IMPORTANCE: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, ...it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. OBJECTIVE: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. DESIGN, SETTING, AND PARTICIPANTS: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer’s and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. MAIN OUTCOMES AND MEASURES: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. RESULTS: A total of 300 TRIAD participants (177 women 59.0%; mean SD age, 64.6 17.6 years), 384 ALFA+ participants (234 women 60.9%; mean SD age, 61.1 4.7 years), and 187 BioCogBank Paris Lariboisière participants (116 women 62.0%; mean SD age, 69.9 9.2 years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean SD, 185.1 93.5 pg/mL, Aβ-positive mean SD, 285.0 142.6 pg/mL; ALFA+: Aβ-negative mean SD, 121.9 42.4 pg/mL, Aβ-positive mean SD, 169.9 78.5 pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean SD, 285.0 142.6 pg/mL, mild cognitive impairment MCI Aβ-positive mean SD, 332.5 153.6 pg/mL; AD mean SD, 388.1 152.8 pg/mL vs CU Aβ-negative mean SD, 185.1 93.5 pg/mL; Paris: MCI Aβ-positive, mean SD, 368.6 158.5 pg/mL; AD dementia, mean SD, 376.4 179.6 pg/mL vs CU Aβ-negative mean SD, 161.2 67.1 pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. CONCLUSIONS AND RELEVANCE: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.
•Urban environmental exposures were evaluated in individuals living in Barcelona.•Urban environmental exposures were not associated with cognitive performance.•Air pollution impacts cortical ...thickness of brain regions related to AD vulnerability.•Results suggest a link between environmental exposures and cerebral vulnerability to AD.
Air quality might contribute to incidence of dementia-related disorders, including Alzheimer’s dementia (AD). The aim of our study is to evaluate the effect of urban environmental exposures (including exposure to air pollution, noise and green space) on cognitive performance and brain structure of cognitively unimpaired individuals at risk for AD.
The ALFA (ALzheimer and FAmilies) study is a prospective cohort of middle-age, cognitively unimpaired subjects, many of them offspring of AD patients. Cognitive performance was measured by the administration of episodic memory and executive function tests (N = 958). Structural brain imaging was performed in a subsample of participants to obtain morphological information of brain areas, specially focused on cortical thickness, known to be affected by AD (N = 228). Land Use Regression models were used to estimate residential exposure to air pollutants. The daily average noise level at the street nearest to each participant's residential address was obtained from noise maps. For each participant residential green exposure indicators, such as surrounding greenness or amount of green, were generated. General linear models were conducted to assess the association between environmental exposures, cognitive performance and brain structure in a cross-sectional analysis.
No significant associations were observed between urban environmental exposures and the cognitive composite (p > 0.1). Higher exposure to air pollutants, but not noise, was associated with lower cortical thickness in brain regions known to be affected by AD, especially NO2 (β = −16.4; p = 0.05) and PM10 (β = −5.34; p = 0.05). On the other hand, increasing greenness indicators was associated with greater thickness in these same areas (β = 0.08; p = 0.03).
In cognitively unimpaired adults with increased risk for AD, increased exposure to air pollution was suggested to be associated with greater global atrophy and reduced volume and thickness in specific brain areas known to be affected in AD, thus suggesting a potential link between environmental exposures and cerebral vulnerability to AD. Although more research in the field is needed, air pollution reduction is crucial for decreasing the burden of age-related disorders.
Objective
To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans‐synaptic degeneration in multiple ...sclerosis (MS).
Methods
We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer RNFL thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel‐based morphometry (VBM), multiple linear regressions, and general linear models.
Results
VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion (p < 0.05). Visual cortex volume (β = +0.601, 95% confidence interval CI = +0.04 to +1.16), N‐acetyl aspartate in visual cortex (β = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (β = −2.551, 95% CI = −3.910 to −1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm3 in visual cortex volume predicts a reduction of 0.6μm in RNFL thickness. This association was also observed after 1 year of follow‐up. Patients with severe prior ON (adjusted difference = −3.01, 95% CI = −5.08 to −0.95) and mild prior ON (adjusted difference = −1.03, 95% CI = −3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON.
