White Matter Degeneration Research Articles

White matter integrity linked to memory retrieval deficits in posterior cortical atrophy

AbstractBackgroundPosterior cortical atrophy (PCA) is an atypical form of Alzheimer’s disease characterised by visuospatial abilities, with episodic memory traditionally thought to be relatively preserved. However, recent work suggests that verbal memory is impaired at clinical presentation (Ahmed et al., 2016) associated with changes in functional connectivity of parietal attention networks (Veldsman et al., 2018). It is currently unclear how structural connectivity changes may contribute to memory functioning within this patient group. Here, we examine the relationship between white matter integrity and verbal episodic memory in PCA.MethodEighteen patients with PCA and eighteen healthy controls underwent diffusion tensor imaging (DTI) MRI scanning. Episodic memory of patients was assessed with the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT‐IR). Voxel‐wise statistical analyses of fractional anisotropy and mean diffusivity measures in patient and control groups were carried out using tract‐based spatial statistics. Relationships between white matter microstructure and memory performance were examined with partial correlations controlling for age.ResultThere was no difference in encoding of verbal items between patients and healthy controls. However, PCA patients presented with significant impairments of memory retrieval on the FCSRT‐IR. In line with previous neuroimaging research, white matter degeneration in PCA was restricted to posterior regions of the cortex. Within the patient group, reduced integrity of the splenium of the corpus callosum was associated with less free recall of task items.ConclusionThis study demonstrates that splenial atrophy may contribute to deficits in episodic memory retrieval in PCA. The findings have implications for supporting diagnostic profiling in PCA.

Stage‐dependent amyloid beta‐ and tau‐associated longitudinal white matter degeneration in early stages of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease(AD) is associated with pathological deposition of amyloid‐beta(Aβ) plaques and neurofibrillary tau tangles which have been shown to be related to poorer white‐matter(WM) integrity using diffusion‐MRI(dMRI) [Vipin et al.,2019;Jacobs et al.,2018]. However, possible interactive effects between Aβ and tau on microstructural WM changes remain unclear. Additionally, partial volume artefacts impact dMRI sensitivity but can be corrected through free‐water(FW) correction to provide FW and FW‐corrected tissue measures(FAt)[Pasternak et al.,2009]. Thus, we examined additive and interactive effects of Aβ and tau burden on temporal progression of FW‐corrected WM changes in temporoparietal WM fibres at baseline and over‐time in cognitively normal elderly(CN) and mild cognitive impairment(MCI). We hypothesize that MCI subjects would show more widespread Aβ and tau‐related temporoparietal WM alterations than CN. Additionally, based on prior evidence, Aβ and tau interactive effects would be more prevalent for FW than tissue‐based measures.MethodWe used dMRI data from 72 CN and 82 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative followed over 2‐4 time‐points(55‐90 years). Aβ burden was quantified using AV‐45 PET standardized uptake value and tau burden was quantified using cerebrospinal fluid phosphorylated‐tau(Ptau) levels. We derived subject‐specific FW and FAt fibre maps using the longitudinal TRActs‐Constrained‐by‐UnderLying‐Anatomy method[Yendiki et al.,2016].ResultCN with higher Aβ burden showed faster decline in RUNC FAt (uncorrected‐p=0.0055; Fig.1). However, in MCI, widespread Ptau effects were found(Fig.2) i.e. higher baseline Ptau burden was associated with lower fibre FAt in left superior longitudinal fasciculus parietal (SLFP; uncorrected‐p=0.039) and left(uncorrected‐p=0.0062) and right(uncorrected‐p=0.026) superior longitudinal fasciculus temporal(SLFT). Synergistic Aβ*Ptau effects were instead observed in right cingulum angular bundle(CAB) FW in CN at baseline and over‐time (FDR‐corrected:p<0.05; Fig.3). This effect was more widespread in MCI‐ higher Aβ combined with higher Ptau associated with higher FW in right CAB, SLFP, SLFT and uncinate fasciculus fibres at baseline(Fig.4).ConclusionOur findings provide insights into stage‐dependent differences in additive and synergistic influences of Aβ and Ptau between tissue‐based and FW‐based WM metrics. Thus, together with Aβ and Ptau burden, FW‐corrected WM measures likely provide more detailed insight regarding the regions showing alterations related to the interaction between neuropathological hallmarks of AD to collectively inform regarding disease progression.

