Peak Width Of Skeletonized Mean Diffusivity Research Articles

Evidence of small vessel disease in patients with transient global amnesia based on the peak width of skeletonized mean diffusivity.

The peak width of skeletonized mean diffusivity (PSMD) is a novel marker of small vessel disease. In this study, we aimed to investigate the presence of small vessel disease in patients with transient global amnesia (TGA) using the PSMD. We enrolled 75 patients newly diagnosed with TGA and included 65 age-and sex-matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3T magnetic resonance imaging scanner. We measured the PSMD based on DTI using the FSL program. This measure was compared between patients with TGA and healthy controls. Additionally, we conducted a correlation analysis to explore the relationship between PSMD and clinical factors. A significant difference in the PSMD between patients with TGA and healthy controls was observed. Patients with TGA exhibited higher a PSMD compared to healthy controls (2.297±0.232 vs. 2.188±0.216 ×10-4 mm2/s, p=0.005). Additionally, patients with TGA but without any vascular risk factors, such as diabetes, hypertension or dyslipidemia, also exhibited higher a PSMD compared to healthy controls (2.278±0.253 vs. 2.188±0.216 ×10-4 mm2/s, p=0.036). The PSMD positively correlated with age (r=0.248, p=0.032); however, it was not associated with duration of amnesia. This finding underscores the feasibility of using PSMD as a marker for detecting small vessel diseases in patients with neurological disorders. Furthermore, our study also implies the presence of small vessel disease may be present in patients with TGA. TGA=transient global amnesia; TIA= transient ischemic attack; PSMD= peak width of skeletonized mean diffusivity; DTI= diffusion tensor imaging.

Cognitive impairment mediates the white matter injury load and gait disorders in subcortical ischemic vascular disease.

Gait disorders are common in patients with subcortical ischemic vascular disease (SIVD). We aim to explore the impact of white matter (WM) damage on gait disorders in SIVD. 21 SIVD patients and 20 normal controls (NC) were included in the study. Montreal Cognitive Assessment (MoCA) was used to evaluate general cognition, while Speed-Accuracy Trade-Off (SAT) was used to assess executive function. Gait velocity, cadence, and stride length were measured. Diffusion Tensor Imaging (DTI) data were analyzed using Tract-Based Spatial Statistics (TBSS) and Peak Width of Skeletonized Mean Diffusivity (PSMD). The relationships among WM damage, gait disorders, and cognitive function were examined through mediation analysis. SIVD scored lower than NC in MoCA and SAT tests (P < 0.001). Gait velocity and stride length were decreased in SIVD. SIVD had lower PSMD (P < 0.001). PSMD correlated with gait parameters, which were totally mediated by MoCA and partially mediated by SAT. The fractional anisotropy (FA) and mean diffusivity (MD) of the genu of the corpus callosum (GCC) and body of CC (BCC) were correlated with gait parameters. The FA of the bilateral anterior corona radiata (ACR) was positively correlated with gait parameters, while the MD of the bilateral superior corona radiata (SCR), bilateral superior longitudinal fasciculus (SLF), and left external capsule (EC) were negatively correlated with them (P < 0.05). Gait impairments in SIVD were associated with cognitive deficits. Cognitive impairment mediated the WM damage and gait disorders. The microstructural alterations of CC, SLF, EC, and CR may be related to changes in gait.

Peak width of skeletonized mean diffusivity as a neuroimaging biomarker in first-episode schizophrenia.

