It is becoming increasingly recognized that there is a vascular contribution to the pathogenesis of Alzheimer’s disease (AD). We use a unique four dimensional MRI technique, (termed Phase Contrast Vastly undersampled Isotropic PRojection imaging, PC VIPR), that allows us to examine volumetric blood flow in the arteries of the Circle of Willis. Reduced flow is believed to be indicative of suboptimal vascular health. 38 Mild Cognitive Impairment (MCI) participants (diagnosed via clinical consensus conference; mean age 73.33±8.45 years, 42% female, 50% APOE ε4+), underwent a comprehensive neuroimaging protocol (including PC VIPR) and a standard neuropsychological battery. A subset of participants also underwent lumbar puncture (LP) for CSF analysis. To investigate the relationship between arterial flow and cognition, we ran linear regressions with cognitive performance as the outcome, flow measured in the distal petrous portion of the ICA as the predictor variable (Figure 1), and age, sex, years of education, and interval between MRI scan and neuropsychological testing as covariates. Cut-offs for biomarker positivity resulting from an ROC analysis of AD cases and controls in the Wisconsin ADRC sample were used to identify subsets of MCIs as biomarker positive or negative on CSF Aß42 (cut-off for positivity=below 477 ng/L) and CSF total-tau/Aß42 (cut-off ratio for positivity=above 0.9). ANCOVA models controlling for age, sex, and interval between MRI and LP were run to determine the relationship between biomarker positivity and arterial health. Lower ICA mean flow predicted worse performance on Trails B, Animal Naming, WAIS-Digit Symbol, and RAVLT learning total trials 1-5 (p<0.05) but not Boston Naming or RAVLT long delay (Table 1, Figure 2). Patients who were Aß42 or total-tau/Aß42 positive had significantly lower ICA mean flow than did subjects with negative biomarker profiles (p≤0.05,Figure 3). Mean ICA arterial flow predicted cognitive performance in MCI subjects and biomarker positivity was associated with perturbed flow. This suggests an increasing role for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a window of opportunity to intervene in the disease process. It also exemplifies a role for novel 4D flow imaging to better understand AD pathology. PC VIPR angiogram (Adapted from Berman et al. 2015). Green planes denote locations of measurements taken to analyse arterial health metrics of the Circle of Willis. Planes marked with arrows represent the distal petrous portion of the ICA (left and right), the average of which was used as a metric of ICA flow in this abstract. Graphical representation of significant relationships (from Table 1) between ICA mean flow and cognitive performance. ICA mean flow is on the x-axis, and cognitive scores adjusted for covariates (age, gender, interval between MRI and neuropsychological testing, and years of education) are on the y-axis. For all cognitive test, with the exception of Trails B, higher scores indicate better cognitive performance. Boxplots depicting the comparison of ICA mean flow in biomarker positive vs. biomarker negative individuals with MCI. Biomarker positivity status for amyloid and the ratio of total-tau to amyloid is denoted on the y-axis, while ICA mean flow adjusted for age, sex, and interval between MRI and LP is on the y-axis. Amyloid negative subjects have high Aβ-42 in the CSF, while amyloid positive subjects have low Aβ-42 in the CSF.
Delirium is common among dementia patients and can be distressing to both patients and their caregivers. Distress, the subjective experience of delirium (i.e. “delirium burden”), was measured using newly developed patient and caregiver delirium-burden questionnaires, in a subset of patients and/or caregivers (n=267) from the Better Assessment of Illness (BASIL) study, an ongoing prospective, observational study of surgical and medical patients ≥70 years old. Thirty percent of the cohort had dementia as defined by proxy Informant Questionnaire on Cognitive Decline in the Elderly score ≥3.5 or ICD-9 codes from chart review; 22% experienced delirium by the Confusion Assessment Method (CAM). Delirium-burden instruments were reliable in patients with dementia (Cronbach’s α=0.82) and their caregivers (α=0.77). Delirium resulted in higher caregiver delirium-burden, regardless of dementia status (mean difference [compared to cognitively normal, CN]=6.87, 95% CI [4.02–9.72] with dementia; mean difference=6.03, 95% CI [2.80–9.27] without dementia). Delirium increased patient delirium-burden overall (mean difference [compared to CN]=7.99, 95% CI [5.57–10.42]); this effect was attenuated by dementia (mean difference [compared to CN =2.97, 95% CI [0.34–5.59]). Caregiver delirium-burden correlated with delirium-severity in patients with (r=.21) and without dementia (r=0.30); however, patient delirium-burden correlated with delirium severity only in patients without (r=.43) but not with dementia (r=.06). Instruments for measuring delirium burden are useful for estimating distress in caregivers and in patients without dementia; however, reporting in patients with dementia may be limited. Such measures are important to ultimately lessen the distress of delirium for patients and family caregivers.
