Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of ...observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer's disease (AD).
The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I (2) statistic.
Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I (2) = 0%-40%, p ≥ .16).
An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.
MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH ...volume.
Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating CDR score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software.
Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p < 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally.
Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes.
To use fMRI to investigate whether hippocampal and entorhinal activation during learning is altered in the earliest phase of mild cognitive impairment (MCI).
Three groups of older individuals were ...studied: 10 cognitively intact controls, 9 individuals at the mild end of the spectrum of MCI, and 10 patients with probable Alzheimer disease (AD). Subjects performed a face-name associative encoding task during fMRI scanning, and were tested for recognition of stimuli afterward. Data were analyzed using a functional-anatomic method in which medial temporal lobe (MTL) regions of interest were identified from each individual's structural MRI, and fMRI activation was quantified within each region.
Significantly greater hippocampal activation was present in the MCI group compared to controls; there were no differences between these two groups in hippocampal or entorhinal volumes. In contrast, the AD group showed hippocampal and entorhinal hypoactivation and atrophy in comparison to controls. The subjects with MCI performed similarly to controls on the fMRI recognition memory task; patients with AD exhibited poorer performance. Across all 29 subjects, greater mean entorhinal activation was found in the subgroup of 13 carriers of the APOE epsilon4 allele than in the 16 noncarriers.
The authors hypothesize that there is a phase of increased medial temporal lobe activation early in the course of prodromal Alzheimer disease followed by a subsequent decrease as the disease progresses.
Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the ..."disease signature" of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up.
We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals.
AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (> 1). Of the 11 CN individuals with baseline low AD-signature thickness (≥ 1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥ 1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4.
By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.
In normal humans, relationships between cognitive test performance and cortical structure have received little study, in part, because of the paucity of tools for measuring cortical structure. ...Computational morphometric methods have recently been developed that enable the measurement of cortical thickness from MRI data, but little data exist on their reliability. We undertook this study to evaluate the reliability of an automated cortical thickness measurement method to detect correlates of interest between thickness and cognitive task performance. Fifteen healthy older participants were scanned four times at 2-week intervals on three different scanner platforms. The four MRI data sets were initially treated independently to investigate the reliability of the spatial localization of findings from exploratory whole-cortex analyses of cortical thickness–cognitive performance correlates. Next, the first data set was used to define cortical ROIs based on the exploratory results that were then applied to the remaining three data sets to determine whether the relationships between cognitive performance and regional cortical thickness were comparable across different scanner platforms and field strengths. Verbal memory performance was associated with medial temporal cortical thickness, while visuomotor speed/set shifting was associated with lateral parietal cortical thickness. These effects were highly reliable – in terms of both spatial localization and magnitude of absolute cortical thickness measurements – across the four scan sessions. Brain–behavior relationships between regional cortical thickness and cognitive task performance can be reliably identified using an automated data analysis system, suggesting that these measures may be useful as imaging biomarkers of disease or performance ability in multicenter studies in which MRI data are pooled.
Military training is physically arduous and associated with high injury incidence. Unlike in high‐performance sport, the interaction between training load and injury has not been extensively ...researched in military personnel. Sixty‐three (43 men, 20 women; age 24 ± 2 years; stature 1.76 ± 0.09 m; body mass 79.1 ± 10.8 kg) British Army Officer Cadets undergoing 44 weeks of training at the Royal Military Academy Sandhurst volunteered to participate. Weekly training load (cumulative 7‐day moderate‐vigorous physical activity MVPA, vigorous PA VPA, and the ratio between MVPA and sedentary‐light PA SLPA; MVPA:SLPA) was monitored using a wrist‐worn accelerometer (GENEActiv, UK). Self‐report injury data were collected and combined with musculoskeletal injuries recorded at the Academy medical center. Training loads were divided into quartiles with the lowest load group used as the reference to enable comparisons using odds ratios (OR) and 95% confidence intervals (95% CI). Overall injury incidence was 60% with the most common injury sites being the ankle (22%) and knee (18%). High (load; OR; 95% CI >2327 mins; 3.44; 1.80–6.56) weekly cumulative MVPA exposure significantly increased odds of injury. Similarly, likelihood of injury significantly increased when exposed to low‐moderate (0.42–0.47; 2.45 1.19–5.04), high‐moderate (0.48–0.51; 2.48 1.21–5.10), and high MVPA:SLPA loads (>0.51; 3.60 1.80–7.21). High MVPA and high‐moderate MVPA:SLPA increased odds of injury by ~2.0 to 3.5 fold, suggesting that the ratio of workload to recovery is important for mitigating injury occurrence.
Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically ...increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses.
We studied 51 older individuals without dementia (Clinical Dementia Rating CDR at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data.
Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE epsilon4 carrier status.
Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.
To use functional MRI (fMRI) to investigate whether hippocampal activation during a memory task can predict cognitive decline in individuals with mild cognitive impairment (MCI).
25 older individuals ...with MCI performed a visual scene encoding task during fMRI scanning, and were followed clinically for at least 4 years after scanning. A hypothesis driven analysis of fMRI data was performed. First, fMRI data were analysed at the group level to identify the regions of the hippocampal formation that were engaged by this memory task. Parameter estimates of each subject's memory related hippocampal activation (% signal change) were extracted and were analysed with a linear regression model to determine whether hippocampal activation predicted the degree or rate of cognitive decline, as measured by change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB).
Over 5.9 (1.2) years of follow-up after scanning, subjects varied widely in degree and rate of cognitive decline (change in CDR-SB ranged from 0 to 6, and the rate ranged from 0 to 1 CDR-SB unit/year). Greater hippocampal activation predicted greater degree and rate of subsequent cognitive decline (p<0.05). This finding was present even after controlling for baseline degree of impairment (CDR-SB), age, education and hippocampal volume, as well as gender and apolipoprotein E status. In addition, an exploratory whole brain analysis produced convergent results, demonstrating that the hippocampal formation was the only brain region where activation predicted cognitive decline.
In individuals with MCI, greater memory task related hippocampal activation is predictive of a greater degree and rate of cognitive decline subsequent to scanning. fMRI may provide a physiological imaging biomarker useful for identifying the subgroup of MCI individuals at highest risk of cognitive decline for potential inclusion in disease modifying clinical trials.
To determine whether APOE epsilon 4 predicts rate of cognitive change in incident and prevalent Alzheimer disease (AD).
Individuals were recruited from two longitudinal cohort studies-the Washington ...Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based)--and were followed for an average of 4 years. Three samples of participants diagnosed with AD, with diverse demographic characteristics and baseline cognitive functioning, were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3) 156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental State Examination in Predictors, varied as a function of epsilon 4 status in each sample.
The presence of at least one epsilon 4 allele was associated with faster cognitive decline in the incident population-based AD group (p = 0.01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analyses.
APOE epsilon 4 may influence rate of cognitive decline most significantly in the earliest stages of Alzheimer disease.
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