Diffeomorphic Metric Mapping and Probabilistic Atlas Generation of Hybrid Diffusion Imaging based on BFOR Signal Basis

We propose a large deformation diffeomorphic metric mapping algorithm to align multiple b-value diffusion weighted imaging (mDWI) data, specifically acquired via hybrid diffusion imaging (HYDI), denoted as LDDMM-HYDI. We then propose a Bayesian model for estimating the white matter atlas from HYDIs. We adopt the work given in Hosseinbor et al. (2012) and represent the q-space diffusion signal with the Bessel Fourier orientation reconstruction (BFOR) signal basis. The BFOR framework provides the representation of mDWI in the q-space and thus reduces memory requirement. In addition, since the BFOR signal basis is orthonormal, the L2 norm that quantifies the differences in the q-space signals of any two mDWI datasets can be easily computed as the sum of the squared differences in the BFOR expansion coefficients. In this work, we show that the reorientation of the $q$-space signal due to spatial transformation can be easily defined on the BFOR signal basis. We incorporate the BFOR signal basis into the LDDMM framework and derive the gradient descent algorithm for LDDMM-HYDI with explicit orientation optimization. Additionally, we extend the previous Bayesian atlas estimation framework for scalar-valued images to HYDIs and derive the expectation-maximization algorithm for solving the HYDI atlas estimation problem. Using real HYDI datasets, we show the Bayesian model generates the white matter atlas with anatomical details. Moreover, we show that it is important to consider the variation of mDWI reorientation due to a small change in diffeomorphic transformation in the LDDMM-HYDI optimization and to incorporate the full information of HYDI for aligning mDWI

Longitudinal diffusion tensor imaging and neuropsychological correlates in traumatic brain injury patients

Traumatic brain injury (TBI) often involves focal cortical injury and white matter (WM) damage that can be measured shortly after injury. Additionally, slowly evolving WM change can be observed but there is a paucity of research on the duration and spatial pattern of long-term changes several years post-injury. The current study utilized diffusion tensor imaging to identify regional WM changes in 12 TBI patients and nine healthy controls at three time points over a four year period. Neuropsychological testing was also administered to each participant at each time point. Results indicate that TBI patients exhibit longitudinal changes to WM indexed by reductions in fractional anisotropy (FA) in the corpus callosum, as well as FA increases in bilateral regions of the superior longitudinal fasciculus (SLF) and portions of the optic radiation (OR). FA changes appear to be driven by changes in radial (not axial) diffusivity, suggesting that observed longitudinal FA changes may be related to changes in myelin rather than to axons. Neuropsychological correlations indicate that regional FA values in the corpus callosum and sagittal stratum (SS) correlate with performance on finger tapping and visuomotor speed tasks (respectively) in TBI patients, and that longitudinal increases in FA in the SS, SLF, and OR correlate with improved performance on the visuomotor speed (SS) task as well as a derived measure of cognitive control (SLF, OR). The results of this study showing progressive WM deterioration for several years post-injury contribute to a growing literature supporting the hypothesis that TBI should be viewed not as an isolated incident but as a prolonged disease state. The observations of long-term neurological and functional improvement provide evidence that some ameliorative change may be occurring concurrently with progressive degeneration

Posterior Cingulate and Lateral Parietal Gray Matter Volume in Older Adults with Depressive Symptoms

Depressive symptoms occurring late in life are an important risk factor for Alzheimer’s disease (AD). The latest research finds that onset of depressive symptoms in late life may herald the development of AD, not only for amnestic Mild Cognitive Impairment (aMCI) patients, but also for cognitively-normal older adults. Neuroimaging of brain structure, blood flow, and glucose metabolism indicates that depressive symptoms in late life are accompanied by structural and functional changes in limbic brain regions vulnerable to AD. The present cross-sectional study was guided by the hypothesis that compared to their non-depressed counterparts, older adults with mild to moderate depressive symptoms have less volume in limbic structures vulnerable to changes in AD—specifically, cortical midline structures such as anterior cingulate and posterior cingulate cortex as well as mesial temporal regions such as bilateral hippocampi and amygdalae. Consistent with our hypothesis, results of a voxel-based morphometry analysis revealed smaller retrosplenial, posterior cingulate, and precuneus gray matter volumes in depressed individuals relative to healthy controls. Right lateral parietal cortex—another region vulnerable to change in AD—was also smaller in the group with depressive symptoms. Contrary to our hypothesis, no volumetric differences were found in the anterior cingulate cortex or mesial temporal lobe. Results of this study show a relationship between geriatric depressive symptoms and brain volume in regions vulnerable to AD. Follow-up of participants over time will tell if brain changes detected here predict development of AD