Peak width of skeletonized mean diffusivity (PSMD), a fully automated diffusion tensor imaging (DTI) biomarker of white matter (WM) microstructure damage, has been shown to be associated with cognition in various WM pathologies. However, its application in schizophrenic disease remains unexplored. This study aims to investigate PSMD along with other DTI markers in first-episode schizophrenia patients compared to healthy controls (HCs), and explore the correlations between these metrics and clinical characteristics. A total of 56 first-episode drug-naive schizophrenia patients and 64 HCs were recruited for this study. Participants underwent structural imaging and DTI, followed by comprehensive clinical assessments, including the Positive and Negative Syndrome Scale (PANSS) for patients and cognitive function tests for all participants. We calculated PSMD, peak width of skeletonized fractional anisotropy (PSFA), axial diffusivity (PSAD), radial diffusivity (PSRD) values, skeletonized average mean diffusivity (MD), average fractional anisotropy (FA), average axial diffusivity (AD), and average radial diffusivity (RD) values as well as structural network global topological parameters, and examined between-group differences in these WM metrics. Furthermore, we investigated associations between abnormal metrics and clinical characteristics. Compared to HCs, patients exhibited significantly increased PSMD values (t = 2.467, p = 0.015), decreased global efficiency (Z = -2.188, p = 0.029), and increased normalized characteristic path length (lambda) (t = 2.270, p = 0.025). No significant differences were observed between the groups in the remaining metrics, including PSFA, PSAD, PSRD, average MD, FA, AD, RD, local efficiency, normalized cluster coefficient, small-worldness, assortativity, modularity, or hierarchy (p > 0.05). After adjusting for relevant variables, both PSMD and lambda values exhibited a significant negative correlation with reasoning and problem-solving scores (PSMD: r = -0.409, p = 0.038; lambda: r = -0.520, p = 0.006). No statistically significant correlations were observed between each PANSS score and the aforementioned metrics in the patient group (p > 0.05). Multivariate linear regression analysis revealed that increased PSMD (β = -0.426, t = -2.260, p = 0.034) and increased lambda (β = -0.490, t = -2.994, p = 0.007) were independently associated with decreased reasoning and problem-solving scores respectively ( = 0.295, F = 2.951, p = 0.029). But these significant correlations did not withstand FDR correction (p_FDR > 0.05). PSMD can be considered as a valuable neuroimaging biomarker that complements conventional diffusion measurements for investigating abnormalities in WM microstructural integrity and cognitive functions in schizophrenia.

Alterations in the Glymphatic System and Association with Brain Structure and Cognitive Function in Moyamoya Disease.

The glymphatic system is crucial for clearing metabolic waste from the brain, maintaining neural health and cognitive function. This study explores the glymphatic system's role in Moyamoya disease (MMD), characterized by progressive cerebral artery stenosis and brain structural lesions. We assessed 33 MMD patients and 21 healthy controls using diffusion tensor imaging along the perivascular space (DTI-ALPS) and global cortical gray matter-cerebrospinal fluid (CSF) coupling indices (gBOLD-CSF), which are indirect measurements of the glymphatic system. Cerebral perfusion in patients was evaluated via computed tomography perfusion imaging. We also measured the peak width of skeletonized mean diffusivity (PSMD), white matter hyperintensity (WMH) burden, and cognitive function. MMD patients exhibited lower ALPS and gBOLD-CSF coupling indices compared to controls (P < 0.01), indicating disrupted glymphatic function. Significant cognitive impairment was also observed in MMD patients (P < 0.01). ALPS indices varied with cerebral perfusion stages, being higher in earlier ischemic stages (P < 0.05). Analysis of brain structure showed increased CSF volume, PSMD index, and higher WMH burden in MMD patients (P < 0.01). The ALPS index positively correlated with white matter volume and cognitive scores, and negatively correlated with CSF volume, PSMD, and WMH burden (P < 0.05). Mediation analysis revealed the number of periventricular WMH significantly mediated the relationship between glymphatic dysfunction and cognitive impairment. In summary, MMD patients exhibit significant glymphatic system impairments, associated with brain structural changes and cognitive deficits.

Associations between white and grey matter damage and gait impairment in cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is associated with white matter damage and neurodegeneration. Gait is impaired in CAA; however, the neural basis of this impairment is unclear. Research questionAre gait impairments in patients with CAA associated with altered cerebral white matter diffusivity and/or atrophy of cortical and subcortical grey matter. MethodsParticipants with CAA (n=29), Alzheimer’s disease (AD; n=16), and normal controls (n=47) were included. Gait was assessed using a 6 m walkway with parameters categorized into rhythm, pace, postural control, and variability domains. The dual-task cost (DTC) of gait speed was calculated for counting backwards, animal fluency, and serial sevens tasks. Whole-brain white matter disruption was quantified using the peak width of skeletonized mean diffusivity (PSMD), and thickness and volume of select cortical, subcortical, and cerebellar regions were quantified using FreeSurfer. ResultsIn CAA participants, associations were found between PSMD and pace (standardized parameter estimate (β), 95 % confidence interval (CI): 0.17, 0.03–0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95 % CI: −5.7 %/SD, −0.24 to −11.23). Across all groups, including CAA, associations were found between PSMD and pace, variability, counting backwards DTC, and animal fluency DTC; between frontal cortical thickness and pace, counting backwards DTC, and animal fluency DTC; between cortical regions affected by AD (inferior parietal cortex, inferior and middle temporal gyrus) and counting backwards DTC; and between thalamus volume and postural control. SignificanceReduced white matter structural integrity and grey matter loss is associated with poor overall gait performance in CAA, AD, and normal controls.

