Letter to the Editor: "The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma".

This letter to the editor discusses the findings of Yu et al. (2024), which highlight the prognostic significance of volumetric assessments over cross-product measurements in pediatric diffuse intrinsic pontine glioma (DIPG). The study's methodology enhances precision in monitoring therapeutic responses, offering insights into treatment adjustments based on detailed imaging features. Emphasizing the value of volumetric MRI, this letter suggests its potential to improve surgical planning and therapeutic strategies, thereby optimizing patient management. This approach could revolutionize treatment paradigms, emphasizing personalized care through advanced imaging techniques.

Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients.

INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.

A Case Report of Isolated Cervical Ligament Rupture With Hyper-Pronation Injury: Specific MRI Protocol and Surgical Reconstruction.

Background: The aim of this case report is to present a case of chronic cervical ligament tear and instability, which occurred by an unusual work injury with an eversion/hyper-pronation mechanism in contrast to the usual mechanism of inversion. The ligament was reconstructed using an allograft with satisfactory results up to 30 months after surgery. A new magnetic resonance imaging protocol (MRI) was developed to better evaluate the cervical ligament/graft. Conclusion: In diagnosis of foot sprains, a specific ligament injury should always be sought. In this case, physical examination producing tenderness at the location of the cervical ligament and correlating this with an oblique intercolumn stress test that reproduced pain with apprehension and gross instability supported the diagnosis. Retrospectively applying anatomic knowledge to the earlier MRI findings of bone marrow edema at the insertion points of the cervical ligament on the talus and calcaneus was important in confirming the diagnosis. To better evaluate the cervical ligament allograft tendon reconstruction, a novel volumetric MRI sequence was developed which may prove helpful to also diagnose cervical ligament injuries in future cases. Anatomic reconstruction of the cervical ligament provided satisfactory clinical and radiographic results at 30-month follow-up.Level of Evidence: V.

A longitudinal analysis of brain volume changes in myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross-sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow-up period of 2 years and compared this to changes in people with multiple sclerosis (pwMS). METHODS: This is a retrospective single-center study over a 7-year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow-up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell-based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow-up on remission were collected from 32-matched pwMS for comparison. Statistical analysis was done using analysis of variance. RESULTS: There is evidence of TBV loss, affecting particularly GM, over an approximately 2-year follow-up period in pwMOGAD (p < .05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p > .1). CONCLUSION: We found evidence of loss of GM and TBV over time  in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged.

Treatment reduces the incidence of newly appearing multiple sclerosis lesions evolving into chronic active, slowly expanding lesions: A retrospective analysis.

BACKGROUND AND PURPOSE: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. METHODS: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation-based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed-effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. RESULTS: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (ß = -0.04, 95% confidence interval [CI] = -0.07 to -0.01, p = 0.015; ß = -0.36, 95% CI = -0.67 to -0.06, p = 0.019, respectively). CONCLUSIONS: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number.

Evaluation of 'Normal' Cognitive Functions and Correlation With MRI Volumetry: Towards a Definition of Vascular Cognitive Impairment.

Introduction It is important to establish criteria to define vascular cognitive impairment (VCI) in India as VCI is an image-based diagnosis and magnetic resonance imaging (MRI) changes resulting from age with prevalent vascular risk factors may confound MRI interpretation. The objective of this study was to establish normative community data for MRI volumetry including white matter hyperintensity volume (WMHV), correlated with age-stratified cognitive scores and vascular risk factors (VRFs), in adults aged 40 years and above.  Methods We screened 2651 individuals without known neurological morbidity, living in Mumbai and nearby rural areas, using validated Marathi translations of Kolkata Cognitive Battery (KCB) and geriatric depression score (GDS). We stratified 1961 persons with GDS ≤9 by age and cognitive score, and randomly selected 10% from each subgroup for MRI brain volumetry. Crude volumes were standardized to reflect percentage of intracranial volume.  Results MRI volumetry studies were done in 199 individuals (F/M = 90/109; 73 with body mass index (BMI) ≥25; 44 hypertensives; 29 diabetics; mean cognitive score 76.3). Both grey and white matter volumes decreased with increasing age. WMHV increased with age and hypertension. Grey matter volume (GMV) decreased with increasing WMHV. Positive predictors of cognition included standardized hippocampal volume (HCV), urban living, education, and BMI, while WMHV and age were negative predictors. Urban dwellers had higher cognitive scores than rural, and, paradoxically, smaller HCV.  Conclusion In this study of MRI volumetry correlated with age, cognitive scores and VRFs, increasing age and WMHV predicted lower cognitive scores, whereas urban living and hippocampal volume predicted higher scores. Age and WMHV also correlated with decreasing GMV. Further study is warranted into sociodemographic and biological factors that mutually influence cognition and brain volumes, including nutritional and endocrine factors, especially at lower cognitive score bands. In this study, at the lower KCB score bins, the lack of laboratory data pertaining to nutritional and endocrine deficiencies is a drawback that reflects the logistical limitations of screening large populations at the community level. Our volumetric data which is age and cognition stratified, and takes into account the vascular risk factors associated, nevertheless constitutes important baseline data for the Indian population. Our findings could possibly contribute to the formulation of baseline criteria for defining VCI in India and could help in early diagnosis and control of cognitive decline and its key risk factors.