Blood Flow Improvement Trial: Design and Enrollment Developing Topics

Background Midlife insulin resistance (IR) has previously been shown to be associated with lower cerebral blood flow (CBF), and is a potentially modifiable risk factor for dementia. The Blood Flow Improvement Trial (BFiT), NCT03117829 , tested a 12 week carbohydrate restricted diet (CRD) and exercise behavioral intervention to reverse IR, and aimed to 1) determine the extent to which improving or normalizing glucose homeostasis improves CBF and cognitive function in individuals with IR, 2) determine whether participants continue to maintain improved or normalized glycemic control for 6 months, and 3) determine changes in the human metabolome as individuals improve or normalize IR and glucose homeostasis through diet and exercise. Method Participants were recruited from the Wisconsin Alzheimer’s Disease Research Center and screened for metabolic risk factor eligibility based on the criteria shown in Table 1. The design involved a 12 week diet and exercise intervention focused on self‐monitoring to promote adherence. Exercise was conducted in a supervised group setting 3 days/week for 50 minutes and participants were instructed to exercise on their own an additional 2 days/week. Participants followed a CRD and monitored their own blood glucose with the goal of achieving and maintaining fasting blood glucose/dL. Participants underwent baseline, 12 week, and 6 month procedures including urine and blood labs/metabolomics, cognitive testing, fitness testing, and blood flow imaging via MRI (Table 2). Result The enrollment goal was 40 participants. 118 individuals were screened for eligibility, and 72.5% of the target enrollment was met; of those participants, nearly 80% completed the 12 week intervention. Of the 23 participants that completed the intervention, mean attendance was 70% for supervised exercise sessions and 81% for weekly behavioral coaching sessions. Figure 1 summarizes screening, enrollment, and procedure completion. Conclusion IR may be a modifiable risk factor for dementia. The BFiT pilot trial was designed to test the feasibility of exercise and CRD to reduce IR and improve brain blood flow in middle‐aged adults. Reasonable enrollment and completion N were achieved. Future analysis will center on barriers to enrollment and adherence, as well as analysis of the primary and secondary outcome measures

Low HDL Cholesterol is Associated with Lower Gray Matter Volume in Cognitively Healthy Adults

Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 ± 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline

Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer's disease

Breakdown of the neurovascular unit is associated with blood-brain barrier (BBB) leakiness contributing to cognitive decline and disease pathology in the early stages of Alzheimer's disease (AD). Vascular stability depends on angiopoietin-1 (ANGPT-1) signalling, antagonised by angiopoietin-2 (ANGPT-2) expressed upon endothelial injury. We examined the relationship between CSF ANGPT-2 and CSF markers of BBB leakiness and core AD biomarkers across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 20 participants with mild cognitive impairment (MCI), and 17 with AD); (iii) a neurologically normal cohort aged 23-78 years with paired CSF and serum samples. CSF ANGPT-2, sPDGFRβ, albumin and fibrinogen levels were measured by sandwich ELISA. In cohort (i), CSF ANGPT-2 was elevated in AD and correlated with CSF t-tau and p-tau181 but not Aβ42. ANGPT-2 also correlated positively with CSF sPDGFRβ and fibrinogen - markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT-2 was highest in MCI and correlated with CSF albumin in the CU and MCI cohorts but not in AD. CSF ANGPT-2 also correlated with CSF t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT-2 correlated strongly with the CSF/serum albumin ratio. Serum ANGPT-2 showed non-significant positive associations with CSF ANGPT-2 and the CSF/serum albumin ratio. Together, these data indicate that CSF and possibly serum ANGPT-2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT-2 as a biomarker of BBB damage in AD requires further study

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study

OBJECTIVE: The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid β 1-42 (Aβ42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. METHOD: Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. RESULTS: We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aβ42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). CONCLUSIONS: Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2022 APA, all rights reserved)