Gerard R. Ridgway

Background: Previous investigations into neurodegenerative diseases demonstrated the utility of cortical diffusivity metrics in assessing microstructural changes. Objective: The objective of this study was to explore cortical diffusivity metrics in genetic Parkinson's disease (PD) with glucocerebrosidase 1 (GBA1) and Leucine‐rich repeat kinase 2 (LRRK2) mutations, encompassing both nonmanifest carriers (NMCs) and manifest PD, and healthy control subjects (HCs). Methods: T1‐structural and diffusion magnetic resonance imaging (MRI) scans were analyzed to calculate diffusion metrics related to cortical columnar structure (angle between the radial minicolumnar axis and the principal diffusion direction [AngleR], parallel diffusivity [ParlPD], perpendicular diffusivity of multiple components [PerpPD ⁺ ]) and cortical mean diffusivity for 143 participants (60 HCs, 19 NMC GBA1, 30 NMC LRRK2, 11 PD GBA1, and 23 PD LRRK2) from the Parkinson's Progression Markers Initiative (PPMI). The first available time point including both T1‐weighted and diffusion MRI acquisitions was used for each participant. Whole‐brain, regional, and functional hierarchy macroregional values were used to investigate group differences. Results are reported after multiple comparison correction. Results: Grouped together, results indicated significantly lower ParlPD values in manifest PD compared with the NMC group in whole‐brain analysis. Regional analyses showed a progressive reduction in cortical ParlPD across the genetic groups, primarily in mesocortex (Braak stage 4) for NMC cases, extending to neocortex (Braak stage 5) for manifest genetic PD. Subgroup analyses demonstrated a more pronounced pattern of cortical alterations in subjects with GBA1 mutations compared with patients with LRRK2 mutations. Conclusions: Cortical diffusivity metrics effectively capture cortical architectural changes across clinical stages of genetic PD, supporting their use as microstructural markers of neurodegeneration in PD. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND: This study evaluates the capability of cortical microstructural measures from diffusion magnetic resonance imaging (MRI) to predict progression from mild cognitive impairment (MCI) to dementia, compared to commonly used macrostructural measures. Identification of high‐risk individuals can support both clinical practice and trials.METHODS: Structural and diffusion MRI scans of 826 participants from the National Alzheimer's Coordinating Center (NACC) were analyzed to extract macrostructural measures and three minicolumn‐related diffusivity metrics: AngleR, PerpPD⁺, and ParlPD. Kaplan–Meier survival analysis was used to investigate time to progression to dementia, with participants stratified by biomarker metrics.RESULTS: Cortical diffusivity (PerpPD⁺ in medial–temporal and connected regions) outperformed hippocampal volume, cortical volume, and cortical thickness in Kaplan–Meier survival analysis, predicting faster conversion to dementia.DISCUSSION: Cortical microstructural measures from diffusion MRI provide powerful biomarkers for predicting progression from MCI to dementia, offering enhanced prognostic capabilities that could support earlier intervention strategies in clinical practice and improve the power of clinical trials.Highlights: Cortical minicolumn‐related diffusivity metrics measure neurodegeneration. We compare the predictive value of magnetic resonance imaging (MRI) measures for mild cognitive impairment to dementia progression. Microstructural cortical disarray outperforms macrostructural markers. These results support using diffusion MRI biomarkers to identify and monitor at‐risk patients.

Objective: To investigate cortical microstructural measures from diffusion MRI as “neurodegeneration” markers that could improve prognostic accuracy in mild cognitive impairment (MCI).Methods: 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.Results: 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%).Interpretation: 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.

Background: The 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.Method: The study was registered on Oct 5^th 2021 (jRCT1032210367). Scanning took place between Oct 13^th 2021 and June 30^th 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).Result: Of 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⁺ > 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).Conclusion: The 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.

Background: Evidence in support of the amyloid cascade hypothesis for Alzheimer’s disease (AD) suggests that pathological amyloid‐beta (Aβ) is initially associated with synaptic hyperactivity and accumulates in an activity dependent fashion. These findings are corroborated by longitudinal data from cohort studies with Aβ‐PET imaging, wherein Aβ accumulates first in gray matter (GM) cortices associated with the default‐mode network (DMN) before spreading in a semi‐hierarchical pattern to different neocortical regions as the disease progresses (Mattsson et al. 2019). Mapping brain regions most frequently affected by Aβ pathology at different stages of disease may provide a framework for investigation of new drug entities targeting other components of Aβ toxicity using less invasive imaging modalities. The hypothesis here is that indicators of disease specific, tissue‐level treatment effects should be first detectable in brain regions most frequently affected by active pathology.Method: XPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a small, open‐label phase‐1b dose finding study (NCT03943264) in patients with AD. Clinical trial results for patients (n = 9) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met criteria for post‐hoc analysis. Exploratory outcomes included the novel cortical diffusivity measurement PerpPD⁺. PerpPD⁺ represents the diffusion components perpendicular to cortical GM minicolumns, indicates microscopic disruption when increased, and has proven more sensitive than standard volumetrics to changes in indicators of synaptic function, neuroinflammation and neurodegeneration across the AD continuum.Result: Mean MMSE scores at baseline were 23.7 (SD = 2.5) and 15.8 (SD = 7.0) in the low‐dose and high‐dose groups, respectively, indicating varying degrees of severity. Week‐12 results showed decreases in bilateral PerPD⁺ at the whole brain level and in multiple GM cortices documented in the literature with the highest frequency of early (precuneus, isthmus cingulate, posterior cingulate, insula, and lateral and medial orbitofrontal) and late (lingual, pericalcarine, paracentral, precentral, and postcentral) Aβ accumulation (Figures1‐2).Conclusion: Cortical diffusivity measurements related to minicolumnar microstructure may provide an opportunity for noninvasive detection of early, disease specific, tissue‐level target engagement in clinical trials for investigational new drugs in AD.

Background: Previous 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.Method: Three hundred and thirty‐five cognitively normal (MMSE > 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 (p17,317 = 7.065, p = 0.008; PerpPD⁺ F_17,317 = 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.Conclusion: Cortical 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.References: (1) Torso et al. 2022, PMID:36281682(2) Ingala et al. 2021 PMID:33811742

Background: Apolipoprotein 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).Method: Forty‐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 & 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<0.05).Result: The 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.Conclusion: Cortical 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.

Background: Previous 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.Method: Three hundred and thirty‐five cognitively normal (MMSE > 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<0.05/5).Result: The 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.Conclusion: Cortical 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. References: (1) Torso et al. 2022, PMID:36281682 (2) Ingala et al. 2021 PMID:33811742

Background: The 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.Method: The 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).Result: Of 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+ > 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).Conclusion: The 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.