Assessment the Impact of IDH Mutation Status on MRI Assessments of White Matter Integrity in Glioma Patients: Insights From Peak Width of Skeletonized Mean Diffusivity and Free Water Metrics.

Gliomas are highly invasive brain tumors that evade accurate geographic assessment by conventional MRI due to microscopic invasion along white matter (WM) tracts. Advanced diffusion MRI techniques are needed to assess occult WM involvement. To evaluate peak width of skeletonized mean diffusivity (PSMD) and peak width of skeletonized free water (PSFW), and axonal water fraction (AWF) for assessing glioma-induced alterations in normal-appearing WM and their relationship with isocitrate dehydrogenase 1 (IDH1) mutation. Retrospective. One hundred five glioma patients (46 ± 13 years), 53 healthy controls (HCs) (46 ± 9 years). 3.0 T, T1WI, T1-CE, T2WI, T2FLAIR, and DKI. PSMD and PSFW were compared between lesion and contralateral sides in glioma patients and between patients and HCs. The associations between these metrics and clinical variables, including IDH1 mutation, was assessed. Corpus callosum (CC) injury, quantified by the AWF, was evaluated for its mediated effect of IDH1 mutation on contralesional PSMD and PSFW. Paired-t tests, ANCOVA, univariate and multivariate linear regression, and mediation analysis with significance set at P < 0.05. Contralateral PSMD and PSFW were significantly higher in left-sided gliomas (PSMD: 0.206 ± 0.027 vs. 0.193 ± 0.023; PSFW: 0.119 ± 0.019 vs. 0.106 ± 0.020) than in HCs, with similar increases in right-sided gliomas (PSMD: 0.219 ± 0.036 vs. 0.195 ± 0.023; PSFW: 0.129 ± 0.031 vs. 0.109 ± 0.020). IDH1 wild-type gliomas were associated with higher contralateral PSMD and PSFW (β = -0.302 and -0.412). AWF of CC mediated the impact of IDH1 mutations on contralesional PSMD and PSFW (mediated proportion: 42.7% and 53.7%). PSMD and PSFW are effective biomarkers for assessing WM integrity in gliomas, significantly associated with IDH1 mutation status. AWF of CC mediates the relationship between IDH1 mutation and contralesional PSMD and PSFW. 4 TECHNICAL EFFICACY: Stage 2.

Microstructural white matter damage on MRI is associated with disease severity in Dutch-type cerebral amyloid angiopathy.

Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77-9.50]mm2/s × 10-4) compared with presymptomatic mutation-carriers (2.62 [1.96-3.43]mm2/s × 10-4) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16-0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08-0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22-0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13-0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = -0.42 [-0.69-0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA.

Macro- and microvascular contributions to cerebral structural alterations in patients with asymptomatic carotid artery stenosis

Atherosclerosis can underly internal carotid artery stenosis (ICAS), a major risk factor for ischemic stroke, as well as small vessel disease (SVD). This study aimed to investigate hemodynamics and structural alterations associated with SVD in ICAS patients. 28 patients with unilateral asymptomatic ICAS and 30 age-matched controls underwent structural (T1-/T2-weighted and diffusion tensor imaging [DTI]) and hemodynamic (pseudo-continuous arterial spin labeling and dynamic susceptibility contrast) magnetic resonance imaging. SVD-related alterations were assessed using free water (FW), FW-corrected DTI, and peak-width of skeletonized mean diffusivity (PSMD). Furthermore, cortical thickness, cerebral blood flow (CBF), and capillary transit time heterogeneity (CTH) were analyzed. Ipsilateral to the stenosis, cortical thickness was significantly decreased in the posterior dorsal cingulate cortex (p = 0.024) and temporal pole (p = 0.028). ICAS patients exhibited elevated PSMD (p = 0.005), FW (p < 0.001), and contralateral alterations in FW-corrected DTI metrics. We found significantly lateralized CBF (p = 0.011) and a tendency for lateralized CTH (p = 0.067) in the white matter (WM) related to ICAS. Elevated PSMD and FW may indicate a link between SVD and WM changes. Contralateral alterations were seen in FW-corrected DTI, whereas hemodynamic and cortical changes were mainly ipsilateral, suggesting SVD might influence global brain changes concurrent with ICAS-related hemodynamic alterations.

Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.

Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA. Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers. One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]). These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.

White matter integrity in hospitalized COVID-19 patients is not associated with short- and long-term clinical outcomes.

SARS-CoV-2 infection is associated with a decline in functional outcomes; many patients experience persistent symptoms, while the underlying pathophysiology remains unclear. This study investigated white matter (WM) integrity on brain MRI in hospitalized COVID-19 patients and its associations with clinical outcomes, including long COVID. We included hospitalized COVID-19 patients and controls from CORONavirus and Ischemic Stroke (CORONIS), an observational cohort study, who underwent MRI-DWI imaging at baseline shortly after discharge (<3 months after positive PCR) and 3 months after baseline scanning. We assessed WM integrity using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) and performed comparisons between groups and within patients. Clinical assessment was conducted at 3 and 12 months with functional outcomes such as modified Rankin Scale (mRS), Post-COVID-19 Functional Status scale (PCFS), Visual Analogue Scale (VAS), and long COVID, cognitive assessment was conducted by the Modified Telephone Interview for Cognitive Status (TICS-M), and the Hospital Anxiety and Depression Scale (HADS) was used to assess mood disorder. Associations between WM integrity and clinical outcomes were evaluated using logistic regression and linear regression. A total of 49 patients (mean age 59.5 years) showed higher overall peak width of skeletonized mean diffusivity (PSMD) (p = 0.030) and lower neurite density index (NDI) in several WM regions compared with 25 controls at the baseline (p < 0.05; FWE-corrected) but did not remain statistically significant after adjusting for WM hyperintensities. Orientation dispersion index (ODI) increased after 3-month follow-up in several WM regions within patients (p < 0.05), which remained significant after correction for changes in WMH volume. Patients exhibited worse clinical outcomes compared with controls. Low NDI at baseline was associated with worse performance on the Post-COVID-19 Functional Status scale after 12 months (p = 0.018). After adjusting for WMH, hospitalized COVID-19 patients no longer exhibited lower WM integrity compared with controls. WM integrity was generally not associated with clinical assessments as measured shortly after discharge, suggesting that factors other than underlying WM integrity play a role in worse clinical outcomes or long COVID.

White matter injury mediates the effects of PS1 mutation position on clinical measures in late disease stage

AbstractBackgroundClinical presentation of dominantly inherited Alzheimer disease (DIAD) varies across individuals with Presenilin‐1 (PS1) pathogenic mutations. Previous findings suggest that individuals with a PS1 mutation after codon 200 have more small vessel disease (SVD) pathology (Mann et al., 2001; Ryan et al., 2015). We investigated the effect of mutation position on clinical measures, including indirect effects via SVD as estimated by imaging markers of white matter injury.MethodWe evaluated 393 individuals with DIAD family history of PS1 mutations who underwent clinical and imaging assessments from the DIAN study. Among them, 245 carried a mutation before (Pre‐200MC, n = 83) or after codon‐200 (Post‐200MC, n = 162) and the remaining were non‐carriers (NC, n = 148). We assessed clinical disease stage with the Clinical Dementia Rating® Sum of Boxes (CDR®‐SB) scale and the estimated years to symptoms onset (EYO). White matter injury metrics included periventricular white matter hyperintensity (PVWMH) volumes from T2‐FLAIR and the peak width of skeletonized mean diffusivity (PSMD) from DTI (Shirzadi et al., 2022). Accounting for age of onset, sex, education, and APOE‐ɛ4 status, linear mixed‐effects models evaluated mutation position by EYO effect on SVD and on dementia in all participants. Further mediation analysis evaluated these effects within the carrier groups. Missing values were imputed using random forest algorithm.ResultPost‐200MC had more white matter injury with advanced EYO compared to Pre‐200MC (estimatesPVWMH = 65.3±31.8, P‐value&lt;.05, estimatesPSMD = 0.01±0.003, P‐value&lt;.0005) and to non‐carriers (estimatesPVWMH = 61.5±27.4, P‐value&lt;.05, estimatesPSMD = 0.01±0.003, P‐value&lt;.0005; Figure 1A). Post‐200MC presented higher CDR‐SB scores with advanced EYO compared to Pre‐200MC (estimatesCDR‐SB = 0.08±0.03, P‐value&lt;.005) and to non‐carriers (estimatesCDR‐SB = 0.19±0.02, P‐value&lt;.0001; Figure 1B). When EYO&gt;0, the effects of mutation position on CDR‐SB were significantly mediated by PVWMH (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.06[0.;0.14], P‐value&lt;.05) or PSMD (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.2[0.05;0.37], P‐value&lt;.05; Table1).ConclusionThese findings give further insights on how mutation position within the PS1 gene influences clinical disease presentation in DIAD. This characterization may inform future clinical trials in this population as the presence of small vessel disease contributes to a more severe disease course, which may influence treatment outcome and decisions. Funding: AARFD‐20‐681815; U19AG032438.