It is becoming increasingly recognized that cerebrovascular disease is a contributing factor in the pathogenesis of Alzheimer's disease (AD). A unique 4D-Flow magnetic resonance imaging (MRI) technique, phase contrast vastly undersampled isotropic projection imaging (PC VIPR), enables examination of angiographic and quantitative metrics of blood flow in the arteries of the Circle of Willis within a single MRI acquisition. Thirty-eight participants with mild cognitive impairment (MCI) underwent a comprehensive neuroimaging protocol (including 4D-Flow imaging) and a standard neuropsychological battery. A subset of participants (n = 22) also underwent lumbar puncture and had cerebrospinal fluid (CSF) assayed for AD biomarkers. Cut-offs for biomarker positivity in CSF resulting from a receiver operating characteristic curve analysis of AD cases and controls from the larger Wisconsin Alzheimer's Disease Research Center cohort were used to classify MCI participants as biomarker positive or negative on amyloid-β (Aβ42), total-tau and total-tau/Aβ42 ratio. Internal carotid artery (ICA) and middle cerebral artery (MCA) mean flow were associated with executive functioning performance, with lower mean flow corresponding to worse performance. MCI participants who were biomarker positive for Aβ42 had lower ICA mean flow than did those who were Aβ42 negative. In sum, mean ICA and MCA arterial flow was associated with cognitive performance in participants with MCI and lower flow in the ICA was associated with amyloid positivity. This provides further evidence for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a point to intervene in the disease process.
The Role of Inflammation after Surgery for Elders study correlates novel inflammatory markers measured in blood, cerebrospinal fluid (CSF) assays, and [11C]-PBR28 positron-emission tomography imaging. This study involved a prospective cohort design with patients who underwent elective hip and knee arthroplasty under spinal anesthesia. Sixty-five adults participated with their family members. Inflammatory biomarker assays were measured preoperatively on day 1 and postoperatively at one month. On average, participants were 75 years old, and 72% were female. 54% underwent total knee arthroplasty, and 46% underwent total hip arthroplasty. The mean Modified Mini-Mental State (3MS) Examination score was 89.3; four patients (6%) scored ≤77 points. Plasma assays were completed in 63 (97%) participants, cerebrospinal fluid assays in 61 (94%), and PET imaging in 44 (68%). This complex study presents an innovative effort to correlate peripheral and central inflammatory biomarkers before and after major surgery in older adults. Strengths include collecting concurrent blood, cerebrospinal fluid, and positron-emission tomography with detailed clinical characterization of delirium, cognition, and functional status.
Few studies have investigated the relationship between frailty and postoperative delirium. We used the Confusion Assessment Method (CAM) supplemented by medical chart review, CAM-Severity (CAM-S) peak score, and Fried Frailty Index, respectively, to measure delirium, delirium severity, and frailty in the SAGES cohort of 560 older adults (≥70 years) undergoing elective surgery. Delirium prevalence was 13% (8/64), 21% (58/280), and 27% (43/160) in robust, pre-frail, and frail patients, respectively. Frail (odds ratio=2.6, 95% CI 1.1–5.8) but not pre-frail (odds ratio=1.8, 95% CI 0.8–4.1) patients had greater odds of developing delirium compared to robust patients. Frailty was also associated with greater delirium severity: CAM-S peak scores were 0.6 points (95% CI 0.3–0.9) higher in pre-frail patients and 1.7 points (95% CI 1.4–2.0) higher in frail patients compared to robust patients, on average. Preoperative screening for frailty could identify patients who are more likely to develop delirium and have more severe delirium.
Late middle-age is an important period to identify mild cognitive decline expected to precede clinical diagnoses of mild cognitive impairment and dementia. This study aimed to characterize patterns of longitudinal cognitive change in late middle-age and to identify a subgroup at highest risk for dementia. 677 late middle-aged participants enriched for AD risk (mean age at baseline 53.5, 69% female, 77% parental history of AD) who were cognitively healthy at baseline completed 4 or 5 neuropsychological assessments over a period of 8-10 years. Using linear mixed-effects regression, unconditional growth models were conducted for six neuropsychological variables, and the fixed and random effect estimates were combined to obtain slope estimates for each participant. Hierarchical cluster analysis was conducted on slope estimates, and resulting clusters were compared on slopes, intercepts, demographics, AD risk, and clinical outcomes. A subset underwent MRI scans (n=235) and cerebrospinal fluid assays (n=88). ANCOVA models (covarying age and gender) compared clustered groups on brain structure and AD biomarkers. Cluster analysis resulted in three groups: 1) Multi-domain group declining on learning, memory, and executive function measures (n=188), 2) dysexecutive group with mild decline in verbal learning and executive functioning (n=152), and 3) group with normal age-related decline in processing speed only (n=337) (Table 1, Figure 1). The multi-domain cluster was older (F=19.32, p<.001), comprised of more men (X2 = 9.20; p=.01), and endorsed more depressive symptoms (F=3.51, p<.05) at baseline. The multi-domain group included a greater percentage of APOE ε4 carriers (X2 = 5.27, p=.07), individuals with mild clinical symptoms (CDR=0.5, X2 = 20.39, p<.001) and clinical diagnoses (X2 = 52.69, p<.001) at follow-up, and individuals classified as AD biomarker positive (18% total-tau/Aβ-42 positive; X2 = 7.26; p<.05). The dysexecutive cluster had less education (F=5.06, p<.01) and lower literacy estimates (F=14.06, p<.001). The normally aging cluster exhibited higher intercepts on neuropsychological measures (p'S < .02) and less global atrophy (F=6.80, p=.001) (Figure 2). Annual rates of change on neuropsychological measures included in cluster analysis projected over 20-year period (note: Increase in Trailmaking Test Part B = worse performance). Mean global atrophy in three clusters. Full model also included age, gender, and intracranial Cluster analysis of slopes reflecting annual rates of cognitive change provides a data-driven method to identify mild cognitive decline in late middle-age that may indicate increased risk for dementia due to AD.