Tau-related white-matter alterations along spatially selective pathways

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

Neuroanatomical associations of the Edinburgh cognitive and Behavioural ALS screen (ECAS).

Cognitive impairment is now recognized in a subset of patients with amyotrophic lateral sclerosis (ALS). The objective of the study was to identify group differences and neuroanatomical correlates of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in participants ALS. Fifty-three ALS patients and 43 healthy controls recruited as a part of our multicentre study (CALSNIC) were administered the ECAS and underwent an MRI scan. Voxel-based morphometry and tract based spatial statistics (TBSS) was performed to identify structural changes and associations with impaired ECAS scores. Lower performance in the ECAS verbal fluency and executive domains were noted in ALS patients as compared to controls (p < 0.01). Extensive white matter degeneration was noted in the corticospinal tract in all ALS patients, while ALS patients with impaired verbal fluency or executive domains (ALS-exi, n = 22), displayed additional degeneration in the corpus callosum, cingulum and superior longitudinal fasciculus as compared to controls (p < 0.05, TFCE corrected). Mild grey matter changes and associations with ECAS verbal fluency or executive performance were noted at lenient statistical thresholds (p < 0.001, uncorrected). Executive impairment was detected using the ECAS in our multicentre sample of Canadian ALS patients. White matter degeneration in motor regions was revealed in ALS patients with extensive spread to frontal regions in the ALS-exi sub-group. Mild associations between ECAS verbal fluency, executive function scores and MRI metrics suggest that reduced performance may be associated with widespread structural integrity.

Brain Neurodegeneration in the Chronic Stage of the Survivors from Severe Non-Missile Traumatic Brain Injury: A Voxel-Based Morphometry Within-Group at One versus Nine Years from a Head Injury.

The long-term time course of neuropathological changes occurring in survivors from severe traumatic brain injury (TBI) remains uncertain. We investigated the brain morphometry and memory performance modifications within the same group of severe non-missile traumatic brain injury patients (nmTBI) after about ∼one year and at ∼ nine years from injury. Brain magnetic resonance imaging (MRI) measurements were performed with voxel-based morphometry (VBM) to determine specific changes in the gray matter (GM) and white matter (WM) and the overall gray matter volume modifications (GMV) and white matter volume modifications (WMV). Contemporarily, memory-tests were also administered. In comparison with healthy control subjects (HC), those with nmTBI showed a significant change and volume reduction in the GM and WM and also in the GMV and WMV after ∼one year; conversely, ∼nine years after injury, neurodegenerative changes spared the GM and GMV, but a prominent loss was detected in WMV and in WM sites, such as the superior longitudinal fasciculi, the body of the corpus callosum, the optic radiation, and the uncinate fasciculus. Memory performance at ∼one year in comparison with ∼nine years was stable with a subtle but significant trend toward recovery. These data demonstrate that patients with nmTBI undergo neurodegenerative processes during the chronic stage affecting mainly the cerebral WM rather than GM. Despite these anatomical brain parenchyma losses, memory performance tends to be stable or even slightly recovered. These results suggest possible correlations between progressive demyelinization and/or neuropsychiatric changes other than memory performance, and support possible treatments to prevent long-term WM degeneration of the examined nmTBI.

Plasma neurofilament light protein correlates with diffusion tensor imaging metrics in frontotemporal dementia.