Interpretation
Our results suggest the presence of trans‐synaptic degeneration as a contributor to chronic axon damage in MS. ANN NEUROL 2014;75:98–107
Background Brain areas interact mutually to perform particular complex brain functions such as memory or language. Furthermore, under resting-state conditions several spatial patterns have been ...identified that resemble functional systems involved in cognitive functions. Among these, the default-mode network (DMN), which is consistently deactivated during task periods and is related to a variety of cognitive functions, has attracted most attention. In addition, in resting-state conditions some brain areas engaged in focused attention (such as the anticorrelated network, AN) show a strong negative correlation with DMN; as task demand increases, AN activity rises, and DMN activity falls. Objective We combined transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) to investigate these brain network dynamics. Methods Ten healthy young volunteers underwent four blocks of resting-state fMRI (10-minutes), each of them immediately after 20 minutes of sham or active tDCS (2 mA), on two different days. On the first day the anodal electrode was placed over the left dorsolateral prefrontal cortex (DLPFC) (part of the AN) with the cathode over the contralateral supraorbital area, and on the second day, the electrode arrangement was reversed (anode right-DLPFC, cathode left-supraorbital). Results After active stimulation, functional network connectivity revealed increased synchrony within the AN components and reduced synchrony in the DMN components. Conclusions Our study reveals a reconfiguration of intrinsic brain activity networks after active tDCS. These effects may help to explain earlier reports of improvements in cognitive functions after anodal-tDCS, where increasing cortical excitability may have facilitated reconfiguration of functional brain networks to address upcoming cognitive demands.
Corpus callosum (CC) is a common target for multiple sclerosis (MS) pathology. We investigated the influence of CC damage on physical disability and cognitive dysfunction using a multimodal approach.
...Twenty-one relapsing-remitting MS patients and 13 healthy controls underwent structural MRI and diffusion tensor of the CC (fractional anisotropy; mean diffusivity, MD; radial diffusivity, RD; axial diffusivity). Interhemisferic transfer of motor inhibition was assessed by recording the ipsilateral silent period (iSP) to transcranial magnetic stimulation. We evaluated cognitive function using the Brief Repeatable Battery and physical disability using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC) z-score.
The iSP latency correlated with physical disability scores (r ranged from 0.596 to 0.657, P values from 0.004 to 0.001), and with results of visual memory (r = -0.645, P = 0.002), processing speed (r = -0.51, P = 0.018) and executive cognitive domain tests (r = -0.452, P = 0.039). The area of the rostrum correlated with the EDSS (r = -0.442, P = 0.045). MD and RD correlated with cognitive performance, mainly with results of visual and verbal memory tests (r ranged from -0.446 to -0.546, P values from 0.048 to 0.011). The iSP latency correlated with CC area (r = -0.345, P = 0.049), volume (r = -0.401, P = 0.002), MD (r = 0.404, P = 0.002) and RD (r = 0.415, P = 0.016).
We found evidence for structural and microstructural CC abnormalities associated with impairment of motor callosal inhibitory conduction in MS. CC damage may contribute to cognitive dysfunction and in less extent to physical disability likely through a disconnection mechanism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer's disease. During middle age, cognitively healthy APOE-ε4 carriers already show several ...brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail.
We examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics.
Healthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage.
These findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD.
The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of ...decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.
A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging (
Fflutemetamol and
Fflorbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ
, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.
All Centiloid cut-offs fell within the range of 25-35, except for CSF Aβ
that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ
ratios was higher than that of CSF Aβ
. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.
A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.
ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969.
Abstract Background Verbal fluency relies on the coordinated activity between left frontal and temporal areas. Patients with Parkinson’s disease (PD) present phonemic and semantic fluency deficits. ...Recent studies suggest that transcranial direct current stimulation (tDCS) enhances adaptative patterns of brain activity between functionally connected areas. Objective The aim of this study was to assess the differences in the effects induced by tDCS applied to frontal and temporo-parietal areas on phonemic and semantic fluency functional networks in patients with PD. Method Sixteen patients were randomized to receive tDCS to left dorsolateral prefrontal cortex (DLPFC) and left temporo-parietal cortex (TPC) in a counterbalanced order. Immediately following stimulation, patients underwent a verbal fluency paradigm inside a fMRI scanner. Changes induced by tDCS in activation and deactivation task-related pattern networks were studied using free-model independent component analyses (ICA). Results Functional connectivity in verbal fluency and deactivation task-related networks was significantly more enhanced by tDCS to DLPFC than to TPC. In addition, DLPFC tDCS increased performance on the phonemic fluency task, after adjusting for baseline phonemic performance. Conclusions These findings provide evidence that tDCS to specific brain regions induces changes in large scale functional networks that underlay behavioural effects, and suggest that tDCS might be useful to enhance phonemic fluency in PD.
Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to ...psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles.
We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects.
Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders.
The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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