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The prevalence of neurodegenerative diseases is increasing as human longevity increases. The objective biomarkers that enable the staging and early diagnosis of neurodegenerative diseases are eagerly anticipated. It has recently become possible to determine pathological changes in the brain without autopsy with the advancement of diffusion magnetic resonance imaging techniques. Diffusion magnetic resonance imaging is a robust tool used to evaluate brain microstructural complexity and integrity, axonal order, density, and myelination via the micron-scale displacement of water molecules diffusing in tissues. Diffusion tensor imaging, a type of diffusion magnetic resonance imaging technique is widely utilized in clinical and research settings; however, it has several limitations. To overcome these limitations, cutting-edge diffusion magnetic resonance imaging techniques, such as diffusional kurtosis imaging, neurite orientation dispersion and density imaging, and free water imaging, have been recently proposed and applied to evaluate the pathology of neurodegenerative diseases. This review focused on the main applications, findings, and future directions of advanced diffusion magnetic resonance imaging techniques in patients with Alzheimer's and Parkinson's diseases, the first and second most common neurodegenerative diseases, respectively.

Although free‐water diffusion reconstruction for diffusion‐weighted imaging (DWI) data can be applied to both single‐shell and multishell data, recent finding in synthetic data suggests that the free‐water indices from single‐shell acquisition should be interpreted with care, as they are heavily influenced by initialization parameters and cannot discriminate between free‐water and mean diffusivity modifications. However, whether using a longer multishell acquisition protocol significantly improve reconstruction for real human MRI data is still an open question. In this study, we compare canonical diffusion tensor imaging (DTI), single‐shell and multishell free‐water imaging (FW) indices derived from a short, clinical compatible diffusion protocol (b = 500 s/mm2, b = 1,000 s/mm2, 32 directions each) on their power to predict brain age. Age was chosen as it is well‐known to be related to widespread modification of the white matter and because brain‐age estimation has recently been found to be relevant to several neurodegenerative diseases. We used a previously developed and validated data‐driven whole‐brain machine learning pipeline to directly compare the precision of brain‐age estimates in a sample of 89 healthy males between 20 and 85 years old. We found that multishell FW outperform DTI indices in estimating brain age and that multishell FW, even when using low (500 ms2) b‐values secondary shell, outperform single‐shell FW. Single‐shell FW led to lower brain‐age estimation accuracy even of canonical DTI indices, suggesting that single‐shell FW indices should be used with caution. For all considered reconstruction algorithms, the most discriminant indices were those measuring free diffusion of water in the white matter. Multishell but not single‐shell free‐water diffusion imaging predicts brain age better than canonical diffusion imaging. Multishell free‐water in isolation performs similarly to more complex models including FA, MD, RD and AD.

Introduction Free‐water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods Seventy‐one participants underwent multi‐shell diffusion MRI, 18F‐THK5351 PET, 11C‐Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) (n = 40) and AD‐spectrum group (AD‐S) (n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results In AD‐S group, there was a significant positive correlation between FW and 18F‐THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18F‐THK5351 and cognitive function in the same regions. Discussion FW imaging could be a biomarker for tau in AD alongside clinical correlations.

INTRODUCTION The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55–86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea‐hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water‐corrected diffusion tensor imaging. RESULTS Higher levels of OSA‐related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION OSA may contribute to fornix damage and memory dysfunction in MCI. Highlights Sleep apnea‐related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

There has been an increasing prevalence of neurodegenerative diseases with the rapid increase in aging societies worldwide. Biomarkers that can be used to detect pathological changes before the development of severe neuronal loss and consequently facilitate early intervention with disease-modifying therapeutic modalities are therefore urgently needed. Diffusion magnetic resonance imaging (MRI) is a promising tool that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, as well as axonal density, order, and myelination, through the utilization of water molecules that are diffused within the tissue, with displacement at the micron scale. Diffusion tensor imaging is the most commonly used diffusion MRI technique to assess the pathophysiology of neurodegenerative diseases. However, diffusion tensor imaging has several limitations, and new technologies, including neurite orientation dispersion and density imaging, diffusion kurtosis imaging, and free-water imaging, have been recently developed as approaches to overcome these constraints. This review provides an overview of these technologies and their potential as biomarkers for the early diagnosis and disease progression of major neurodegenerative diseases.

In this study we explore the spatio‐temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free‐water imaging. Twenty‐seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3–7) received diffusion MRI 3–5 days, 1 month, 3 months, and 12 months after symptom‐onset. Extracellular free‐water and fractional anisotropy of the tissue (FA T ) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free‐water and decreased FA T in the white matter of patients with subcortical stroke (lesion [free‐water/FA T , mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3–5 days, 1 month, 3 months, and 12 months after symptom‐onset]: +41/−34, +111/−37, +208/−26, +251/−18; perilesional tissue [range in %]: +[5–24]/−[0.2–7], +[2–20]/−[3–16], +[5–43]/−[2–16], +[10–110]/−[2–12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free‐water elevations continuously increased over time and peaked after 12 months, FA T decreases were most evident 1 month post‐stroke, gradually returning to baseline values thereafter. Higher perilesional free‐water and higher lesional FA T at baseline were correlated with greater reductions in lesion size (rho = −0.51, p  = .03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio‐temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy.