Neurofilaments are structural components of neurons and are particularly abundant in highly myelinated axons. The levels of neurofilament light chain (NfL) in both cerebrospinal fluid (CSF) and plasma have been related to degeneration in several neurodegenerative conditions including frontotemporal dementia (FTD) and NfL is currently considered as the most promising diagnostic and prognostic fluid biomarker in FTD. Although the location and function of filaments in the healthy nervous system suggests a link between increased NfL and white matter degeneration, such a claim has not been fully elucidated in vivo, especially in the context of FTD. The present study provides evidence of an association between the plasma levels of NfL and white matter involvement in behavioral variant FTD (bvFTD) by relating plasma concentration of NfL to diffusion tensor imaging (DTI) metrics in a group of 20 bvFTD patients. The results of both voxel-wise and tract specific analysis showed that increased plasma NfL concentration is associated with a reduction in fractional anisotropy (FA) in a widespread set of white matter tracts including the superior longitudinal fasciculus, the fronto-occipital fasciculus the anterior thalamic radiation and the dorsal cingulum bundle. Plasma NfL concentration also correlated with cortical thinning in a portion of the right medial prefrontal cortex and of the right lateral orbitofrontal cortex. These results support the hypothesis that blood NfL levels reflect the global level of neurodegeneration in bvFTD and help to advance our understanding of the association between this blood biomarker for FTD and the disease process.

Brain White-Matter Degeneration Due to Aging and Parkinson Disease as Revealed by Double Diffusion Encoding.

Microstructure imaging by means of multidimensional diffusion encoding is increasingly applied in clinical research, with expectations that it yields a parameter that better correlates with clinical disability than current methods based on single diffusion encoding. Under the assumption that diffusion within a voxel can be well described by a collection of diffusion tensors, several parameters of this diffusion tensor distribution can be derived, including mean size, variance of sizes, orientational dispersion, and microscopic anisotropy. The information provided by multidimensional diffusion encoding also enables us to decompose the sources of the conventional fractional anisotropy and mean kurtosis. In this study, we explored the utility of the diffusion tensor distribution approach for characterizing white-matter degeneration in aging and in Parkinson disease by using double diffusion encoding. Data from 23 healthy older subjects and 27 patients with Parkinson disease were analyzed. Advanced age was associated with greater mean size and size variances, as well as smaller microscopic anisotropy. By analyzing the parameters underlying diffusion kurtosis, we found that the reductions of kurtosis in aging and Parkinson disease reported in the literature are likely driven by the reduction in microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in the patients with Parkinson disease. The present results support the use of multidimensional diffusion encoding in clinical studies and are encouraging for its future clinical implementation.

Association between Matrix Metalloproteinases, Their Tissue Inhibitor and White Matter Lesions in Mild Cognitive Impairment.

White matter lesions are frequently found in mild cognitive impairments and Alzheimer's disease. Matrix metalloproteinases and the tissue inhibitor of metalloproteinases are implicated in amyloid-β catabolism and blood brain barrier permeability. However, it remains unclear whether they are associated with white matter lesions in Alzheimer's disease. The aim of this study was to examine the association of matrix metalloproteinases and tissue inhibitor of metalloproteinases with white matter degeneration in subjects with amyloid-positive mild cognitive impairment. Thirty subjects with amnestic mild cognitive impairment (14 men and 16 women; mean age, 75.6 ± 5.8 years) underwent magnetic resonance imaging, 11C-Pittsburgh Compound B positron emission tomography, and 18F-fluorodeoxyglucose positron emission tomography. Levels of plasma matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured using multiplex assays. All subjects had an abnormal brain amyloid burden. Subjects were divided into two groups according to the presence of white matter lesions using the Fazekas scale. Cognitive function testing results i.e., mean 11C-Pittsburgh Compound B and 18F-fluorodeoxyglucose uptake, concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases, and matrix metalloproteinases/tissue inhibitor of metalloproteinases ratios were compared between the groups. Correlation analysis was conducted to investigate the association between Fazekas scale score and clinical and neuroimaging variables as well as concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Matrix metalloproteinases-2, -8, and -9 levels, matrix metalloproteinases-2/ tissue inhibitor of metalloproteinases-2, matrix metalloproteinases-8/ tissue inhibitor of metalloproteinases-1, and matrix metalloproteinases-9/tissue inhibitor of metalloproteinases-1 significantly increased and tissue inhibitor of metalloproteinases-1 and-2 levels significantly decreased in the group with white matter lesions compared with the group without white matter lesions. Matrix metalloproteinases-2, -8, and -9 levels correlated positively and tissue inhibitor of metalloproteinases-1 and -2 levels correlated negatively with Fazekas scale score. Plasma matrix metalloproteinases-2, -8, -9 and tissue inhibitor of metalloproteinases-1 and -2 levels are associated with white matter lesions in the mild cognitive impairment stage of Alzheimer's disease.

FROM THE SPINAL CORD TO THE MUSCLE: O.09 Spinal cord MRI for early detection of presymptomatic pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative conditions with shared genetic susceptibility and a large portion of familial cases due to c9orf72 gene mutations. Brain imaging studies in asymptomatic c9orf72 carriers have demonstrated white (WM) and grey matter (GM) degeneration before the age of 40. The aim of this study was to investigate whether cervical spinal cord (SC) degeneration can be detected in asymptomatic c9orf72 hexanucleotide carriers using multimodal quantitative imaging. 72 asymptomatic individuals were enrolled in a prospective observational study of first-degree relatives of ALS and FTD patients carrying the c9orf72 mutation. 40 (C9+) carried the pathogenic repeat expansion. Each subject underwent a 3T cervical SC MRI. Quantitative measures of GM and WM atrophy and DTI parameters were evaluated at baseline, after 18 and after 36 months. Data were analysed on the total population and in two subgroups composed by subjects younger and older than 40 years of age. No significant difference was observed between C9+ and C9- subjects younger than 40 years of age regarding morphometric and DTI parameters at each time point. At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ compared to C9- subjects older than 40 years of age (p-value < 0.05) without associated changes in GM and DTI parameters. At 18 and 36-month follow-up, WM atrophy in C9+ subjects older than 40 years was accompanied by significant and progressive corticospinal tract fractional anisotropy (FA) reduction compared to C9- subjects (p-value = 0.031). Intriguingly, asymptomatic C9+ subjects older than 40 years with a family history of ALS exhibited significant global CSA and CST FA reduction on their baseline scans. Cervical SC imaging of c9orf72 hexanucleotide carriers does not detect degeneration in subjects younger than 40 years, but WM atrophy is observed in C9+ subjects older than 40 years of age. While WM atrophy remains stable, progressive pyramidal tract FA reduction can be detected on follow-up acquisitions. SC MRI in c9orf 72 related conditions is a powerful tool to characterise presymptomatic pathological changes and it may also have a role to predict phenotypic conversion.

Degeneration of gray and white matter differs between hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD: a longitudinal MRI − PET multimodal study

Objective [18F]-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) imaging and magnetic resonance imaging (MRI) of brain in ALS patients with frontotemporal lobe dementia (ALS-FTD) reveal hypometabolism and hypermetabolism, as well as gray matter (GM) and white matter (WM) abnormalities in different brain regions, respectively. Hypometabolism arising from neuronal dysfunction or loss is the most recognized pathophysiologic change in neurodegeneration, whereas mechanisms underlying hypermetabolism remain unclear. We hypothesize that hypometabolic and hypermetabolic brain regions in ALS-FTD represent differential degeneration of GM and WM structures, as revealed by co-registered MRI in a two time-point longitudinal multimodal study. Methods: A 69-year-old female with ALS-FTD underwent 18F-FDG PET, diffusion tensor imaging (DTI), and T1-weighted MRI at baseline (15 months after symptom onset), and 20.4 months later. Cerebral glucose metabolism rate, cortical thickness, cortical area, and WM network changes were measured longitudinally. Results and conclusion: The patient had symptoms and signs of bulbar-onset upper motor neuron (UMN)-predominant ALS with language and behavioral dysfunction. Evaluation at baseline showed bulbar dysfunction, and impaired language and executive function. At follow-up, worsened bulbar and other motor functions, and prominent FTD both reflected significant progression. Cortical thickness and surface area showed differential involvement in the hypometabolic and hypermetabolic regions. WM connections from frontal regions to other brain regions were completely absent by graph theory-based network analysis when compared to temporal regions indicating prominent frontal lobe degeneration. Structural neuroimaging reveals different patterns of GM and WM involvement in the hypometabolic and hypermetabolic brain regions in a patient with ALS-FTD.