Clinical Manifestations.

Education level is a well-recognized co-factor for cognitive performance and a potential confounder in the application of cognitive evaluations in diverse populations. The Montreal Cognitive Assessment (MoCA) is a widely utilized screening tool for Mild Cognitive Impairment (MCI) composed of 6 domains of cognition: Executive Function (EFC), Attention and Concentration (AC), Language (LANG), Visuospatial (VIS), Memory (MEM), and Orientation (ORIEN). Education is currently accounted for globally by adding 1 point to the total MoCA score. This study considers the impact of education level on a domain-specific scoring of the MoCA. We utilized longitudinal subject level data from one site within the MarkVCID Consortium (UCSF) composed of 578 subjects (59.5% female; 82.9% white), mean age 71.5 (+/- 8.7). Mean educational level was 15.3 (+/-4.7) years. Within the cohort, 37 subjects lacked educational level and were omitted (final n = 541). Multivariate linear regression models were used to relate educational level with total and domain specific MoCA score performance at baseline while controlling for the influence of age, sex, and recognized MarkVCID biomarkers that impact cognitive performance including white matter hyperintensity (logWMH), fractional anisotropy (FA), free water (FW), and peak width of skeletonized mean diffusivity (PSMD). An age-, sex-adjusted model replicated a significant association of education level with MoCA total score (p<0.001, b = .336). Among the MoCA domains, EFC was most affected by education level (p<.001, b = .412), followed by AC (p<.001, b = .352). Other MoCA domains were not significantly associated with educational level. Several MoCA domains, namely MEM and ORIEN, showed an association with MarkVCID biomarkers including WMH and FW (p-values <.001). In regression models controlled for MarkVCID imaging biomarkers, educational level remained significantly associated with total and domain-specific MoCA performance. Education does not equally contribute to all cognitive domains assessed by the MoCA, mostly affecting EFC and AC. These findings suggest that considering education level in a domain-specific manner could provide a more accurate interpretation of the cognitive impairment.

Systemic vascular risk, white matter injury, and relative cerebral blood flow independently contribute to cognitive decline beyond amyloid and tau burden

AbstractBackgroundAge, systemic vascular risk factors, white matter injury, cerebral blood flow, amyloid, and tau burden are well‐established contributors to late‐life cognitive decline. Given the strong relationship among these measures, we proposed a model to extract latent factors and isolate domain‐specific measures that underlie cognitive decline in preclinical AD.MethodData were available for 166 cognitively unimpaired older adults from Harvard Aging Brain Study (Table1). We used the following measures: 1) cortical amyloid burden from PiB‐PET; 2) inferior temporal cortex FTP‐PET; 3) relative cerebral blood flow (R1) from dynamically‐acquired PiB‐PET; 4) white matter hyperintensities (WMH) from FLAIR‐MRI; 5) Peak width of skeletonized mean diffusivity (PSMD) from DTI‐MRI; 6) gray matter volume (GMV) from MPRAGE‐MRI; 7) Framingham Heart Study cardiovascular disease risk (CVD); 8) Preclinical Alzheimer Cognitive Composite‐5 (PACC). We extracted slopes using linear mixed effect models for longitudinal PACC decline and GMV atrophy (follow‐up = 7.4±2.8 years). The remaining data were obtained from baseline. We used exploratory factor analysis (varimax rotations) to extract orthogonal factors. These factors were used in a regression model to explain PACC decline. We next examined whether GMV atrophy acts as a mediator of factors and PACC decline. Subsequently, we investigated whether factors interact to further explain PACC decline.ResultsOriginal variables were highly interrelated (Figure1A) and correlated with PACC decline (Figure1B). Scree test showed 6 factors were sufficient (cumulative variance:96%, Figure2A). All factors except Factor5 (age) independently explained PACC decline (Figure2B, r2 = 0.44). Including GMV atrophy removed effect of Factor1 (white matter injury, Figure2B, r2 = 0.51). Factor3 (amyloid) interacted with Factor1 and Factor4 (tau) in explaining PACC decline (Figure2C, r2 = 0.58).ConclusionLatent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow (but not age) independently explain cognitive decline beyond amyloid and tau burden in this preclinical AD cohort. GMV atrophy mediates these associations with the strongest effect on white matter injury suggesting a strong link between white matter injury and neurodegeneration. These results suggest that current markers of cerebrovascular injury contribute to cognitive decline beyond systemic vascular risk (CVD), amyloid, and tau burden. The mechanism by which systemic vascular risk impacts cognition requires further explication.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Cerebral small vessel disease burden is associated with decreased abundance of gut Barnesiella intestinihominis bacterium in the Framingham Heart Study

