Cortical Microstructural Changes Research Articles

Early Cortical Microstructural Changes in Aging Are Linked to Vulnerability to Alzheimer’s Disease Pathology

BackgroundEarly identification of Alzheimer’s disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess neurodegeneration in AD. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in nonclinical populations, who are precisely the target for early risk identification. MethodsIn 194 adults, we calculated magnetic resonance imaging–derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5 to 6 years (mean age: time 1 = 61.82 years; time 2 = 67.48 years). Episodic memory was assessed using 3 well-established tests. We obtained positron emission tomography–derived maps of AD pathology deposition (amyloid-β, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps. ResultsSpatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r = −0.31, p < .05), whereas microstructural changes resembled the patterns of tau deposition in AD (r = 0.39, p = .015). Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β = 0.21, p = .036). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps < .05). ConclusionsPatterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.

Assessment of Gray Matter Microstructural Alterations in Alzheimer's Disease by Free Water Imaging.

Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

Cortical Macro- and Microstructural Changes in Parkinson's Disease with Probable Rapid Eye Movement Sleep Behavior Disorder.

Evidence regarding cortical atrophy patterns in Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-pRBD) remains scarce. Cortical mean diffusivity (cMD), as a novel imaging biomarker highly sensitive to detecting cortical microstructural changes in different neurodegenerative diseases, has not been investigated in PD-pRBD yet. The aim was to investigate cMD as a sensitive measure to identify subtle cortical microstructural changes in PD-pRBD and its relationship with cortical thickness (CTh). Twenty-two PD-pRBD, 31 PD without probable RBD (PD-nonpRBD), and 28 healthy controls (HC) were assessed using 3D T1-weighted and diffusion-weighted magnetic resonance imaging on a 3-T scanner and neuropsychological testing. Measures of cortical brain changes were obtained through cMD and CTh. Two-class group comparisons of a general linear model were performed (P < 0.05). Cohen's d effect size for both approaches was computed. PD-pRBD patients showed higher cMD than PD-nonpRBD patients in the left superior temporal, superior frontal, and precentral gyri, precuneus cortex, as well as in the right middle frontal and postcentral gyri and paracentral lobule (d > 0.8), whereas CTh did not detect significant differences. PD-pRBD patients also showed increased bilateral posterior cMD in comparison with HCs (d > 0.8). These results partially overlapped with CTh results (0.5 < d < 0.8). PD-nonpRBD patients showed no differences in cMD when compared with HCs but showed cortical thinning in the left fusiform gyrus and lateral occipital cortex bilaterally (d > 0.5). cMD may be more sensitive than CTh displaying significant cortico-structural differences between PD subgroups, indicating this imaging biomarker's utility in studying early cortical changes in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diffusion weighted magnetic resonance spectroscopy revealed neuronal specific microstructural alterations in Alzheimer's disease.

In Alzheimer's disease, reconfiguration and deterioration of tissue microstructure occur before substantial degeneration become evident. We explored the diffusion properties of both water, a ubiquitous marker measured by diffusion MRI, and N-acetyl-aspartate, a neuronal metabolite probed by diffusion-weighted magnetic resonance spectroscopy, for investigating cortical microstructural changes downstream of Alzheimer's disease pathology. To this aim, 50 participants from the Swedish BioFINDER-2 study were scanned on both 7 and 3 T MRI systems. We found that in cognitively impaired participants with evidence of both abnormal amyloid-beta (CSF amyloid-beta42/40) and tau accumulation (tau-PET), the N-acetyl-aspartate diffusion rate was significantly lower than in cognitively unimpaired participants (P < 0.05). This supports the hypothesis that intraneuronal tau accumulation hinders diffusion in the neuronal cytosol. Conversely, water diffusivity was higher in cognitively impaired participants (P < 0.001) and was positively associated with the concentration of myo-inositol, a preferentially astrocytic metabolite (P < 0.001), suggesting that water diffusion is sensitive to alterations in the extracellular space and in glia. In conclusion, measuring the diffusion properties of both water and N-acetyl-aspartate provides rich information on the cortical microstructure in Alzheimer's disease, and can be used to develop new sensitive and specific markers to microstructural changes occurring during the disease course.

Diffusion MRI tracks cortical microstructural changes during the early stages of Alzheimer's disease.

There is increased interest in developing markers reflecting microstructural changes that could serve as outcome measures in clinical trials. This is especially important after unexpected results in trials evaluating disease-modifying therapies targeting amyloid-β (Aβ), where morphological metrics from MRI showed increased volume loss despite promising clinical treatment effects. In this study, changes over time in cortical mean diffusivity, derived using diffusion tensor imaging, were investigated in a large cohort (n = 424) of non-demented participants from the Swedish BioFINDER study. Participants were stratified following the Aβ/tau (AT) framework. The results revealed a widespread increase in mean diffusivity over time, including both temporal and parietal cortical regions, in Aβ-positive but still tau-negative individuals. These increases were steeper in Aβ-positive and tau-positive individuals and robust to the inclusion of cortical thickness in the model. A steeper increase in mean diffusivity was also associated with both changes over time in fluid markers reflecting astrocytic activity (i.e. plasma level of glial fibrillary acidic protein and CSF levels of YKL-40) and worsening of cognitive performance (all P < 0.01). By tracking cortical microstructural changes over time and possibly reflecting variations related to the astrocytic response, cortical mean diffusivity emerges as a promising marker for tracking treatments-induced microstructural changes in clinical trials.

Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aß‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.MethodMean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aß‐negative/tau‐negative, Aß‐positive/tau‐negative, and Aß‐positive/tau‐positive based on CSF levels of Aß42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.ResultAnalyses of MD revealed widespread differences in rates of change already between Aß‐negative/tau‐negative and Aß‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aß accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aß early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps&lt;0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aß‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.ConclusionMean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.

Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aβ‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.MethodsMean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on CSF levels of Aβ42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.ResultsAnalyses of MD revealed widespread differences in rates of change already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aβ early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps&lt;0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aβ‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.ConclusionMean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.

Apoe ε4 exacerbates age‐dependent decline of cortical microstructural changes in cognitively normal midlife individuals: the PREVENT‐Dementia and ALFA studies

AbstractBackgroundThe APOE e4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease (AD). However, the mechanisms by which APOE e4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE e4 and its interactions with age and education on cortical microstructure in cognitively normal individuals.MethodData from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE e4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE e4, and the (b) interactions of APOE e4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models.ResultAPOE e4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE e4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE &lt; 0.05), indicating steeper age‐dependent ODI changes in APOE e4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE e4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE e4 x age x education; steeper age‐related ODI declines among APOE e4 carriers with lower years of education (Figure 3, TFCE p FWE &lt; 0.05). There were no significant main effects or interactions of APOE e4 on cortical thickness.ConclusionWe found novel evidence that APOE e4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE e4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE e4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD.

APOE4 affects cortical microstructural alterations in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort

AbstractBackgroundApolipoprotein E e4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer’s disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC).MethodForty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer’s Coordinating Center (NACC; n = 34) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks. Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche &amp; Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682). Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR&lt;0.05).ResultThe cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal). Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration.

APOE4 affects cortical microstructural alterations in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort.

AbstractBackgroundApolipoprotein E ε4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer’s disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC).MethodForty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer’s Coordinating Center (NACC; n = 34) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks.Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche &amp; Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682).Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR&lt;0.05).ResultThe cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal).Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration.

Sequencing cortical microstructural changes along the Alzheimer’s disease continuum

AbstractBackgroundMicrostructural abnormalities likely precede macrostructural changes in the Alzheimer’s disease (AD) cascade. Diffusion MRI (dMRI) is sensitive to microstructural properties of brain tissue but few studies have evaluated dMRI measures in cortical gray matter where many early AD histopathological changes occur. Event‐based modeling (EBM) is a data‐driven approach for probabilistically sequencing cross‐sectional biomarkers in the order that they likely become abnormal. Here, we used EBM to examine the sequence of changes in cortical dMRI measures relative to more widely used amyloid, tau, brain volume, and cognitive biomarkers in two independent AD studies.MethodT1w, dMRI, and amyloid‐PET (FBB/FBP) data were analyzed in 461 ADNI3 participants and 188 OASIS3 participants (Figure 1A). Some ADNI3 participants also had tau‐PET (AV‐1451) and CSF pTAU‐181 and Aß1‐42 data. In addition to DTI, novel single‐shell adaptations of multi‐shell models, NODDI‐DTI and MAP‐AMURA, were fit to the dMRI data. 10 mean cortical dMRI measures were extracted using FreeSurfer parcellated T1w‐images (Figure 1B). T1w cortical and hippocampal volumes were also extracted, and all MRI measures harmonized using ComBat. Mean cortical amyloid‐PET SUVRs were converted to centiloids. Associations between each of 17 biomarkers (Figure 1C) and cognitive impairment (CI –MCI+Dementia– vs CN) were tested in ADNI3. Significant biomarkers were included in an ADNI3 EBM to determine event ordering.The EBM was validated in OASIS3 and used to classify clinical diagnosis.ResultAll biomarkers except DTI FA showed significant differences between CN and CI ADNI3 participants (Figure 2A). ADNI3 EBM confirmed existing AD models: CSF amyloid abnormalities preceded PET, followed by CSF pTau, while cognitive and volumetric abnormalities occurred at later stages. Changes in all dMRI biomarkers preceded CSF or PET Tau, cognitive, and volumetric abnormalities (Figure 2B). Estimated disease stages in ADNI3 distinguish dementia from CN with an AUC = 0.96 (10‐fold cross‐validation). OASIS3 disease stages, estimated using ADNI3 biomarker distributions excluding CSF measures and tau‐PET, classified diagnosis with an AUC = 0.85 (Figure 3).ConclusionCortical microstructural measure abnormalities, including greater diffusivity, lower restriction and lower dispersion potentially due to neurite loss and lower dendritic arborization complexity, may precede those detectable with conventional T1w biomarkers.

Sequencing cortical microstructural changes along the Alzheimer’s disease continuum

AbstractBackgroundMicrostructural abnormalities likely precede macrostructural changes in the Alzheimer’s disease (AD) cascade. Diffusion MRI (dMRI) is sensitive to microstructural properties of brain tissue but few studies have evaluated dMRI measures in cortical gray matter where many early AD histopathological changes occur. Event‐based modeling (EBM) is a data‐driven approach for probabilistically sequencing cross‐sectional biomarkers in the order that they likely become abnormal. Here, we used EBM to examine the sequence of changes in cortical dMRI measures relative to more widely used amyloid, tau, brain volume, and cognitive biomarkers in two independent AD studies.MethodT1w, dMRI, and amyloid‐PET (FBB/FBP) data were analyzed in 461 ADNI3 participants and 188 OASIS3 participants (Figure 1A). Some ADNI3 participants also had tau‐PET (AV‐1451) and CSF pTAU‐181 and Aβ1‐42 data. In addition to DTI, novel single‐shell adaptations of multi‐shell models, NODDI‐DTI and MAP‐AMURA, were fit to the dMRI data. 10 mean cortical dMRI measures were extracted using FreeSurfer parcellated T1w‐images (Figure 1B). T1w cortical and hippocampal volumes were also extracted, and all MRI measures harmonized using ComBat. Mean cortical amyloid‐PET SUVRs were converted to centiloids. Associations between each of 17 biomarkers (Figure 1C) and cognitive impairment (CI –MCI+Dementia– vs CN) were tested in ADNI3. Significant biomarkers were included in an ADNI3 EBM to determine event ordering.The EBM was validated in OASIS3 and used to classify clinical diagnosis.ResultAll biomarkers except DTI FA showed significant differences between CN and CI ADNI3 participants (Figure 2A). ADNI3 EBM confirmed existing AD models: CSF amyloid abnormalities preceded PET, followed by CSF pTau, while cognitive and volumetric abnormalities occurred at later stages. Changes in all dMRI biomarkers preceded CSF or PET Tau, cognitive, and volumetric abnormalities (Figure 2B). Estimated disease stages in ADNI3 distinguish dementia from CN with an AUC = 0.96 (10‐fold cross‐validation). OASIS3 disease stages, estimated using ADNI3 biomarker distributions excluding CSF measures and tau‐PET, classified diagnosis with an AUC = 0.85 (Figure 3).ConclusionCortical microstructural measure abnormalities, including greater diffusivity, lower restriction and lower dispersion potentially due to neurite loss and lower dendritic arborization complexity, may precede those detectable with conventional T1w biomarkers.

Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects

AbstractBackgroundPrevious research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.MethodThree hundred and thirty‐five cognitively normal (MMSE &gt; 24) participants with baseline CSF Aß42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aß42‐ (N = 231) or Aß42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM. Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p&lt;0.05/5).ResultThe interaction between Aß42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aß42‐ HIGH compared to Aß42‐ LOW and significantly higher PerpPD+ values in Aß42+ HIGH compared to Aß42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aß42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aß42+ HIGH may indicate the secondary cortical microstructural damage.

Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects

AbstractBackgroundPrevious research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.MethodThree hundred and thirty‐five cognitively normal (MMSE &gt; 24) participants with baseline CSF Aβ42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aβ42‐ (N = 231) or Aβ42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM.Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p&lt;0.05/5).ResultThe interaction between Aβ42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aβ42‐ HIGH compared to Aβ42‐ LOW and significantly higher PerpPD+ values in Aβ42+ HIGH compared to Aβ42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aβ42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aβ42+ HIGH may indicate the secondary cortical microstructural damage.

Changes in Cortical Microstructure of the Human Brain Resulting from Long-Term Motor Learning.

The mechanisms subserving motor skill acquisition and learning in the intact human brain are not fully understood. Previous studies in animals have demonstrated a causal relationship between motor learning and structural rearrangements of synaptic connections, raising the question of whether neurite-specific changes are also observable in humans. Here, we use advanced diffusion magnetic resonance imaging (MRI), sensitive to dendritic and axonal processes, to investigate neuroplasticity in response to long-term motor learning. We recruited healthy male and female human participants (age range 19-29) who learned a challenging dynamic balancing task (DBT) over four consecutive weeks. Diffusion MRI signals were fitted using Neurite Orientation Dispersion and Density Imaging (NODDI), a theory-driven biophysical model of diffusion, yielding measures of tissue volume, neurite density and the organizational complexity of neurites. While NODDI indices were unchanged and reliable during the control period, neurite orientation dispersion increased significantly during the learning period mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor areas. Importantly, reorganization of cortical microstructure during the learning phase predicted concurrent behavioral changes, whereas there was no relationship between microstructural changes during the control phase and learning. Changes in neurite complexity were independent of alterations in tissue density, cortical thickness, and intracortical myelin. Our results are in line with the notion that structural modulation of neurites is a key mechanism supporting complex motor learning in humans.SIGNIFICANCE STATEMENT The structural correlates of motor learning in the human brain are not fully understood. Results from animal studies suggest that synaptic remodeling (e.g., reorganization of dendritic spines) in sensorimotor-related brain areas is a crucial mechanism for the formation of motor memory. Using state-of-the-art diffusion magnetic resonance imaging (MRI), we found a behaviorally relevant increase in the organizational complexity of neocortical microstructure, mainly in primary sensorimotor, prefrontal, premotor, supplementary, and cingulate motor regions, following training of a challenging dynamic balancing task (DBT). Follow-up analyses suggested structural modulation of synapses as a plausible mechanism driving this increase, while colocalized changes in cortical thickness, tissue density, and intracortical myelin could not be detected. These results advance our knowledge about the neurobiological basis of motor learning in humans.

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid

IntroductionNon-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology.Methods122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models.ResultsWe find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants.ConclusionsThe combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer’s Disease-related episodic memory decline, suggesting utility in clinical trials.

The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid‐β and tau pathology and astroglial activation

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ‐related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures.MethodWe applied the mean apparent diffusion propagator model (MAP‐MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐2 cohort. MAP‐MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on Aβ‐ and tau‐PET uptake. Cortical regional values of both MAP‐MRI metrics and CT were compared across groups. Associations between regional values of MAP‐MRI metrics and both Aβ‐ and tau‐PET uptake were also investigated as well as the association between MAP‐MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants).ResultMean square displacement (MSD) from MAP‐MRI revealed widespread microstructural differences already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ‐ and tau‐PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ‐PET, tau‐PET and GFAP were largely independent from macrostructural changes (figures 2‐3).ConclusionMetrics of cortical microstructural alteration derived from MAP‐MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ‐PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti‐Aβ treatments in clinical trials.aging after age 90.

Cortical mean diffusivity is reliable in measuring brain abnormalities in drug-naïve essential tremor patients

ObjectiveEssential tremor (ET) is a common movement disorder, but the pathogenesis is poorly understood. Several associated brain areas were reported with inconsistent results due to heterogeneous populations. It is necessary to analyze a more homogeneous patient group. MethodsWe recruited 25 drug-naïve ET patients and 36 age- and sex-matched controls. All participants were right-handed. ET. ET was defined according to diagnostic criteria of the Consensus Statement of the Movement Disorder Society on Tremor. ET patients were divided into sporadic (SET) and familial ET (FET). We assessed tremor severity in ET. The cortical microstructural changes were compared between ET patients and controls using mean diffusivity (MD) of diffusion tensor imaging, and cortical thickness. The correlation of tremor severity with the cortical MD and thickness were respectively analyzed. ResultsMD values were increased in the insular, precuneus, medial orbitofrontal, posterior, and isthmus cingulate and temporo-occipital areas in ET. In comparison between SET and FET, MD values were higher in the superior and caudal middle frontal, postcentral, and temporo-occipital regions in FET. The cortical thickness of ET patients was more increased in the left lingual gyrus and lower in the right bankssts gyrus. We could not find any correlation of tremor severity with the MD values in ET patients. Still, there was a positive correlation with the cortical thickness of the frontal and parietal areas. ConclusionsOur results support the idea that ET is a disorder that disrupts widespread brain regions and indicates that cortical MD may be more sensitive to measure brain abnormalities than cortical thickness.

Ante mortem imaging of cortical microstructure relates to post mortem locus coeruleus hypopigmentation in autopsy‐confirmed Alzheimer’s disease

AbstractBackgroundSeveral lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer’s disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh).MethodParticipants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe).Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR&lt;0.05).ResultThe more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1).ConclusionTogether, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system.

Ante mortem imaging of cortical microstructure relates to post mortem locus coeruleus hypopigmentation in autopsy‐confirmed Alzheimer’s disease

AbstractBackgroundSeveral lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer’s disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh).MethodParticipants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe).Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR&lt;0.05).ResultThe more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1).ConclusionTogether, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system.