Physical exercise has been shown to increase brain volume and improve cognition in randomized trials of non-demented elderly. Although greater social engagement was found to reduce dementia risk in observational studies, randomized trials of social interventions have not been reported. A representative sample of 120 elderly from Shanghai, China was randomized to four groups (Tai Chi, Walking, Social Interaction, No Intervention) for 40 weeks. Two MRIs were obtained, one before the intervention period, the other after. A neuropsychological battery was administered at baseline, 20 weeks, and 40 weeks. Comparison of changes in brain volumes in intervention groups with the No Intervention group were assessed by t-tests. Time-intervention group interactions for neuropsychological measures were evaluated with repeated-measures mixed models. Compared to the No Intervention group, significant increases in brain volume were seen in the Tai Chi and Social Intervention groups (p < 0.05). Improvements also were observed in several neuropsychological measures in the Tai Chi group, including the Mattis Dementia Rating Scale score (p = 0.004), the Trailmaking Test A (p = 0.002) and B (p = 0.0002), the Auditory Verbal Learning Test (p = 0.009), and verbal fluency for animals (p = 0.01). The Social Interaction group showed improvement on some, but fewer neuropsychological indices. No differences were observed between the Walking and No Intervention groups. The findings differ from previous clinical trials in showing increases in brain volume and improvements in cognition with a largely non-aerobic exercise (Tai Chi). In addition, intellectual stimulation through social interaction was associated with increases in brain volume as well as with some cognitive improvements.
Cognition; exercise; intervention studies; magnetic resonance imaging; pilot study; Tai Chi
Background and Purpose
This scientific statement provides an overview of the evidence on
vascular contributions to cognitive impairment and dementia. Vascular
contributions to cognitive impairment and dementia of later life are common.
Definitions of vascular cognitive impairment (VCI), neuropathology, basic
science and pathophysiological aspects, role of neuroimaging and vascular
and other associated risk factors, and potential opportunities for
prevention and treatment are reviewed. This statement serves as an overall
guide for practitioners to gain a better understanding of VCI and dementia,
prevention, and treatment.
Writing group members were nominated by the writing group co-chairs
on the basis of their previous work in relevant topic areas and were
approved by the American Heart Association Stroke Council Scientific
Statement Oversight Committee, the Council on Epidemiology and Prevention,
and the Manuscript Oversight Committee. The writing group used systematic
literature reviews (primarily covering publications from 1990 to May 1,
2010), previously published guidelines, personal files, and expert opinion
to summarize existing evidence, indicate gaps in current knowledge, and,
when appropriate, formulate recommendations using standard American Heart
Association criteria. All members of the writing group had the opportunity
to comment on the recommendations and approved the final version of this
document. After peer review by the American Heart Association, as well as
review by the Stroke Council leadership, Council on Epidemiology and
Prevention Council, and Scientific Statements Oversight Committee, the
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee.
The construct of VCI has been introduced to capture the entire
spectrum of cognitive disorders associated with all forms of cerebral
vascular brain injury—not solely stroke—ranging from mild
cognitive impairment through fully developed dementia. Dysfunction of the
neurovascular unit and mechanisms regulating cerebral blood flow are likely
to be important components of the pathophysiological processes underlying
VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk
for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage
of the brain, and VCI. The neuropathology of cognitive impairment in later
life is often a mixture of Alzheimer disease and microvascular brain damage,
which may overlap and synergize to heighten the risk of cognitive
impairment. In this regard, magnetic resonance imaging and other
neuroimaging techniques play an important role in the definition and
detection of VCI and provide evidence that subcortical forms of VCI with
white matter hyperintensities and small deep infarcts are common. In many
cases, risk markers for VCI are the same as traditional risk factors for
stroke. These risks may include but are not limited to atrial fibrillation,
hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore,
these same vascular risk factors may be risk markers for Alzheimer disease.
Carotid intimal-medial thickness and arterial stiffness are emerging as
markers of arterial aging and may serve as risk markers for VCI. Currently,
no specific treatments for VCI have been approved by the US Food and Drug
Administration. However, detection and control of the traditional risk
factors for stroke and cardiovascular disease may be effective in the
prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are
important. Understanding of VCI has evolved substantially in recent years,
based on preclinical, neuropathologic, neuroimaging, physiological, and
epidemiological studies. Transdisciplinary, translational, and transactional
approaches are recommended to further our understanding of this entity and
to better characterize its neuropsychological profile. There is a need for
prospective, quantitative, clinical-pathological-neuroimaging studies to
improve knowledge of the pathological basis of neuroimaging change and the
complex interplay between vascular and Alzheimer disease pathologies in the
evolution of clinical VCI and Alzheimer disease. Long-term vascular risk
marker interventional studies beginning as early as midlife may be required
to prevent or postpone the onset of VCI and Alzheimer disease. Studies of
intensive reduction of vascular risk factors in high-risk groups are another
important avenue of research.