A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer's disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance of Pseudobutyrivibrio and Ruminococcus genera was associated with lower WMH and PSMD (p values < 0.001), as well as better executive function (p values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacterium Barnesiella intestinihominis was strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses using PICRUSt implicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and β-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.

Distinct cerebral small vessel disease impairment in early-and late-onset Alzheimer's disease.

This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. Prospective. Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). 3-T, single-shot echo-planar imaging sequence. Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (β = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (β = 5.67, 95% CI 4.56, 6.97), executive function (β = 2.34, 95% CI 1.49, 3.20), and PSMD (β = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. 2 TECHNICAL EFFICACY: Stage 2.

Association between periodontal disease and microstructural brain alterations in the Hamburg City Health Study.

The aim of the PAROBRAIN study was to examine the association of periodontal health with microstructural white matter integrity and cerebral small vessel disease (CSVD) in the Hamburg City Health Study, a large population-based cohort with dental examination and brain magnetic resonance imaging (MRI). Periodontal health was determined by measuring clinical attachment loss (CAL) and plaque index. Additionally, the decayed/missing/filled teeth (DMFT) index was quantified. 3D-FLAIR and 3D-T1-weighted images were used for white matter hyperintensity (WMH) segmentation. Diffusion-weighted MRI was used to quantify peak width of skeletonized mean diffusivity (PSMD). Data from 2030 participants were included in the analysis. Median age was 65 years, with 43% female participants. After adjusting for age and sex, an increase in WMH load was significantly associated with more CAL, higher plaque index and higher DMFT index. PSMD was significantly associated with the plaque index and DMFT. Additional adjustment for education and cardiovascular risk factors revealed a significant association of PSMD with plaque index (p < .001) and DMFT (p < .01), whereas effects of WMH load were attenuated (p > .05). These findings suggest an adverse effect of periodontal health on CSVD and white matter integrity. Further research is necessary to examine whether early treatment of periodontal disease can prevent microstructural brain damage.

White Matter and Gray Matter Changes Related to Cognition in Community populations (P12-6.008)

<h3>Objective:</h3> To investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. <h3>Background:</h3> Further studies in associations of cortical and subcortical changes with cognitive function would better explain the pathology of cognitive impairment. <h3>Design/Methods:</h3> A cross-sectional analysis was performed based on 995 subjects (aged 56.8±9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. <h3>Results:</h3> Global mean FA and MD were associated with VFT performances (FA, β=0.119, p&lt;0.001; MD, β=−0.128, p&lt;0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics, disrupted white matter integrity was related to cognitive impairment mainly in visuomotor processing speed and executive function (TMT-A and VFT), rather than short-term memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex and left central sulcus were positively associated with MMSE and MoCA scores. These associations were independent of the connecting white matter tract. <h3>Conclusions:</h3> Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract. <b>Disclosure:</b> Mrs. Li has nothing to disclose. Jing Yuan has nothing to disclose. Fei Han has nothing to disclose. Lixin Zhou has nothing to disclose. Jun Ni has nothing to disclose. Ming Yao has nothing to disclose. Shuyang Zhang has nothing to disclose. Zhengyu Jin has nothing to disclose. Liying Cui has nothing to disclose. Feifei Zhai has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Peak width of skeletonized mean diffusivity and cognitive performance in cerebral amyloid angiopathy.

Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA. Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained. The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) (p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10-4 mm2/s] compared to HCs [(3.28 ± 0.51) × 10-4 mm2/s] (p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs (ß = 0.45, 95% CI 0.13-0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed (p < 0.001), executive functioning (p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain. Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice.