Cortical Mean Diffusivity Research Articles

Unveiling the link between glymphatic function and cortical microstructures in post-traumatic stress disorder

PurposeThe discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. Materials and methodsWe analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aβ PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aβ accumulation, and thickness, accounting for age and APOE ε4 allele variations. ResultsThe cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aβ deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. ConclusionThe study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment.

Spatial and temporal patterns of cortical mean diffusivity in Alzheimer's disease and suspected non-Alzheimer's disease pathophysiology.

The spatial and temporal patterns of cortical mean diffusivity (cMD), as well as its association with Alzheimer's disease (AD) and suspected non-Alzheimer's pathophysiology (SNAP), are not yet fully understood. We compared baseline (n=617) and longitudinal changes (n=421) of cMD, cortical thickness, and gray matter volume and their relations to vascular risk factors, amyloid beta (Aβ), and tau positron emission tomography (PET), and longitudinal cognitive decline in Aβ PET negative and positive older adults. cMD increases were more sensitive to detecting brain structural alterations than cortical thinning and gray matter atrophy. Tau-related cMD increases partially mediated Aβ-related cognitive decline in AD, whereas vascular disease-related increased cMD levels substantially mediated age-related cognitive decline in SNAP. These findings revealed the dynamic changes of microstructural and macrostructural indicators and their associations with AD and SNAP, providing novel insights into understanding upstream and downstream events of cMD in neurodegenerative disease. Cortical mean diffusivity (cMD) was more sensitive to detecting structural changes than macrostructural factors. Tau-related cMD increases partially mediated amyloid beta-related cognitive decline in Alzheimer's disease (AD). White matter hyperintensity-related higher cMD mainly explained the age-related cognitive decline in suspected non-Alzheimer's pathophysiology (SNAP). cMD may assist in tracking earlier neurodegenerative signs in AD and SNAP.

Clinical utility of diffusion MRI-derived measures of cortical microstructure in a real-world memory clinic setting.

To investigate cortical microstructural measures from diffusion MRI as "neurodegeneration" markers that could improve prognostic accuracy in mild cognitive impairment (MCI). The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status. T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD+), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices. A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A-T-. Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A-T- progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A-T- patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%). Results support the clinical utility of cortical microstructure to aid prognosis, especially in A-T- patients. Further work will investigate other complexities of the real-world clinical setting, including A-T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

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 = .038). Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β = 0.22, p = .029). 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.

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.

Neuroanatomical profiles of cognitive phenotypes in patients with primary brain tumors.

Patients with brain tumors demonstrate heterogeneous patterns of cognitive impairment, likely related to multifactorial etiologies and variable tumor-specific factors. Cognitive phenotyping offers a patient-centered approach to parsing heterogeneity by classifying individuals based on patterns of impairment. The aim of this study was to investigate the neuroanatomical patterns associated with each phenotype to gain a better understanding of the mechanisms underlying impairments. Patients with primary brain tumors were recruited for a prospective, observational study. Patients were cognitively phenotyped using latent profile analysis in a prior study, revealing 3 distinct groups: generalized, isolated verbal memory, and minimal impairment. Whole brain cortical thickness (CT), fractional anisotropy, and mean diffusivity (MD) were compared across phenotypes, and associations between imaging metrics and cognitive scores were explored. Neurocognitive, structural MRI, and diffusion MRI data were available for 82 participants at baseline. Compared to the minimal impairment group, the generalized impairment group showed a widespread, bi-hemispheric pattern of decreased CT (P-value range: .004-.049), while the verbal memory impairment group showed decreased CT (P-value range: .006-.049) and increased MD (P-value range: .015-.045) bilaterally in the temporal lobes. In the verbal memory impairment group only, increased parahippocampal MD was associated with lower verbal memory scores (P-values < .01). Cognitive phenotypes in patients with brain tumors showed unique patterns of brain pathology, suggesting different underlying mechanisms of their impairment profiles. These distinct patterns highlight the biological relevance of our phenotyping approach and help to identify areas of structural and microstructural vulnerability that could inform treatment decisions.

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.

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.

An exploratory pilot study on diffusion MRI measurement of cortical microstructural neurodegeneration for the assessment of dementia in a Japanese hospital setting

AbstractBackgroundThe use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer’s disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered.MethodThe study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer’s disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited.Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐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+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022).ResultOf the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1.Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ &gt; 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone.The Cohen’s d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a).ConclusionThe pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted.

An exploratory pilot study on diffusion MRI measurement of cortical microstructural neurodegeneration for the assessment of dementia in a Japanese hospital setting

AbstractBackgroundThe use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer’s disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered.MethodThe study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer’s disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited. Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐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+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022).ResultOf the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1. Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ &gt; 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone. The Cohen’s d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a).ConclusionThe pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted.

In vivo cortical diffusion imaging relates to Alzheimer’s disease neuropathology

BackgroundThere has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology.This study aimed to characterise the associations between the main Alzheimer’s disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated.MethodsForty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the “ABC score” from NIA-AA recommendations).Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated.Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed.ResultsCortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+.LCh was associated with PerpPD+, ParlPD, and MD.Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology.ConclusionsCortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain.Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making.Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.

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.

Atypical forms of Alzheimer's disease: patients not to forget.

The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

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.

Association of Cortical and Subcortical Microstructure With Clinical Progression and Fluid Biomarkers in Patients With Parkinson Disease.

Mean diffusivity (MD) of diffusion MRI (dMRI) has been used to measure cortical and subcortical microstructural properties. This study investigated relationships of cortical and subcortical MD, clinical progression, and fluid biomarkers in Parkinson disease (PD). This longitudinal study using data from the Parkinson's Progression Markers Initiative was collected from April 2011 to July 2022. Clinical symptoms were assessed with Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS) and Montreal Cognitive Assessment (MoCA) scores. Clinical assessments were followed up to 5 years. Linear mixed-effects (LME) models were performed to examine associations of MD and the annual rate of changes in clinical scores. Partial correlation analysis was conducted to examine the associations of MD and fluid biomarker levels. A total of 174 patients with PD (age 61.9 ± 9.7 years, 63% male) with baseline dMRI and at least 2 years of clinical follow-up were included. Results of LME models revealed a significant association between MD values, predominantly in subcortical regions, temporal lobe, occipital lobe, and frontal lobe, and annual rate of changes in clinical scores (UPDRS-Part-I, standardized β > 2.35; UPDRS-Part-II, standardized β > 2.34; postural instability and gait disorder score, standardized β > 2.47; MoCA, standardized β < -2.42; all p < 0.05, false discovery rate [FDR] corrected). In addition, MD was associated with the levels of neurofilament light chain in serum (r > 0.22) and α-synuclein (right putamen r = 0.31), β-amyloid 1-42 (left hippocampus r = -0.30), phosphorylated tau at 181 threonine position (r > 0.26), and total tau (r > 0.23) in CSF at baseline (all p < 0.05, FDR corrected). Furthermore, the β coefficients derived from MD and annual rate of changes in the clinical score recapitulated the spatial distribution of dopamine (DAT, D1, and D2), glutamate (mGluR5 and NMDA), serotonin (5-HT1a and 5-HT2a), cannabinoid (CB1), and γ-amino butyric acid A receptor neurotransmitter receptors/transporters (p < 0.05, FDR corrected) derived from PET scans in the brain of healthy volunteers. In this cohort study, cortical and subcortical MD values at baseline were associated with clinical progression and baseline fluid biomarkers, suggesting that microstructural properties could be useful for stratification of patients with fast clinical progression.

Higher cortical thickness/volume in Alzheimer’s-related regions: protective factor or risk factor?

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer’s disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51–60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

Childhood Disadvantage Moderates Late Midlife Default Mode Network Cortical Microstructure and Visual Memory Association.