Structural alterations in the amygdala and impaired social incentive learning in a mouse model of a genetic variant associated with neurodevelopmental disorders.

Copy number variants (CNVs) are robustly associated with psychiatric disorders and their dimensions and changes in brain structures and behavior. However, as CNVs contain many genes, the precise gene-phenotype relationship remains unclear. Although various volumetric alterations in the brains of 22q11.2 CNV carriers have been identified in humans and mouse models, it is unknown how the genes in the 22q11.2 region individually contribute to structural alterations and associated mental illnesses and their dimensions. Our previous studies have identified Tbx1, a T-box family transcription factor encoded in 22q11.2 CNV, as a driver gene for social interaction and communication, spatial and working memory, and cognitive flexibility. However, it remains unclear how TBX1 impacts the volumes of various brain regions and their functionally linked behavioral dimensions. In this study, we used volumetric magnetic resonance imaging analysis to comprehensively evaluate brain region volumes in congenic Tbx1 heterozygous mice. Our data show that the volumes of anterior and posterior portions of the amygdaloid complex and its surrounding cortical regions were reduced in Tbx1 heterozygous mice. Moreover, we examined the behavioral consequences of an altered volume of the amygdala. Tbx1 heterozygous mice were impaired for their ability to detect the incentive value of a social partner in a task that depends on the amygdala. Our findings identify the structural basis for a specific social dimension associated with loss-of-function variants of TBX1 and 22q11.2 CNV.

Evaluation of the cognitive outcome after out-of-hospital cardiac arrest: The role of thalamus.

Cardiac arrest survivors develop a variety of neuropsychological impairments and neuroanatomical lesions. The goal of this study is to evaluate if brain voxel-based morphometry and lesional Magnetic Resonance Imaging (MRI) analyses performed in the acute phase of an Out-of-Hospital Cardiac Arrest (OHCA) can be sensitive enough to predict the persistence of neuropsychological disorders beyond 3 months. Survivors underwent a prospective brain MRI during the first month after an OHCA and performed neuropsychological assessments at 1 and 3 months. According to the second neuropsychological assessment, survivors were separated into two subgroups, a deficit subgroup with persistent memory, executive functions, attention and/or praxis disorders (n = 11) and a preserved subgroup, disorders free (n = 14). Brain vascular lesion images were investigated, and volumetric changes were compared with healthy controls. Correlations were discussed between brain MRI results, OHCA data and the second neuropsychological assessment. Analyses of acute ischemic lesions did not reveal significant differences between the two subgroups (p = .35), and correlations with cognitive impairments could not be assessed. voxel-based morphometry analyses revealed a global cerebral volume reduction for the two subgroups and a clear decrease of the right thalamic volume for the deficit subgroup. It was associated with a cognitive dysexecutive syndrome represented by four executive indexes according to the 'Groupe de Réflexion pour l'Evaluation des Fonctions EXécutives' criteria. The right thalamus atrophy seems to be more predictive than the vascular lesions and more specific than a global cerebral volume reduction of post-OHCA neuropsychological executive disorders.

Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult-Onset Degenerative Ataxia.

BACKGROUND: Sporadic adult-onset ataxias without known genetic or acquired cause are subdivided into multiple system atrophy of cerebellar type (MSA-C) and sporadic adult-onset ataxia of unknown etiology (SAOA). OBJECTIVES: To study the differential evolution of both conditions including plasma neurofilament light chain (NfL) levels and magnetic resonance imaging (MRI) markers. METHODS: SPORTAX is a prospective registry of sporadic ataxia patients with an onset >40 years. Scale for the Assessment and Rating of Ataxia was the primary outcome measure. In subgroups, blood samples were taken and MRIs performed. Plasma NfL was measured via a single molecule assay. Regional brain volumes were automatically measured. To assess signal changes, we defined the pons and middle cerebellar peduncle abnormality score (PMAS). Using mixed-effects models, we analyzed changes on a time scale starting with ataxia onset. RESULTS: Of 404 patients without genetic diagnosis, 130 met criteria of probable MSA-C at baseline and 26 during follow-up suggesting clinical conversion to MSA-C. The remaining 248 were classified as SAOA. At baseline, NfL, cerebellar white matter (CWM) and pons volume, and PMAS separated MSA-C from SAOA. NfL decreased in MSA-C and did not change in SAOA. CWM and pons volume decreased faster, whereas PMAS increased faster in MSA-C. In MSA-C, pons volume had highest sensitivity to change, and PMAS was a predictor of faster progression. Fulfillment of possible MSA criteria, NfL and PMAS were risk factors, CWM and pons volume protective factors for conversion to MSA-C. CONCLUSIONS: This study provides detailed information on differential evolution and prognostic relevance of biomarkers in MSA-C and SAOA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis.

BACKGROUND: Magnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). OBJECTIVES: To identify the relationship between SELs and PRLs in MS, and their association with disability. METHODS: 61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs. RESULTS: The median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients. CONCLUSION: SELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.

TDP-43 pathology effect on volume and flortaucipir uptake in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) patients ≥70 years show smaller medial temporal volumes despite less 18 F-flortaucipir-positron emission tomography (PET) uptake than younger counterparts. We investigated whether TAR DNA-binding protein 43 (TDP-43) was contributing to this volume-uptake mismatch. METHODS: Seventy-seven participants with flortaucipir-PET and volumetric magnetic resonance imaging underwent postmortem AD and TDP-43 pathology assessments. Bivariate-response linear regression estimated the effect of age and TDP-43 pathology on volume and/or flortaucipir standardized uptake volume ratios of the hippocampus, amygdala, entorhinal, inferior temporal, and midfrontal cortices. RESULTS: Older participants had lower hippocampal volumes and overall flortaucipir uptake. TDP-43-immunoreactivity correlated with reduced medial temporal volumes but was unrelated to flortaucipir uptake. TDP-43 effect size was consistent across the age spectrum. However, at older ages, the cohort mean volumes moved toward those of TDP-43-positives, reflecting the increasing TDP-43 pathology frequency with age. DISCUSSION: TDP-43 pathology is a relevant contributor driving the volume-uptake mismatch in older AD participants. HIGHLIGHTS: TDP-43 pathology affects medial temporal volume loss but not tau radiotracer uptake. Greater TDP-43 pathology effect is seen in old age due to its increasing frequency. TDP-43 pathology is a relevant driver of the volume-uptake mismatch in old AD patients.

Reduced power and phase-locking values were accompanied by thalamus, putamen, and hippocampus atrophy in Parkinson's disease with mild cognitive impairment: an event-related oscillation study.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder accompanied by mild cognitive impairment (MCI) as a crucial nonmotor manifestation. Event-related oscillations (EROs) are suggested to reflect cognitive status associated with subcortical structures in neurodegenerative conditions. In this study, 36 individuals with PD-MCI and 32 PD-CN were compared with 60 healthy control (HC) participants using visual EROs by measures of event-related spectral perturbation and inter-trial coherence, along with subcortical gray matter volumes based on the FIRST algorithm. Cross-correlations among electrophysiological, neuropsychological, and structural parameters were investigated exploratively. Both PD-MCI and PD-CN patients had diminished delta and alpha phase-locking than HC, however, electrophysiological abnormalities were more pronounced in PD-MCI over frontal, central, parietal, and temporal locations in almost all frequency bands, accompanied by bilateral thalamus, hippocampus, and right putamen atrophy. PD-CN had lower hippocampal volumes than HC, without exhibiting any subcortical differences from PD-MCI. Lastly, EROs showed low-to-high correlations with structural and neuropsychological measures. These findings may highlight the complex interplay between electrophysiological, neuropsychological, and structural parameters in detected abnormalities of PD-CN and PD-MCI.

Spatiotemporal encoding MRI using subspace-constrained sampling and locally-low-rank regularization: Applications to diffusion weighted and diffusion kurtosis imaging of human brain and prostate.

The benefits of performing locally low-rank (LLR) reconstructions on subsampled diffusion weighted and diffusion kurtosis imaging data employing spatiotemporal encoding (SPEN) methods, is investigated. SPEN allows for self-referenced correction of motion-induced phase errors in case of interleaved diffusion-oriented acquisitions, and allows one to overcome distortions otherwise observed along EPI's phase-encoded dimension. In combination with LLR-based reconstructions of the pooled imaging data and with a joint subsampling of b-weighted and interleaved images, additional improvements in terms of sensitivity as well as shortened acquisition times are demonstrated, without noticeable penalties. Details on how the LLR-regularized, subspace-constrained image reconstructions were adapted to SPEN are given; the improvements introduced by adopting these reconstruction frameworks for the accelerated acquisition of diffusivity and of kurtosis imaging data in both relatively homogeneous regions like the human brain and in more challenging regions like the human prostate, are presented and discussed within the context of similar efforts in the field.

