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.

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.

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.

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.

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.

Differential association of cortical, subcortical and spinal cord damage with multiple sclerosis disability milestones: A multiparametric MRI study.

BACKGROUND: In multiple sclerosis (MS), cortical, subcortical and infratentorial structural damage may have a differential contribution to clinical disability according to disease phases. PURPOSE: To determine the relative contributions of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage to MS disability milestones. METHODS: Multi-centre 3T brain and cervical cord T2- and three-dimensional (3D) T1-weighted images were acquired from 198 MS patients (139 relapsing-remitting (RR) MS, 59 progressive (P) MS) and 67 healthy controls. Brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry and cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of expanded disability status scale (EDSS) disability milestones (EDSS = 3.0, 4.0 and 6.0). RESULTS: MS patients had widespread atrophy in all investigated compartments versus controls (p-range: ⩽0.001-0.05). Informative determinants of EDSS = 3.0 were cord CSA, brain lesion volume, frontal CTh and thalamic and cerebellar atrophy (out-of-bag (OOB) accuracy = 0.84, p-range: ⩽0.001-0.05). EDSS = 4.0 was mainly predicted by cerebellar and cord atrophy, frontal and sensorimotor CTh and cord lesion number (OOB accuracy = 0.84, p-range: ⩽0.001-0.04). Cervical cord CSA (p = 0.001) and cord lesion number (p = 0.003) predicted EDSS = 6.0 (OOB accuracy = 0.77). CONCLUSION: Brain lesion burden, cortical and thalamic atrophy were the main determinants of EDSS = 3.0 and 4.0, while cord damage played a major contribution to EDSS = 6.0.

Phenotyping the Preterm Brain: Characterizing Individual Deviations From Normative Volumetric Development in Two Large Infant Cohorts.

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterizing brain volumetric development in 274 term-born infants, modeling for age at scan and sex. We then compared 89 preterm infants scanned at term-equivalent age with these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalizability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, nonuniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguises a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterization of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

High coffee consumption, brain volume and risk of dementia and stroke.

BACKGROUND: Coffee is a highly popular beverage worldwide, containing caffeine which is a central nervous system stimulant. OBJECTIVES: We examined whether habitual coffee consumption is associated with differences in brain volumes or the odds of dementia or stroke. METHODS: We conducted prospective analyses of habitual coffee consumption on 398,646 UK Biobank participants (age 37-73 years), including 17,702 participants with MRI information. We examined the associations with brain volume using covariate adjusted linear regression, and with odds of dementia (4,333 incident cases) and stroke (6,181 incident cases) using logistic regression. RESULTS: There were inverse linear associations between habitual coffee consumption and total brain (fully adjusted ß per cup -1.42, 95% CI -1.89, -0.94), grey matter (ß -0.91, 95% CI -1.20, -0.62), white matter (ß -0.51, 95% CI -0.83, -0.19) and hippocampal volumes (ß -0.01, 95% CI -0.02, -0.003), but no evidence to support an association with white matter hyperintensity (WMH) volume (ß -0.01, 95% CI -0.07, 0.05). The association between coffee consumption and dementia was non-linear (Pnon-linearity = 0.0001), with evidence for higher odds for non-coffee and decaffeinated coffee drinkers and those drinking >6 cups/day, compared to light coffee drinkers. After full covariate adjustment, consumption of >6 cups/day was associated with 53% higher odds of dementia compared to consumption of 1-2 cups/day (fully adjusted OR 1.53, 95% CI 1.28, 1.83), with less evidence for an association with stroke (OR 1.17, 95% CI 1.00, 1.37, p = 0.055). CONCLUSION: High coffee consumption was associated with smaller total brain volumes and increased odds of dementia.

Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia.

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.

Longitudinal analysis of regional brain changes in anti-NMDAR encephalitis: a case report.

BACKGROUND: Anti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations. CASE PRESENTATION: A previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient's clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402-18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient's treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient's clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain. CONCLUSIONS: Our results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

Cerebellar Volume Is Associated with Cognitive Decline in Mild Cognitive Impairment: Results from ADNI.

Alzheimer's disease (AD) is a disease with dysfunctional brain network. Previous studies found the cerebellar volume changes over the course of AD disease progression; however, whether cerebellar volume change contributes to the cognitive decline in AD, or its earlier disease stage (i.e., mild cognitive impairment [MCI]) remains unclear. In ADNI, cognitive function was assessed using Alzheimer's Disease Assessment Scale-Cognitive Behavior section (ADAS-Cog). We used linear regression and linear mixed effects models to examine whether cerebellar volume is associated with either baseline cognition or with cognitive changes over time in MCI or in AD. We used logistic regression to assess the relationship between cerebellar volume and disease progression to MCI and AD. We found that cerebellar volume is associated with cognition in patients with MCI, after adjusting for age, gender, education, hippocampal volume, and APOE4 status. Consistently, cerebellar volume is associated with increased odds of the disease stages of MCI and AD when compared to controls. However, cerebellar volume is not associated with cognitive changes over time in either MCI or AD. In summary, cerebellar volume may contribute to cognition level in MCI, but not in AD, indicating that the cerebellar network might modulate the cognitive function in the early stage of the disease. The cerebellum may be a potential target for neuromodulation in treating MCI.

Subcortical nuclei volumes are associated with cognition in children post-convulsive status epilepticus: Results at nine years follow-up.

PURPOSE: The purpose of the present study was to investigate the relationship between subcortical nuclei volume and cognition in children with post-convulsive status epilepticus (CSE). METHODS: Structural T1-weighted magnetic resonance imaging (MRI) scans (Siemens Avanto, 1.5 T) and neuropsychological assessments (full-scale intelligence quotient (FSIQ) and Global Memory Scores (GMS)) were collected from subjects at a mean 8.5 years post-CSE (prolonged febrile seizures (PFS), n = 30; symptomatic/known, n = 28; and other, n = 12) and from age- and sex-matched healthy controls (HC). Subjects with CSE were stratified into those with lower cognitive ability (LCA) (CSE+, n = 22) and those without (CSE-, n = 48). Quantitative volumetric analysis using Functional MRI of the Brain Software Library (FSL) (Analysis Group, FMRIB, Oxford) provided segmented MRI brain volumes. Univariate analysis of covariance (ANCOVA) was performed to compare subcortical nuclei volumes across subgroups. Multivariable linear regression was performed for each subcortical structure and for total subcortical volume (SCV) to identify significant predictors of LCA (FSIQ <85) while adjusting for etiology, age, socioeconomic status, sex, CSE duration, and intracranial volume (ICV); Bonferroni correction was applied for the analysis of individual subcortical nuclei. RESULTS: Seventy subjects (11.8 ±â€¯3.4 standard deviation (SD) years; 34 males) and 72 controls (12.1 ±â€¯3.0SD years; 29 males) underwent analysis. Significantly smaller volumes of the left thalamus, left caudate, right caudate, and SCV were found in subjects with CSE+ compared with HC, after adjustment for intracranial, gray matter (GM), or cortical/cerebellar volume. When compared with subjects with CSE-, subjects with CSE+ also had smaller volumes of the left thalamus, left pallidum, right pallidum, and SCV. Individual subcortical nuclei were not associated, but SCV was associated with FSIQ (p = 0.005) and GMS (p = 0.014). Intracranial volume and etiology were similarly predictive. CONCLUSIONS: Nine years post-CSE, SCV is significantly lower in children who have LCA compared with those that do not. However, in this cohort, we are unable to determine whether the relationship is independent of ICV or etiology. Future, larger scale studies may help tease this out.

PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly.

OBJECTIVE: The object of this study was to determine if revision transsphenoidal surgery (TSS), guided by 11C-methionine PET/CT coregistered with volumetric MRI (Met-PET/MRCR), can lead to remission in patients with persistent acromegaly due to a postoperative lateral disease remnant. METHODS: The authors identified 9 patients with persistent acromegaly following primary intervention (TSS ± medical therapy ± radiotherapy) in whom further surgery had initially been discounted because of equivocal MRI findings with suspected lateral sellar and/or parasellar disease (cases with clear Knosp grade 4 disease were excluded). All patients underwent Met-PET/MRCR. Scan findings were used by the pituitary multidisciplinary team to inform decision-making regarding repeat surgery. Revision TSS was performed with wide lateral exploration as guided by the PET findings. Endocrine reassessment was performed at 6-10 weeks after surgery, with longitudinal follow-up thereafter. RESULTS: Met-PET/MRCR revealed focal tracer uptake in the lateral sellar and/or parasellar region(s) in all 9 patients, which correlated with sites of suspected residual tumor on volumetric MRI. At surgery, tumor was identified and resected in 5 patients, although histological analysis confirmed somatotroph tumor in only 4 cases. In the other 4 patients, no definite tumor was seen, but equivocal tissue was removed. Despite the uncertainty at surgery, all patients showed immediate significant improvements in clinical and biochemical parameters. In the 8 patients for whom long-term follow-up data were available, insulin-like growth factor 1 (IGF-1) was ≤ 1.2 times the upper limit of normal (ULN) in all subjects and ≤ 1 times the ULN in 6 subjects, and these findings have been maintained for up to 28 months (median 8 months, mean 13 months) with no requirement for adjunctive medical therapy or radiotherapy. No patient suffered any additional pituitary deficit or other complication of surgery. CONCLUSIONS: This study provides proof of concept that Met-PET/MRCR can be helpful in the evaluation of residual lateral sellar/parasellar disease in persistent acromegaly and facilitate targeted revision TSS in a subgroup of patients.

Differential sensitivity of structural, diffusion, and resting-state functional MRI for detecting brain alterations and verbal memory impairment in temporal lobe epilepsy.

OBJECTIVES: Temporal lobe epilepsy (TLE) is known to affect large-scale gray and white matter networks, and these network changes likely contribute to the verbal memory impairments observed in many patients. In this study, we investigate multimodal imaging patterns of brain alterations in TLE and evaluate the sensitivity of different imaging measures to verbal memory impairment. METHODS: Diffusion tensor imaging (DTI), volumetric magnetic resonance imaging (vMRI), and resting-state functional MRI (rs-fMRI) were evaluated in 46 patients with TLE and 33 healthy controls to measure patterns of microstructural, structural, and functional alterations, respectively. These measurements were obtained within the white matter directly beneath neocortex (ie, superficial white matter [SWM]) for DTI and across neocortex for vMRI and rs-fMRI. The degree to which imaging alterations within left medial temporal lobe/posterior cingulate (LMT/PC) and left lateral temporal regions were associated with verbal memory performance was evaluated. RESULTS: Patients with left TLE and right TLE both demonstrated pronounced microstructural alterations (ie, decreased fractional anisotropy [FA] and increased mean diffusivity [MD]) spanning the entire frontal and temporolimbic SWM, which were highly lateralized to the ipsilateral hemisphere. Conversely, reductions in cortical thickness in vMRI and alterations in the magnitude of the rs-fMRI response were less pronounced and less lateralized than the microstructural changes. Both stepwise regression and mediation analyses further revealed that FA and MD within SWM in LMT/PC regions were the most robust predictors of verbal memory, and that these associations were independent of left hippocampal volume. SIGNIFICANCE: These findings suggest that microstructural loss within the SWM is pronounced in patients with TLE, and injury to the SWM within the LMT/PC region plays a critical role in verbal memory impairment.

Longitudinal quantitative magnetic resonance imaging in adrenomyeloneuropathy.

BACKGROUND AND PURPOSE: Adrenomyeloneuropathy (AMN) is the most frequent metabolic hereditary spastic paraplegia. Accordingly, its main site of pathological changes is the spinal cord. It is difficult to quantify AMN progression because commonly used clinical scales have limitations and reliable biomarkers are lacking. The goal was to investigate whether spinal cord and brain quantitative magnetic resonance imaging may assess structural changes in AMN over a relatively short time period. METHODS: In this longitudinal observational study, the total cord areas (TCAs) from the C2-C3 to T2-T3 level and diffusion tensor imaging (DTI) metrics of the cervical spinal cord and brain portion of the corticospinal tracts in six AMN and six age-matched control subjects at baseline and at a mean follow-up of 22.6 months were assessed. RESULTS: A significant reduction of the mean TCA at the T1-T2 level (-3.79%) and a trend of reduction at the lowest cervical levels were observed only in AMN patients. Additionally, DTI metrics revealed significant changes in fractional anisotropy (-8.84%), mean diffusivity (+12.62%) and radial diffusivity (+25.91%) at the C2-C3 level. DISCUSSION: The study encourages the assessment of TCAs and spinal cord DTI metrics as surrogate outcome measures in AMN, by focusing on the cervical-thoracic junction and the uppermost part of the cervical spinal cord. Despite the limitation of the results due to the small number of investigated subjects, these observations are useful for forthcoming clinical trials in AMN and possibly other hereditary diseases with predominant spinal cord involvement.

Brain volume is related to neurological impairment and to copper overload in Wilson's disease.

INTRODUCTION: To determine whether brain volume was associated with functional and neurological impairments and with copper overload markers in patients with Wilson's disease. METHODS: In 48 treatment-naïve patients, we assessed functional and neurological impairments with the Unified Wilson's Disease Rating Scale, measured normalized brain volumes based on magnetic resonance images, and assessed concentration of non-ceruloplasmin-bound copper. We correlated brain volume measures with functional and neurological impairment scores and copper overload indices. RESULTS: Functional and neurological impairments correlated with all brain volume measures, including the total brain volume and the volumes of white matter and gray matter (both peripheral gray matter and deep brain nuclei). Higher non-ceruloplasmin-bound copper concentrations were associated with greater functional and neurological impairments and lower brain volumes. CONCLUSIONS: Our findings provided the first in vivo evidence that the severity of brain atrophy is a correlate of functional and neurological impairments in patients with Wilson's disease and that brain volume could serve as a marker of neurodegeneration induced by copper.

Clinical and cortical decline in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation. METHODS: Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPAAß+ and PPAAß-), an imaging biomarker of underlying Alzheimer's disease. RESULTS: Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPAAß+. The PPAAß+ group also showed greater decline in performance on most language tasks. There was no obligatory relationship between the logopenic PPA variant and amyloid status. Effect sizes from quantitative MRI data were more robust than neuropsychological metrics. DISCUSSION: Preferential language network neurodegeneration is present in PPA irrespective of amyloid status. Clinical and anatomical progression appears to differ for PPA due to Alzheimer's disease versus non-Alzheimer's disease neuropathology, a distinction that may help to inform prognosis and the design of intervention trials.

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum.

BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.