Search

Introduction Our goal was to determine if features of surgical patients, easily obtained from the medical chart or brief interview, could be used to predict those likely to experience more rapid cognitive decline following surgery. Methods We analyzed data from an observational study of 560 older adults (≥70 years) without dementia undergoing major elective non‐cardiac surgery. Cognitive decline was measured using change in a global composite over 2 to 36 months following surgery. Predictive features were identified as variables readily obtained from chart review or a brief patient assessment. We developed predictive models for cognitive decline (slope) and predicting dichotomized cognitive decline at a clinically determined cut. Results In a hold‐out testing set, the regularized regression predictive model achieved a root mean squared error (RMSE) of 0.146 and a model r‐square (R2) of .31. Prediction of “rapid” decliners as a group achieved an area under the curve (AUC) of .75. Conclusion Some of our models could predict persons with increased risk for accelerated cognitive decline with greater accuracy than relying upon chance, and this result might be useful for stratification of surgical patients for inclusion in future clinical trials.

IntroductionWe examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity.MethodsA total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups.ResultsHigher educational attainment attenuated the negative impact of WMH burden on memory (β=-0.03; 99% CI: -0.071, -0.002) and language decline (β=-0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics.DiscussionEducational attainment does not contribute to CR similarly across racial/ethnic groups.

INTRODUCTION: Older adults, including those with mild cognitive impairment (MCI), are increasingly undergoing surgery. METHODS: Relative risks of MCI alone or with delirium on adverse outcomes were estimated in an ongoing prospective, observational cohort study of 560 non-demented adults ≥70 years old. RESULTS: MCI (n=61, 11%) was associated with increased relative risk (RR) of delirium (RR=1.9, p

Objectives: The purpose of this study was to investigate the longitudinal trajectory of self- and informant-subjective cognitive complaints (SCC), and to determine if SCC predict longitudinal changes in objective measures (OM) of cognitive function. Methods: The study included healthy and cognitively normal late middle-aged adults enriched with a family history of AD who were evaluated at up to three visits over a 4-year period. At each visit (Visit 1–3), self- and informant-SCC and OM were evaluated. Linear mixed models were used to determine if the longitudinal rate of change of self- and informant-SCC were associated with demographic variables, depressive symptoms, family history (FH), and apolipoprotein epsilon 4 (APOE4) status. The same modeling approach was used to examine the effect of Visit 1 SCC on longitudinal cognitive change after controlling for the same variables. Results: At Visit 1, more self-SCC were associated with fewer years of education and more depressive symptoms. SCC were also associated with poorer performance on cognitive measures, such that more self-SCC at Visit 1 were associated with poorer performance on memory and executive functioning measures at Visit 1, while more informant-SCC were associated with faster rate of longitudinal decline on a measure of episodic learning and memory. FH and APOE4 status were not associated with SCC. Discussion: Self- and informant-SCC showed an association with OM, albeit over different time frames in our late middle-aged sample. Additional longitudinal follow-up will likely assist in further clarifying these relationships as our sample ages and more pronounced cognitive changes eventually emerge. (JINS, 2017, 23, 617–626)

Falls are viewed as a preventable cause of injury, functional loss, and death in older adults with dementia, and have been used as a marker of quality of care in long-term care facilities. Despite intensive intervention around fall prevention in these settings, falls and injury remain frequent, particularly among residents in the advanced stages of dementia. In this clinical review, we consider the common challenges and pitfalls in both the management of falls and the provision of palliative care in advanced dementia. We then describe a palliative approach to falls in advanced dementia that involves identifying individuals who would benefit from this care approach, framing falls and loss of mobility as a quality of life issue, and devising an individualized symptom assessment and management plan. A palliative approach can lead to recognition and acceptance that recurrent falls are often symptomatic of advanced dementia, and that not all falls are preventable. We conclude that falls in the advanced stage of dementia can be sentinel events indicating the need for a palliative approach to care. Rather than replace falls prevention activities, a palliative approach to falls prompts us to select dementia stage-appropriate interventions with a focus on symptom management, comfort, and dignity.