A-037 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarctions and Leukoencephalopathy: A Neuropsychological Case Review

Abstract Objectives Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarctions and Leukoencephalopathy (CADASIL) is a rare genetic disorder. It is caused by a mutation in the NOTCH3 gene on chromosome 19 which damages vascular smooth muscle cells resulting in impaired cerebral blood flow and a progressive vascular dementia. Onset typically occurs by the mid-30’s but varies widely. This case study describes a unique case of rapid disease progression. Methods The patient was a 58-year-old right-handed male. Initial symptom onset occurred at the age of 53, with blurred vision, severe headache, and difficulty speaking. Brain imaging (CT, MRI) showed significant white matter degeneration and cortical volume loss. Multiple sclerosis was hypothesized. Following the development of seizures and a right hemisphere stroke, the patient underwent genetic testing and was diagnosed with CADASIL. Initial neuropsychological evaluation revealed deficits in perceptual reasoning, working memory, processing speed, memory, and executive functioning. Serial evaluation included intelligence testing, academic achievement, the Meyers Neuropsychological Battery, and psychological functioning. Results Intellectual functioning and the overall neuropsychological test battery mean were one and a half to two standard deviations below his estimated premorbid functioning. Executive functioning declined from prior evaluation. Psychologically, the patient reported mild anger, irritability, and interpersonal difficulties. His wife endorsed significant increases in apathy and disinhibition and decline in executive functioning. The patient passed away approximately six months post-evaluation. Conclusion Findings were consistent with moderate-to-severe diffuse and lateralized deficits (RCH &amp;gt; LCH) resulting from subcortical/higher cortical vascular dementia due to CADASIL and its medical sequelae, with quite rapid symptom onset and decline.

Cerebral Modifications and Visual Pathway Reorganization in Maculopathy: A Systematic Review.

BackgroundMacular degeneration (MD) is one of the most frequent causes of visual deficit, resulting in alterations affecting not only the retina but also the entire visual pathway up to the brain areas. This would seem related not just to signal deprivation but also to a compensatory neuronal reorganization, having significant implications in terms of potential rehabilitation of the patient and therapeutic perspectives.ObjectiveThis paper aimed to outline, by analyzing the existing literature, the current understanding of brain structural and functional changes detected with neuroimaging techniques in subjects affected by juvenile and age-related maculopathy.MethodsArticles using various typologies of central nervous system (CNS) imaging in at least six patients affected by juvenile or age-related maculopathy were considered. A total of 142 were initially screened. Non-pertinent articles and duplicates were rejected. Finally, 19 articles, including 649 patients, were identified.ResultsIn these sources, both structural and functional modifications were found in MD subjects’ CNS. Changes in visual cortex gray matter volume were observed in both age-related MD (AMD) and juvenile MD (JMD); in particular, an involvement of not only its posterior part but also the anterior one suggests further causes besides an input-deprivation mechanism only. White matter degeneration was also found, more severe in JMD than in AMD. Moreover, functional analysis revealed differences in cortical activation patterns between MD and controls, suggesting neuronal circuit reorganization. Interestingly, attention and oculomotor training allowed better visual performances and correlated to a stronger cortical activation, even of the area normally receiving inputs from lesioned macula.ConclusionIn MD, structural and functional changes in cerebral circuits and visual pathway can happen, involving both cerebral volume and activation patterns. These modifications, possibly due to neuronal plasticity (already observed and described for several brain areas), can allow patients to compensate for macular damage and gives therapeutic perspectives which could be achievable through an association between oculomotor training and biochemical stimulation of neuronal plasticity.

