in Alzheimers disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. OBJECTIVE To determine whether neuroinflammation exacerbates neural damage in preclinical AD. METHODS We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. RESULTS Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. CONCLUSION Inflammation may play a role in neural damage in preclinical AD.

Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEɛ4 Carriers.

BACKGROUND Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimers disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. OBJECTIVE To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. METHOD Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimers Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ₄₂, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOEɛ4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ₄₂. RESULTS No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aβ₄₂ were observed; however, significant interactions were observed between HOMA-IR and APOEɛ4 on CSF markers related to tau. Among APOEɛ4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOEɛ4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ₄₂ levels in CSF. CONCLUSION IR among asymptomatic APOEɛ4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.

Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults:

Insulin resistance (IR) is associated with poor cerebrovascular health and increased risk for dementia. Little is known about the unique effect of IR on both micro- and macrovascular flow particularly in midlife when interventions against dementia may be most effective. We examined the effect of IR as indexed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) on cerebral blood flow in macro- and microvessels utilizing magnetic resonance imaging (MRI) among cognitively asymptomatic middle-aged individuals. We hypothesized that higher HOMA-IR would be associated with reduced flow in macrovessels and lower cortical perfusion. One hundred and twenty cognitively asymptomatic middle-aged adults (57 ± 5 yrs) underwent fasting blood draw, phase contrast-vastly undersampled isotropic projection reconstruction (PC VIPR) MRI, and arterial spin labeling (ASL) perfusion. Higher HOMA-IR was associated with lower arterial blood flow, particularly within the internal carotid arteries (ICAs), and lower cerebral perfusion in several brain regions including frontal and temporal lobe regions. Higher blood flow in bilateral ICAs predicted greater cortical perfusion in individuals with lower HOMA-IR, a relationship not observed among those with higher HOMA-IR. Findings provide novel evidence for an uncoupling of macrovascular blood flow and microvascular perfusion among individuals with higher IR in midlife.

Fornix Microstructure and Memory Performance Is Associated with Altered Neural Connectivity during Episodic Recognition

OBJECTIVES The purpose of this study was to assess whether age-related differences in white matter microstructure are associated with altered task-related connectivity during episodic recognition. METHODS Using functional magnetic resonance imaging and diffusion tensor imaging from 282 cognitively healthy middle-to-late aged adults enrolled in the Wisconsin Registry for Alzheimers Prevention, we investigated whether fractional anisotropy (FA) within white matter regions known to decline with age was associated with task-related connectivity within the recognition network. RESULTS There was a positive relationship between fornix FA and memory performance, both of which negatively correlated with age. Psychophysiological interaction analyses revealed that higher fornix FA was associated with increased task-related connectivity amongst the hippocampus, caudate, precuneus, middle occipital gyrus, and middle frontal gyrus. In addition, better task performance was associated with increased task-related connectivity between the posterior cingulate gyrus, middle frontal gyrus, cuneus, and hippocampus. CONCLUSIONS The findings indicate that age has a negative effect on white matter microstructure, which in turn has a negative impact on memory performance. However, fornix microstructure did not significantly mediate the effect of age on performance. Of interest, dynamic functional connectivity was associated with better memory performance. The results of the psychophysiological interaction analysis further revealed that alterations in fornix microstructure explain-at least in part-connectivity among cortical regions in the recognition memory network. Our results may further elucidate the relationship between structural connectivity, neural function, and cognition.

Macrovascular and microvascular cerebral blood flow in adults at risk for Alzheimer's disease

Capillary hypoperfusion is reported in asymptomatic adults at‐risk for Alzheimers disease (AD), but the extent that can be explained by reduced flow in intracranial arteries is unknown.

USING MULTIMODAL IMAGING BIOMARKERS TO PREDICT COGNITIVE STATUS IN A COMMUNITY-DWELLING OLDER ADULT COHORT

from the INSIGHT pre-AD cohort were included. Individual functional connectivity matrices were computed for a total of 3,081 connectomes. Canonical partial least squares analysis (PLSC) was used to discover whether any these connectomes were associated with two sets of measures. The setA included seven measures of individual cognitive functioning, age, and cortical amyloid standardized uptake value ratio (SUVr). The setB included six plasma biomarkers (amyloid beta [Ab] peptide 1-40, Ab1-42, the Ab1-40/ Ab1-42 ratio, tau, neurofilament light chain [NFL] protein, and YKL-40). Behaviour-PLSC was performed to compare the combination of the rsfMRI data and the two sets of variables between amyloid positive individuals (A+) and negative (A-). Permutation tests were used to evaluate significance of PLS dimensions. Results:We identified one strong dimension population co-variation for both sets (p<.001). All measures of the setA and four markers of the setB (Ab40, Ab42, tau and Ab42/Ab40 ratio) are strongly associated (positively or negatively) with the first dimension (bootstrap ratios (BR) greater than the critical value j2j). This can be considered a one-dimensional positive-negative axis, all the negatively correlated measures are commonly considered as positive cognitive indicators (e.g., high performance on cognitive tests are inversely correlated with age and SUVr). In the setA, the 265 connectomes presenting BR j2j are mostly included the visual system and the anterior salience network. In the setB, the 172 connectomes presenting BR j2j are mainly included the visual, salience and default mode networks. The first dimension was also significant in the comparison between A+ and Agroups (p1⁄4.001). The previous described one-dimensional positive-negative axis was confirmed only for the A+ group. Conclusions:The integrative connectomics approach relating AD risk factors and pathophysiological biomarkers of brain amyloidosis and neuroinflammation to functional connectivity may help identify early disease endophenotypes at the preclinical stage of AD.