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
We present a method that significantly improves magnetic resonance imaging (MRI) based brain tissue segmentation by modeling the topography of boundaries between tissue compartments. Edge operators are used to identify tissue interfaces and thereby more realistically model tissue label dependencies between adjacent voxels on opposite sides of an interface. When applied to a synthetic MRI template corrupted by additive noise, it provided more consistent tissue labeling across noise levels than two commonly used methods (FAST and SPM5). When applied to longitudinal MRI series it provided lesser variability in individual trajectories of tissue change, suggesting superior ability to discriminate real tissue change from noise. These results suggest that this method may be useful for robust longitudinal brain tissue change estimation.
Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magnitude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task.
We also examined the effects of WMH located in the dorsolateral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior parietal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning.
The time and space complexities of Markov random field (MRF) algorithms for image segmentation increase with the number of edges that represent statistical dependencies between adjacent pixels. This has made MRFs too computationally complex for cutting-edge applications such as joint segmentation of longitudinal sequences of many high-resolution magnetic resonance images (MRIs). Here, we show that simply removing edges from full MRFs can reduce the computational complexity of MRF parameter estimation and inference with no notable decrease in segmentation performance. In particular, we show that for segmentation of white matter hyperintensities in 88 brain MRI scans of elderly individuals, as many as 66% of MRF edges can be removed without substantially degrading segmentation accuracy. We then show that removing edges from MRFs makes MRF parameter estimation and inference computationally tractable enough to enable modeling statistical dependencies within and across a larger number of brain MRI scans in a longitudinal series; this improves segmentation performance compared to separate segmentations of each individual scan in the series.
This study examined the validity of the Spanish and English Neuropsychological Assessment Scales (SENAS) in comparison with clinical diagnosis of normal cognition versus cognitive impairment, not demented (CIND) versus demented in elderly Hispanics and Whites. Relationships between SENAS scales and diagnosis were essentially the same in Hispanics and Whites. Verbal memory measures were most strongly related, with more than 35% of the variance in these measures accounted for by diagnosis independent of effects of education, age, gender, and language. Diagnosis accounted for more than 10% of the variance (19% on average) in 11 of the 17 measures examined in this study. Logistic regressions showed that verbal memory was important both for distinguishing normal from CIND and CIND from demented. Object naming improved discrimination of CIND from demented beyond that of verbal memory alone. These results provide evidence of equivalent validity across Hispanics and Whites.
Neuropsychological assessment; Ethnic groups; Cognitive impairment; Dementia; Early diagnosis; Cognition
Cerebrovascular disease is common and associated with cognitive deficits and increased risk for dementia. Until recently, only limited attention has focused on advances in imaging techniques to better define and quantify the spectrum of asymptomatic cerebrovascular disease commonly seen on magnetic resonance imaging, such as abnormal white matter signals. Abnormal signals in cerebral white matter, although nonspecific, are increased in prevalence and severity in association with aging and cerebrovascular risk factors among older individuals. The ubiquitous occurrence of these abnormal white matter signals commonly referred to as white matter hyperintensities (WMHs) and the association with cerebrovascular risk and cognitive impairment among older individuals make scientific evaluation of WMHs an important and much needed avenue of research. In this section, we review current methods of WMH analysis. Strengths and limitation of both quantitative and qualitative methods are discussed initially, followed by a brief review of current magnetic resonance imaging segmentation and mapping techniques that make it possible to assess the anatomical location of WMHs. We conclude by discussing future analytic methods designed to better understand the pathophysiology and cognitive consequences of WMHs.