Background Mixed vascular and neurodegenerative dementia, such as Alzheimer’s disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. Methods We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. Results The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. Conclusions Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

Abstract Background and Hypothesis Excessive saturated or deficient unsaturated fatty acids and white matter microstructural abnormalities are observed before the psychosis onset. Whereas fatty acids variations are implicated in white matter pathology, conventional Diffusion Tensor Imaging has limitations in disentangling their biological relevance. Free-water imaging provides improved biological specificity to white matter microstructure, such as fractional volume of free-water (FW) and tissue-specific fractional anisotropy (FAt). This study aims to investigate the associations between altered proportion of saturated or unsaturated fatty acids and free-water imaging parameters in prodromal psychosis. Study Design We applied free-water imaging and Tract-Based Spatial Statistics to compare FAt and FW between 78 individuals with at-risk mental state (ARMS) and 129 healthy controls. In a subsample with available blood samples (n = 53 and n = 42, respectively), relationships between fatty acid composition of erythrocyte membrane and FAt or FW were examined alongside clinical and cognitive variables. Study Results Compared to the controls, individuals with ARMS exhibited higher relative concentrations of saturated fatty acids as well as lower FAt and higher FW in multiple association and projection fibers. In the ARMS group, elevated proportion of saturated fatty acids was associated with lower FAt and with positive symptoms and impaired verbal fluency. Conclusions The association of saturated fatty acids with FAt in ARMS suggests that fatty acids may influence disrupted white matter microstructure, such as impaired myelin maintenance prior to psychosis onset. Future studies should explore early interventions to mitigate white matter cellular deterioration by optimizing saturated fatty acid levels.

Background Free-water imaging can predict and monitor dopamine system degeneration in patients with Parkinson’s disease (PD). However, brain cholinergic function has not been investigated to date in LRRK2 mutation carriers with or without PD using free-water imaging. Objectives To investigate the effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of PD using free-water imaging. Methods We recruited participants from the Parkinson’s Progression Markers Initiative (PPMI) data set. We evaluated the effect of LRRK2 mutations on the cholinergic nuclei (i.e., cholinergic nuclei 1, 2, and 3 (Ch123), Ch4, and pedunculopontine nucleus) in manifest and premanifest stages of PD using free-water imaging. We compared free-water values between groups using ANCOVA with adjustment for age. Then, the discriminative power of the free-water content was evaluated by receiver operating characteristic curve (ROC) analysis. Results We included 27 patients with LRRK2 PD, 33 LRRK2 mutation carriers without PD, 281 patients with idiopathic PD, and 98 healthy controls. We noted significant between-group differences in free-water content in Ch4 ( p  = 0.003). LRRK2 mutation carriers without PD had decreased free-water content in the Ch4 compared with healthy controls ( p  = 0.036) and idiopathic patients with PD ( p  = 0.001); LRRK2 patients with PD showed decreased tendency of free-water content in the Ch4 compared with idiopathic patients with PD ( p  = 0.074). Furthermore, ROC analysis showed that free-water content in the Ch4 identified asymptomatic LRRK2 mutation carriers with a high specificity (84.7%). Conclusions LRRK2 mutation is associated with decreased free-water content in the Ch4 (also referred to as nucleus basalis of Meynert, nbM), which might suggest early and sustained attempts to compensate for LRRK2-related dysfunction.

Increased extracellular free water (FW) is considered to provide better pathophysiological information than conventional diffusion tensor imaging (DTI) metrics. The cholinergic brain network is a key hub for cognitive function, and microstructural changes detected by free water imaging in this system may be associated with cognitive impairment in Alzheimer's disease (AD). However, the specific impact of FW changes in the cholinergic brain network on cognitive domains across the AD continuum and their diagnostic value remain unclear. Here, we investigated the basal forebrain cholinergic free water alterations based on free water-corrected diffusion tensor imaging in healthy controls (  = 36), amnestic mild cognitive impairment (aMCI;  = 31), the AD group (  = 33). The cholinergic basal forebrain subregions were divided into the Broca diagonal band (Ch1-3) and the Meynert basal nucleus (Ch4). The cognitive domains performance was measured using the Montreal Cognitive Assessment (MoCA). Additionally, we evaluated the diagnostic value of free water fraction (FWf) within the cholinergic system. FWf in the bilateral Ch1-3 and Ch4 regions increased with age, and was significantly higher in aMCI and AD (  < 0.001). In AD, the FWf within Ch4 was correlated with total MoCA score (  = -0.42,  = 0.015), especially with visual spatial/executive (  = -0.47,  = 0.006) and orientation deficits (  = -0.38,  = 0.029). No significant correlations were found in the aMCI group. ROC curve analysis showed that FWf within the cholinergic brain network had high diagnostic efficacy for AD versus HC (AUC = 0.958, 95% CI = 0.909-1.00), and moderate diagnostic efficacy for aMCI versus HC (AUC = 0.795, 95% CI = 0.685-0.905) and aMCI versus AD (AUC = 0.719, 95% CI = 0.589-0.850). FW imaging captures microstructural damage in the cholinergic brain network across the entire AD continuum. These changes occur early in aMCI but selectively affect domain-specific cognition in the later stages of AD, possibly through cholinergic network dysfunction. Our results highlight the potential of free water imaging as a biomarker for cognitive decline.