Childhood disadvantage is a prominent risk factor for cognitive and brain aging. Childhood disadvantage is associated with poorer episodic memory in late midlife and functional and structural brain abnormalities in the default mode network (DMN). Although age-related changes in DMN are associated with episodic memory declines in older adults, it remains unclear if childhood disadvantage has an enduring impact on this later-life brain-cognition relationship earlier in the aging process. Here, within the DMN, we examined whether its cortical microstructural integrity-an early marker of structural vulnerability that increases the risk for future cognitive decline and neurodegeneration-is associated with episodic memory in adults at ages 56-66, and whether childhood disadvantage moderates this association. Cortical mean diffusivity (MD) obtained from diffusion magnetic resonance imaging was used to measure microstructural integrity in 350 community-dwelling men. We examined both visual and verbal episodic memory in relation to DMN MD and divided participants into disadvantaged and nondisadvantaged groups based on parental education and occupation. Higher DMN MD was associated with poorer visual memory but not verbal memory (β = -0.11, p = .040 vs β = -0.04, p = .535). This association was moderated by childhood disadvantage and was significant only in the disadvantaged group (β = -0.26, p = .002 vs β = -0.00, p = .957). Lower DMN cortical microstructural integrity may reflect visual memory vulnerability in cognitively normal adults earlier in the aging process. Individuals who experienced childhood disadvantage manifested greater vulnerability to cortical microstructure-related visual memory dysfunction than their nondisadvantaged counterparts who exhibited resilience in the face of low cortical microstructural integrity.

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline and language impairments in frontotemporal lobar degeneration

BackgroundCortical and subcortical microstructural modifications are critical to understanding the pathogenic changes in frontotemporal lobar degeneration (FTLD) subtypes. In this study, we investigated cortical and subcortical microstructure underlying cognitive and language impairments across behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant of primary progressive aphasia (nfvPPA) subtypes.MethodsThe current study characterized 170 individuals with 3 T MRI structural and diffusion-weighted imaging sequences as portion of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study: 41 bvFTD, 35 nfvPPA, 34 svPPA, and 60 age-matched cognitively unimpaired controls. To determine the severity of the disease, clinical dementia rating plus national Alzheimer’s coordinating center behavior and language domains sum of boxes scores were used; other clinical measures, including the Boston naming test and verbal fluency test, were also evaluated. We computed surface-based cortical thickness and cortical and subcortical microstructural metrics using tract-based spatial statistics and explored their relationships with clinical and cognitive assessments.ResultsCompared with controls, those with FTLD showed substantial cortical mean diffusivity alterations extending outside the regions with cortical thinning. Tract-based spatial statistics revealed that anomalies in subcortical white matter diffusion were widely distributed across the frontotemporal and parietal areas. Patients with bvFTD, nfvPPA, and svPPA exhibited distinct patterns of cortical and subcortical microstructural abnormalities, which appeared to correlate with disease severity, and separate dimensions of language functions.ConclusionsOur findings imply that cortical and subcortical microstructures may serve as sensitive biomarkers for the investigation of neurodegeneration-associated microstructural alterations in FTLD subtypes.Graphical Flowchart of the study design (see materials and methods for detailed description).

Effects of Brain Maintenance and Cognitive Reserve on Age-Related Decline in Three Cognitive Abilities.

Age-related cognitive changes can be influenced by both brain maintenance (BM), which refers to the relative absence over time of changes in neural resources or neuropathologic changes, and cognitive reserve (CR), which encompasses brain processes that allow for better-than-expected behavioral performance given the degree of life-course-related brain changes. This study evaluated the effects of age, BM, and CR on longitudinal changes over 2 visits, 5 years apart, in 3 cognitive abilities that capture most of age-related variability. Participants included 254 healthy adults aged 20-80 years at recruitment. Potential BM was estimated using whole-brain cortical thickness and white matter mean diffusivity at both visits. Education and intelligence quotient (IQ; estimated with American National Adult Reading Test) were tested as moderating factors for cognitive changes in the 3 cognitive abilities. Consistent with BM-after accounting for age, sex, and baseline performance-individual differences in the preservation of mean diffusivity and cortical thickness were independently associated with relative preservation in the 3 abilities. Consistent with CR-after accounting for age, sex, baseline performance, and structural brain changes-higher IQ, but not education, was associated with reduced 5-year decline in reasoning (β = 0.387, p = .002), and education was associated with reduced decline in speed (β = 0.237, p = .039). These results demonstrate that both CR and BM can moderate cognitive changes in healthy aging and that the 2 mechanisms can make differential contributions to preserved cognition.