Alzheimer's disease (AD) is characterized by substantial neurodegeneration, including both cortical atrophy and loss of underlying white matter fiber tracts. Understanding longitudinal alterations to white matter may provide new insights into trajectories of brain change in both healthy aging and AD, and fluid biomarkers may be particularly useful in this effort. To examine this, 151 late-middle-aged participants enriched with risk for AD with at least one lumbar puncture and two diffusion tensor imaging (DTI) scans were selected for analysis from two large observational and longitudinally followed cohorts. Cerebrospinal fluid (CSF) was assayed for biomarkers of AD-specific pathology (phosphorylated-tau/Aβ42 ratio), axonal degeneration (neurofilament light chain protein, NFL), dendritic degeneration (neurogranin), and inflammation (chitinase-3-like protein 1, YKL-40). Linear mixed effects models were performed to test the hypothesis that biomarkers for AD, neurodegeneration, and inflammation, or two-year change in those biomarkers, would be associated with worse white matter health overall and/or progressively worsening white matter health over time. At baseline in the cingulum, phosphorylated-tau/Aβ42 was associated with higher mean diffusivity (MD) overall (intercept) and YKL-40 was associated with increases in MD over time. Two-year change in neurogranin was associated with higher mean diffusivity and lower fractional anisotropy overall (intercepts) across white matter in the entire brain and in the cingulum. These findings suggest that biomarkers for AD, neurodegeneration, and inflammation are potentially important indicators of declining white matter health in a cognitively healthy, late-middle-aged cohort.

It is not known whether computerized cognitive assessments, like the CogState battery, are sensitive to preclinical cognitive changes or pathology in people at risk for Alzheimer’s disease (AD). In 469 late middle-aged participants from the Wisconsin Registry for Alzheimer’s Prevention (mean age 63.8±7 years at testing; 67% female; 39% APOE4+), we examined relationships between a CogState abbreviated battery (CAB) of seven tests and demographic characteristics, traditional paper-based neuropsychological tests as well as a composite cognitive impairment index, cognitive impairment status (determined by consensus review); and biomarkers for amyloid and tau (CSF phosphorylated-tau/Aβ42 and global PET-PiB burden) and neural injury (CSF neurofilament light protein). CSF and PET-PiB were collected in n=71 and n=91 participants, respectively, approximately four years prior to CAB testing. For comparison, we examined three traditional tests of delayed memory in parallel. Similar to studies in older samples, the CAB was less influenced by demographic factors than traditional tests. CAB tests were generally correlated with most paper-based cognitive tests examined and mapped onto the same cognitive domains. Greater composite cognitive impairment index was associated with worse performance on all CAB tests. Cognitively impaired participants performed significantly worse compared to normal controls on all but one CAB test. Poorer One Card Learning test performance was associated with higher levels of CSF phosphorylated-tau/Aβ42. These results support the use of the CogState battery as measures of early cognitive impairment in studies of people at risk for AD.

IntroductionBiomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD).MethodsCerebrospinal fluid (CSF) collection, [C-11]Pittsburgh compound B (PiB) amyloid imaging, and magnetic resonance imaging were acquired in 104 cognitively healthy adults enriched with risk for sporadic AD. Image-derived cerebral β-amyloid (Aβ) burden, measured concurrently and longitudinally, was regressed on CSF measures of Aβ, neural injury, and inflammation, as well as ratios with Aβ42. Linear mixed-effects regression was used to model the effect of the CSF measures that predicted longitudinal brain amyloid accumulation on longitudinal cognitive decline, measured by memory test scores.ResultsAt baseline, Aβ42/Aβ40 and all CSF ratios to Aβ42 were associated with PiB binding in AD-vulnerable regions. Longitudinally, Aβ42/Aβ40 and ratios of total tau (t-tau), phosphorylated-tau (p-tau), neurofilament light protein, and monocyte chemoattractant protein-1 to Aβ42 were associated with increased Aβ deposition over 2 years, predominantly in lateral parietal and temporal cortex. However, these CSF ratios were not significantly associated with cognitive decline, and the effect seems to be largely driven by Aβ42 in the denominator.DiscussionThese results corroborate previous findings that t-tau/Aβ42 and p-tau/Aβ42 are the strongest candidate biomarkers during the preclinical time frame. They support a framework in which neural injury and amyloid deposition are likely occurring simultaneously. It may be that neurodegenerative processes influence progressive amyloid accumulation, even in the preclinical time frame. CSF biomarkers for nonspecific axonal injury and inflammation may provide more information at more advanced stages of the preclinical time course.