In addition to the development of beta amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) involves the loss of connecting structures including degeneration of myelinated axons and synaptic connections. However, the extent to which white matter tracts change longitudinally, particularly in the asymptomatic, preclinical stage of AD, remains poorly characterized. In this study we used a novel graph wavelet algorithm to determine the extent to which microstructural brain changes evolve in concert with the development of AD neuropathology as observed using CSF biomarkers. A total of 118 participants with at least two diffusion tensor imaging (DTI) scans and one lumbar puncture for CSF were selected from two observational and longitudinally followed cohorts. CSF was assayed for pathology specific to AD (Aβ42 and phosphorylated-tau), neurodegeneration (total-tau), axonal degeneration (neurofilament light chain protein; NFL), and synaptic degeneration (neurogranin). Tractography was performed on DTI scans to obtain structural connectivity networks with 160 nodes where the nodes correspond to specific brain regions of interest (ROIs) and their connections were defined by DTI metrics (i.e., fractional anisotropy (FA) and mean diffusivity (MD)). For the analysis, we adopted a multi-resolution graph wavelet technique called Wavelet Connectivity Signature (WaCS) which derives higher order representations from DTI metrics at each brain connection. Our statistical analysis showed interactions between the CSF measures and the MRI time interval, such that elevated CSF biomarkers and longer time were associated with greater longitudinal changes in white matter microstructure (decreasing FA and increasing MD). Specifically, we detected a total of 17 fiber tracts whose WaCS representations showed an association between longitudinal decline in white matter microstructure and both CSF p-tau and neurogranin. While development of neurofibrillary tangles and synaptic degeneration are cortical phenomena, the results show that they are also associated with degeneration of underlying white matter tracts, a process which may eventually play a role in the development of cognitive decline and dementia.
Abstract Objective To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). Methods We recruited twelve participants with DM1 and, for comparison, two participants with Alzheimer’s Disease (AD). Participants underwent cognitive screening and social cognition testing using the Dépistage Cognitif de Québec (DCQ), among other tests. Biomarkers included Tau PET with [18F]-AV-1451, CSF (Aβ, Tau, phospho-Tau), and plasma (Aβ, Tau, Nf-L, GFAP) studies. Results Of the twelve DM1 participants, seven completed the full protocol (Neurocognition 11/12; PET 7/12, CSF 9/12, plasma 12/12). Three DM1 participants were cognitively impaired (CI). On average, CI DM1 participants had lower scores on the DCQ compared to cognitively unimpaired (CU) DM1 participants (75.5/100 vs. 91.4/100) and were older (54 vs. 44 years old) but did not differ in years of education (11.3 vs. 11.1). The majority (6/7) of DM1 participants had no appreciable PET signal. Only one of the CI participants presented with elevated Tau PET SUVR in bilateral medial temporal lobes. This participant was the eldest and most cognitively impaired, and had the lowest CSF Aβ 1-42 and the highest CSF Tau levels, all suggestive of co-existing AD. CSF Tau and phospho-Tau levels were higher in the 3 CI compared to CU DM1 participants, but with a mean value lower than that typically observed in AD. Nf-L and GFAP were elevated in most DM1 participants (9/11 and 8/11, respectively). Finally, CSF phospho-Tau was significantly correlated with plasma Nf-L concentrations. Conclusions and relevance We observed heterogenous cognitive and biomarker profiles in individuals with DM1. While some participants presented with abnormal PET and/or CSF Tau, these patterns were highly variable and only present in a small subset. Although DM1 may indeed represent a non-AD Tauopathy, the Tau-PET tracer used in this study was unable to detect an in vivo Tau DM1 signature in this small cohort. Interestingly, most DM1 participants presented with elevated plasma Nf-L and GFAP levels, suggestive of other, possibly related, central brain alterations which motivate further research. This pioneering study provides novel insights towards the potential relationship between biomarkers and neurocognitive deficits commonly seen in DM1.
Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, [11C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [11C]PBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, [11C]PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and [11C]PBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between [11C]PBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between [11C]PBR28 binding and fluid inflammatory markers or post-operative delirium.