magnetic resonance imaging; white matter hyperintensities; brain segmentation
Mild cognitive impairment (MCI), defined as episodic memory impairment beyond what is expected in normal aging, is often associated with hippocampal atrophy (HA) and may represent incipient Alzheimer’s disease. However, recent studies suggest that MCI is very heterogeneous and multiple etiologies likely exist. One possibility is small vessel cerebrovascular disease (CVD). Specifically, we hypothesized that white matter hyperintensities(WMH),an MRI marker for CVD, would lead to impairments in executive control processes critical for working memory that may, in turn, result in episodic memory impairment. To test this hypothesis, we examined a group of subjects clinically diagnosed with MCI and used MRI to further subcategorize individuals as either MCI with severe white matter hyperintensities (MCI-WMH) or MCI with severe hippocampal atrophy (MCI-HA). MCI-WMH, MCI-HA, and matched control subjects each performed a battery of working memory and episodic memory tasks. Results showed that MCI-HA and MCI-WMH were equally impaired on the episodic memory task relative to controls, but MCI-WMH were additionally impaired on tests tapping verbal and spatial working memory abilities and attentional control processes. These results suggest that CVD and hippocampal dysfunction are associated with distinct neuropsychological profiles. Although both syndromes are associated with episodic memory deficits, CVD is additionally associated with working memory and executive control deficits. © 2005 Elsevier Ltd. All rights reserved.
Aging; Dementia; White matter hyperintensities; Working memory; Cerebrovascular disease; Hippocampus
This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was quantified using the Framingham Coronary Risk Profile score (FCRP). Cerebral amyloid was measured by 11C-PIB PET and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index (p < .008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of APOE genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol and glycemic status on PIB index were all non-significant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.
vascular risk factors; coronary risk factors; cerebral amyloid; Mild Cognitive Impairment; Normal Aging; Alzheimer’s disease
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
To investigate the effects of baseline white matter hyperintensity (WMH) and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function).
A total of 150 individuals including cognitively normal elderly individuals and those with Alzheimer disease and mild cognitive impairment completed serial episodic memory and executive function evaluations and serial MRI scans sufficient for longitudinal measurement of WMH (mean delay 4.0 years). Incident WMH voxels were categorized as extended (baseline WMH that grew larger) or emergent (newly formed WMH). We used a stepwise regression approach to investigate the effects of baseline WMH and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function).
WMH burden significantly increased over time, and approximately 80% of incident WMH voxels represented extensions of existing lesions. Each 1 mL/y increase in WMH extension was associated with an additional 0.70 SD/y of subsequent episodic memory decrease (p = 0.0053) and an additional 0.55 SD/y of subsequent executive function decrease (p = 0.022). Emergent WMHs were not found to be associated with a change in cognitive measures.
Aging-associated WMHs evolve significantly over a 4-year period. Most of this evolution represents worsening injury to the already compromised surround of existing lesions. Increasing WMH was also significantly associated with declining episodic memory and executive function. This finding supports the view that white matter disease is an insidious and continuously evolving process whose progression has clinically relevant cognitive consequences.
Large genome-wide association studies (GWAS) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a two-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE Study, and from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls in the ADNI Study. A GWAS for each trait was conducted in the two Caucasian datasets in stage 1. Results from the two datasets were combined by meta analysis. In stage 2, one SNP from each region that was nominally significant in each dataset (p<0.05) and strongly associated in both datasets (p<1.0×10−5) was evaluated in the African American dataset.
Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p<5.0×10−8) were attained for HV with SNPs in the APOE, F5/SELP, LHFP and GCFC2 gene regions. All of these associations were supported by evidence in each dataset. Associations with different SNPs in the same gene (p<1×10−5 in Caucasians and p<2.2×10−4 in African Americans) were also observed for PICALM with HV, SYNPR with TCV and TTC27 with WMH.
Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.
Age-related changes in neural circuits, neural networks, and their plasticity are central to our understanding of age changes in cognition and brain structure and function. This paper summarizes selected findings on these topics presented at the Cognitive Aging Summit II. Specific areas discussed were synaptic vulnerability and plasticity, including the role of different types of synaptic spines, and hormonal effects in the dorsolateral prefrontal cortex of nonhuman primates, the impact of both compensatory processes and dedifferentiation on demand-dependent differences in prefrontal activation in relation to age and performance, the role of vascular disease, indexed by white matter signal abnormalities, on prefrontal activation during a functional magnetic resonance imaging-based cognitive control paradigm, and the influence of amyloid-β neuropathology on memory performance in older adults and the networks of brain activity underlying variability in performance. A greater understanding of age-related changes in brain plasticity and neural networks in healthy aging and in the presence of underlying vascular disease or amyloid pathology will be essential to identify new targets for intervention. Moreover, this understanding will assist in promoting the utilization of existing interventions, such as lifestyle and therapeutic modifiers of vascular disease.
cognitive changes; aging; Neural networks
Background and Purpose
White Matter Hyperintensities (WMH) are areas of high signal detected by T2 and FLAIR sequences on brain Magnetic Resonance Imaging (MRI). Although associated with aging, cerebrovascular risk factors and cognitive impairment, the pathogenesis of WMH remains unclear. RNA expression was assessed in the blood of individuals with and without extensive WMH to search for evidence of oxidative stress, inflammation and other abnormalities described in WMH lesions in brain.