Case Report of a Patient With Posttraumatic Perilymphatic Fistula.

On a perilymphatic fistula, there is an extravasation of the perilymph fluid into the middle ear cavity. Cross-sectional imaging techniques have very important role in evaluation of inner and middle ear structures and temporal bone. While thin section CT scans can show successfully pneumolabyrinth and temporal bone fracture, high-resolution 3D volumetric MRI sequences can help to demonstrate posttraumatic ear effusion and cerebrospinal fluid fistula into inner ear or middle ear.

Long-term structural brain changes in adult rats after mild ischaemic stroke.

Preclinical studies of remote degeneration have largely focused on brain changes over the first few days or weeks after stroke. Accumulating evidence suggests that neurodegeneration occurs in other brain regions remote to the site of infarction for months and even years following ischaemic stroke. Brain atrophy appears to be driven by both axonal degeneration and widespread brain inflammation. The evolution and duration of these changes are increasingly being described in human studies, using advanced brain imaging techniques. Here, we sought to investigate long-term structural brain changes in a model of mild focal ischaemic stroke following injection of endothlin-1 in adult Long-Evans rats (n = 14) compared with sham animals (n = 10), over a clinically relevant time-frame of 48 weeks. Serial structural and diffusion-weighted MRI data were used to assess dynamic volume and white matter trajectories. We observed dynamic regional brain volume changes over the 48 weeks, reflecting both normal changes with age in sham animals and neurodegeneration in regions connected to the infarct following ischaemia. Ipsilesional cortical volume loss peaked at 24 weeks but was less prominent at 36 and 48 weeks. We found significantly reduced fractional anisotropy in both ipsi- and contralesional motor cortex and cingulum bundle regions of infarcted rats (P < 0.05) from 4 to 36 weeks, suggesting ongoing white matter degeneration in tracts connected to but distant from the stroke. We conclude that there is evidence of significant cortical atrophy and white matter degeneration up to 48 weeks following infarct, consistent with enduring, pervasive stroke-related degeneration.

Histologic lesion type correlates of magnetic resonance imaging biomarkers in four-repeat tauopathies.

Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis.

BACKGROUND: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated. OBJECTIVES: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. METHODS: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). RESULTS: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). CONCLUSIONS: SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS.

The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer's Disease Risks.

BACKGROUND: The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. OBJECTIVE: To determine the potential interaction between sleep disturbance and Aß, tau, and APOE4 on brain atrophy and cognitive decline. METHODS: Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-ß (Aß42) and p-Tau depositions and APOE4 status were examined using the linear mixed models. RESULTS: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aß and p-Tau/Aß predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition. CONCLUSION: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

Quantified Brain Magnetic Resonance Imaging Volumes Differentiate Behavioral Variant Frontotemporal Dementia from Early-Onset Alzheimer's Disease.

BACKGROUND: The differentiation of behavioral variant frontotemporal dementia (bvFTD) from early-onset Alzheimer's disease (EOAD) by clinical criteria can be inaccurate. The volumetric quantification of clinically available magnetic resonance (MR) brain scans may facilitate early diagnosis of these neurodegenerative dementias. OBJECTIVE: To determine if volumetric quantification of brain MR imaging can identify persons with bvFTD from EOAD. METHODS: 3D T1 MR brain scans of 20 persons with bvFTD and 45 with EOAD were compared using Neuroreader to measure subcortical, and lobar volumes, and Volbrain for hippocampal subfields. Analyses included: 1) discriminant analysis with leave one out cross-validation; 2) input of predicted probabilities from this process into a receiver operator characteristic (ROC) analysis; and 3) Automated linear regression to identify predictive regions. RESULTS: Both groups were comparable in age and sex with no statistically significant differences in symptom duration. bvFTD had lower volume percentiles in frontal lobes, thalamus, and putamen. EOAD had lower parietal lobe volumes. ROC analyses showed 99.3% accuracy with Neuroreader percentiles and 80.2% with subfields. The parietal lobe was the most predictive percentile. Although there were differences in hippocampal (particularly left CA2-CA3) subfields, it did not add to the discriminant analysis. CONCLUSION: Percentiles from an MR based volumetric quantification can help differentiate between bvFTD from EOAD in routine clinical care. Use of hippocampal subfield volumes does not enhance the diagnostic separation of these two early-onset dementias.