IntroductionAlthough cerebrovascular disease has long been known to co-occur with Alzheimer's disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used four dimensional (4D)-flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the circle of Willis. We hypothesized decreased mean blood flow and increased pulsatility, metrics indicative of poor vascular health, would be associated with cerebral atrophy and an AD cerebrospinal fluid (CSF) profile.MethodsA total of 312 patients along the AD continuum (172 middle aged, 60 cognitively healthy older, 44 mild cognitive impairment, and 36 AD) underwent MRI, CSF, and medical examinations. Regression was used to predict CSF biomarkers and atrophy from 4D-flow and analysis of covariance to compare vascular health between groups.ResultsDecreased mean flow in the middle cerebral artery (MCA) and superior portion of the internal carotid artery (sICA) and increased pulsatility in the MCA were associated with greater brain atrophy. Decreased mean flow in the sICA was associated with lower amyloid beta 1–42 (Aβ42) in the CSF, a pathologic biomarker profile associated with AD. Interestingly, although metrics of flow and pulsatility differed markedly across the AD spectrum, there were no significant differences in cardiovascular risk score, mean arterial pressure, and pulse pressure across the three age-matched older cohorts.DiscussionBy measuring intracranial arterial health directly with 4D-flow MRI, these data suggest that intracranial arterial health is compromised in symptomatic AD. Even after accounting for disease stage, cerebral artery health is associated with atrophy and an AD Aβ42 profile, suggesting neurovascular health may contribute to the etiopathogenesis of AD.

Introduction An Alzheimer's disease (AD) biomarker adjusted for age-related brain changes should improve specificity for AD-related pathological burden. Methods We calculated a brain-age-adjusted “personalized AD cortical thickness index” (pADi) in mild cognitive impairment patients from the Alzheimer's Disease Neuroimaging Initiative. We performed receiver operating characteristic analysis for discrimination between patients with and without cerebrospinal fluid evidence of AD and logistic regression in an independent sample to determine if a dichotomized pADi predicted conversion to AD dementia. Results Receiver operating characteristic area under the curve was 0.69 and 0.72 in the two samples. Three empirical methods identified the same cut-point for pADi in the discovery sample. In the validation sample, 83% of pADi+ mild cognitive impairment patients were cerebrospinal fluid AD biomarker positive. pADi+ mild cognitive impairment patients (n = 63, 38%) were more likely to progress to AD dementia after 1 (odds ratio = 2.9) and 3 (odds ratio = 2.6) years. Discussion The pADi is a personalized, magnetic resonance imaging–derived AD biomarker that predicts progression to dementia., Highlights • The personalized AD cortical thickness index (pADi) is a personalized magnetic resonance imaging–derived, brain-age-adjusted Alzheimer's disease (AD) biomarker. • The pADi accurately identifies mild cognitive impairment patients with cerebrospinal fluid markers of AD. • The pADi was consistent across two independent samples with 1.5T and 3T magnetic resonance imaging data. • An optimal cut-point predicted progression to AD dementia over 1 or 3 years. • The pADi can identify mild cognitive impairment likely due to AD in individual patients.

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 (ROC) 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.

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

BACKGROUND Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's 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 Alzheimer's 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.