Subjects included 20 with extensive WMH (WMH+), 45% of whom had Alzheimer’s disease, and 18 with minimal WMH (WMH-), 44% of whom had Alzheimer’s disease. All subjects were clinically evaluated and had quantitative MRIs. Total RNA from whole blood was processed on human whole genome Affymetrix HU133 Plus 2.0 microarrays. RNA expression was analyzed using an analysis of covariance (ANCOVA).
241 genes were differentially regulated at ±1.2 fold difference (p <0.005) in subjects with WMH+ as compared to WMH-, regardless of cognitive status, and 50 genes were differentially regulated with at least ±1.5 fold difference (p <0.005). Cluster and principal components analyses showed that the expression profiles for these genes distinguished WMH+ from WMH- subjects. Function analyses suggested that WMH-specific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long term potentiation and neurotransmission.
The unique RNA expression profile in blood associated with WMH is consistent with roles of systemic oxidative stress and inflammation as well as other potential processes in the pathogenesis or consequences of WMH.
White matter; MRI; gene expression profiling; blood; ischemia; inflammation; oxidative stress; Alzheimer’s disease
The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.
Hippocampal injury in the Alzheimer's Disease (AD) pathological process is region specific and MRI-based measures of localized hippocampus (HP) atrophy are known to detect region specific changes associated with clinical AD, but it is unclear whether these measures provide information that is independent of that already provided by measures of total HP volume. Therefore, this study assessed the strength of association between localized HP atrophy measures and AD-related measures including CSF amyloid beta and tau concentrations, and cognitive performance, in statistical models that also included total HP volume as a covariate. A computational technique termed localized components analysis (LoCA) was used to identify 7 independent patterns of HP atrophy among 390 semi-automatically delineated HP from baseline MRI of participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Among cognitively-normal participants, multiple measures of localized HP atrophy were significantly associated with CSF amyloid concentration, while total HP volume was not. In addition, among all ADNI participants, localized HP atrophy measures and total HP volume were both independently and additively associated with CSF tau concentration, performance on numerous neuropsychological tests, and discrimination between normal, MCI, and AD clinical diagnostic groups. Together, these results suggest that regional measures of hippocampal atrophy provided by LoCA may be more sensitive than total HP volume to the effects of AD pathology burden among cognitively normal individuals and may provide information about HP regions whose deficits may have especially profound cognitive consequences throughout the AD clinical course.
Hippocampus; Alzheimer's Disease; morphometry; biomarkers; shape analysis
The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent MRI, PIB-PET imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD−: N = 27; CVD+: N = 27). PIB-PET ratios of Aβ deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aβ in prespecified regions determined PIB status (PIB−: N = 33; PIB+: N = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aβ, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (P = 0.001) when compared to CVD− individuals. Neither PIB status nor amount of Aβ affected cognition (Ps ≥ .45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aβ aggregation appear to be independent processes with CVD primarily affecting cognition.
PIB; cerebrovascular disease; episodic memory; executive functioning; cognition
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
Several biomarkers have been individually associated with vascular brain injury but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/TIA, and the prevalence of subclinical brain injury.
Methods and Results
In 3127 stroke-free Framingham Offspring (59±10 yrs, 54%F), we related a panel of 8 biomarkers assessing inflammation(C-reactive protein[CRP]), hemostasis(D-dimer and plasminogen activator inhibitor-1), neurohormonal activity(aldosterone-to renin ratio, B-type natriuretic peptide[BNP] and N-terminal pro-atrial natriuretic peptides) and endothelial function (homocysteine and urinary albumin/creatinine ratio[UACR]) measured at the 6th examination(1995–98) to risk of incident stroke/TIA. In a subset of 1901 participants with available brain MRI (1999–2005), we further related these biomarkers to total cerebral brain volume (TCBV), covert brain infarcts (CBI), and large white matter hyperintensity volume(LWMHV).