THE EFFECTS OF DIET INTERVENTION ON METABOLIC HEALTH AND CEREBRAL SPINAL FLUID ALZHEIMER’S DISEASE BIOMARKERS: A RANDOMIZED TRIAL

baseline RAQ scores predicted trial completion and study medication compliance. Youden index was used to estimate optimal cut points. Results: Mean baseline patient RAQ was 31.4 (95%CI 27.0 to 34.7) and mean study partner RAQ was 29.6 (95%CI 24.7 to 33.4). Both patient and study partner RAQ scores at baseline appeared similar to the respective scores at weeks 26 and 52 (all p>0.05). Higher baseline patient RAQ score predicted higher probability of compliance with study medication at weeks 26 and 52 (both p<0.05). Higher baseline study partner RAQ predicted higher probability of trial completion (OR 1⁄4 1.13; p<0.05). Larger disparity between patient and partner RAQ scores predicted lower probability of trial completion (OR1⁄4 0.95; p<0.05). A cut point of 28 optimally discerned between patients who did and did not complete the trial or would be unlikely to be compliant with study medications at a given study visit. In contrast, slightly lower cut points discerned between study partners, 27 and 24 for completion and compliance, respectively. Conclusions:The RAQ may help identify patients and study partners at risk of dropout. Further study is needed in diverse groups and to develop interventions to address the needs of participants identified as at risk for trial dropout.

Positive Affect Predicts Cerebral Glucose Metabolism in Late Middle-aged Adults.

Abstract Positive affect is associated with a number of health benefits; however, few studies have examined the relationship between positive affect and cerebral glucose metabolism, a key energy source for neuronal function and a possible index of brain health. We sought to determine if positive affect was associated with cerebral glucose metabolism in late middle-aged adults (n = 133). Participants completed the positive affect subscale of the Center for Epidemiological Studies Depression Scale at two time points over a two-year period and underwent 18F-fluorodeoxyglucose-positron emission tomography scanning. After controlling for age, sex, perceived health status, depressive symptoms, anti-depressant use, family history of Alzheimer’s disease, APOE ε4 status and interval between visits, positive affect was associated with greater cerebral glucose metabolism across para-/limbic, frontal, temporal and parietal regions. Our findings provide evidence that positive affect in late midlife is associated with greater brain health in regions involved in affective processing and also known to be susceptible to early neuropathological processes. The current findings may have implications for interventions aimed at increasing positive affect to attenuate early neuropathological changes in at-risk individuals.

STRESS IS ASSOCIATED WITH GREATER INSULIN RESISTANCE, HIGHER CSF PHOSPHORYLATED TAU, AND DECREASED GLUCOSE METABOLISM IN THE MEDIAL TEMPORAL LOBE IN APOE Ε4 CARRIERS

labeling (ASL) MRI is decreased in patients with AD (Gao et al. 2013). In this study, ASL measurements with a breath-hold paradigm were used to assess cerebrovascular reactivity and thus vascular injury in normal and cognitively impaired older adults that may be associated with AD pathological processes. Methods: 113 subjects (75 cognitively normal, 34 MCI, and 4 AD; 37M/ 76F; age: 64.667.6) underwent baseline brain MRI as part of several on-going studies of AD prevention and treatment, including ASL at rest and during a 20 second breath-hold with full brain coverage using a 3T Siemens scanner. For the majority of participants, Mini-Mental Status Exam (MMSE) scores and apolipoprotein E (APOE) genotype were available, and for a subset, CSF was collected and amyloid-beta 42 (Ab42) and tau protein levels were measured. Cerebral blood flow (CBF) was quantified from the ASL images. Voxel-wise percent difference maps between baseline and breath-hold CBF were computed and the gray matter (GM) voxels were averaged over the whole brain (see Figure 1 for representative CBF maps). Relationships between breath-hold related changes in CBF and APOE, CSF biomarker levels, and MMSE were examined using regression analyses. Results:Average percent change in GM CBF during a breath-hold paradigm was positively correlated with CSF levels of Ab42 (P1⁄40.025; Figure 2). Decreased CSF measurements of Ab42 peptide are hypothesized to reflect increased Ab plaques in the brain (Blennow, 2004). Thus in our study, increased vascular reactivity is associated with a healthier CSFAb42 profile, likely reflecting less AD pathology. Among subjects with the ε4 allelic variant of the APOE genotype, percent change in GM CBF positively correlated with MMSE (P1⁄40.05), indicating decreased global cognitive function may be associated with cerebrovascular damage. The results of all regression analyses are provided in Table 1.Conclusions:Our findings suggest that brain levels of Ab42 may predict cerebral vascular reactivity in APOE ε4 allele carriers, and this may provide further support for a vascular role in AD risk for these individuals.