During a median follow-up of 9.2 years, 130 participants experienced incident stroke/TIA. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/TIA and with TCBV (p<0.05 for both), but not with CBI or LWMHV (p >0.05). In backwards elimination analyses higher log-BNP (hazards ratio [HR] 1.39/SD, p=0.002) and log-UACR (HR1.31/SD, p=0.004) were associated with increased risk of stroke/TIA and improved risk prediction over using the Framingham stroke risk profile alone; using <5%, 5–15% or >15% 10-year risk categories the net reclassification index was 0.109;p=0.037). Higher CRP (β=−0.21/SD,p=0.008), D-dimer(β==−0.18/SD,p=0.041), tHcy(β=−0.21/SD,p=0.005), and UACR(β=−0.15/SD,p=0.042) were associated with lower TCBV.
In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.
biomarkers; epidemiology; magnetic resonance imaging; risk stratification; stroke prevention
This study investigated the role of genetic and environmental influences on individual differences in brain volumes measured at two time points in normal elderly males from the National Heart, Lung, and Blood Institute Twin Study. The MRI scans were conducted four years apart on 33 monozygotic and 33 dizygotic male twin pairs, aged 68 to 77 years when first scanned. Volumetric measures of total brain and total cerebrospinal fluid were significantly heritable at baseline (over 70%). For both volumes genetic influences at follow-up were entirely accounted for by genetic influences at baseline, suggesting that the same genetic factors influence variability in brain volume at each time of assessment. Variability in 4-year volume change was due to shared and individual-specific environmental influences. There was little evidence for heritable influences on change measures. These results suggest that variation in longitudinal change of some brain volume measures may have different underlying genetic and environmental architecture from variation in repeat cross-sectional measures, which could have implications for intervention strategies for age-related illness associated with brain morphology. The results of this study are discussed in the context of the small sample size and associated limitations of statistical power.
twins; volumetric MRI; longitudinal; aging
Accumulating evidence indicates that white matter degeneration contributes to the neural disconnections that underlie Alzheimer’s disease pathophysiology. Although this white matter degeneration is partly attributable to axonopathy associated with neuronal degeneration, amyloid β (Aβ) protein-mediated damage to oligodendrocytes could be another mechanism. To test this hypothesis, we studied effects of soluble Aβ in oligomeric form on survival and differentiation of cells of the oligodendroglial lineage using highly purified oligodendroglial cultures from rats at different developmental stages. Aβ oligomer at 10 μM or higher reduced survival of mature oligodendrocytes, whereas oligodendroglial progenitor cells (OPCs) were relatively resistant to the Aβ oligomer-mediated cytotoxicity. Further study revealed that Aβ oligomer even at 1 μM accelerated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis in mature oligodendrocytes, and, more significantly, inhibited myelin sheet formation after induction of in vitro differentiation of OPCs. These results imply a novel pathogenetic mechanism underlying Aβ oligomer-mediated white matter degeneration, which could impair myelin maintenance and remyelination by adult OPCs, resulting in accumulating damage to myelinating axons thereby contributing to neural disconnections.
Alzheimer’s disease; Amyloid β; Lipid; Myelin; Oligodendroglia; White matter degeneration
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
Memory and aging centers in California
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
To examine the association between a Mediterranean-style diet (MeDi) and brain MRI white matter hyperintensities (WMH). The MeDi has previously been associated with a reduced risk of cardiovascular morbidity, possibly including stroke. A greater understanding of modifiable risk factors for small vessel damage may facilitate the prevention of stroke and cognitive decline.
A cross-sectional analysis within a longitudinal population-based cohort study. A semi-quantitative food frequency questionnaire was administered and a score (range 0-9) was calculated to reflect increasing similarity to the MeDi pattern.
The Northern Manhattan Study.
1,091 participants, of which 966 had dietary information (mean age 72, 59% women, 65% Hispanic, 16% White, 17% Black).
Main outcome measures
WMH volume was measured by quantitative brain MRI. Linear regression models were constructed to examine the relation between the MeDi score and the log-transformed WMH volume as a proportion of total cranial volume, controlling for sociodemographic and vascular risk factors.
On the MeDi scale, 12% scored 0-2, 16 scored 3, 23% scored 4, 23% scored 5, 26% scored 6-9. Each 1-point increase in MeDi score was associated with a lower log WMH volume (β=-0.04, p=0.02). The only MeDi score component that was an independent predictor of WMH volume was the ratio of monounsaturated to saturated fat (β=-0.20, p=0.001).
A Mediterranean-style diet was associated with a lower WMH burden, a marker of small vessel damage in the brain. However, white matter hyperintensities are etiologically heterogenous and can include neurodegeneration. Replication by other population-based studies is needed.