Evolving diagnostic criteria in primary lateral sclerosis: The clinical and radiological basis of “probable PLS”

IntroductionPrimary lateral sclerosis is a rare neurodegenerative disorder of the upper motor neurons. Diagnostic criteria have changed considerably over the years, and the recent consensus criteria introduced ‘probable PLS’ for patients with a symptom duration of 2–4 years. The objective of this study is the systematic evaluation of clinical and neuroimaging characteristics in early PLS by studying a group of ‘probable PLS patients’ in comparison to a cohort of established PLS patients. MethodsIn a prospective neuroimaging study, thirty-nine patients were stratified by the new consensus criteria into ‘probable’ (symptom duration 2–4 years) or ‘definite’ PLS (symptom duration >4 years). Patients were evaluated with a standardised battery of clinical instruments (ALSFRS-r, Penn upper motor neuron score, the modified Ashworth spasticity scale), whole genome sequencing, and underwent structural and diffusion MRI. The imaging profile of the two PLS cohorts were contrasted to a dataset of 100 healthy controls. All ‘probable PLS’ patients subsequently fulfilled criteria for ‘definite’ PLS on longitudinal follow-up and none transitioned to develop ALS. ResultsPLS patients tested negative for known ALS- or HSP-associated mutations on whole genome sequencing. Despite their shorter symptom duration, ‘probable PLS’ patients already exhibited considerable functional disability, upper motor neuron disease burden and the majority of them required walking aids for safe ambulation. Their ALSFRS-r, UMN and modified Ashworth score means were 83%, 98% and 85% of the ‘definite’ group respectively. Motor cortex thickness was significantly reduced in both PLS groups in comparison to controls, but cortical changes were less widespread in ‘probable’ PLS on morphometric analyses. Corticospinal tract and corpus callosum metrics were relatively well preserved in the ‘probable’ group in contrast to the widespread white matter degeneration observed in the ‘definite’ group. ConclusionsOur clinical and radiological analyses support the recent introduction of the ‘probable’ PLS category, as this cohort already exhibits considerable disability and cerebral changes consistent with established PLS. Before the publication of the new consensus criteria, these patients would have not been diagnosed with PLS on the basis of their symptom duration despite their significant functional impairment and motor cortex atrophy. The introduction of this new category will facilitate earlier recruitment into clinical trials, and shorten the protracted diagnostic uncertainty the majority of PLS patients face.

A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS.

To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. NCT02405182.

Validation of MRI biomarker of white matter degeneration for ALS clinical trials

Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder characterized by degeneration of motor neurons in the brain and spinal cord.1 It is part of the ALS–frontotemporal dementia spectrum of disorders that dismantle systematically the behavioral-executive-motor neuronal supernetwork. Measures of strength or function have served as primary outcome measures for most ALS treatment trials.2 Advanced neuroimaging techniques offer the potential to aid in diagnosing ALS and monitoring disease progression. Diffusion tensor imaging (DTI), a robust MRI tool for in vivo analysis of white matter (WM) neuronal tracts, has been applied successfully to study ALS in cross-sectional and longitudinal single-center cohort studies.3–6 Regional reduction of DTI metrics such as fractional anisotropy (FA) has been used as a marker for axonal degeneration and myelin degradation.3,4

Ultra-High-Field Diffusion Tensor Imaging Identifies Discrete Patterns of Concussive Injury in the Rodent Brain.

Although concussions can result in persistent neurological post-concussion symptoms, they are typically invisible on routine magnetic resonance imaging (MRI) scans. Our study aimed to investigate the use of ultra-high-field diffusion tensor imaging (UHF-DTI) in discerning severity-dependent microstructural changes in the mouse brain following a concussion. Twenty-three C57BL/6 mice were randomly allocated into three groups: the low concussive (LC, n = 9) injury group, the high concussive (HC, n = 6) injury group, and the sham control (SC, n = 7) group. Mice were perfused on day 2 post-injury, and the brains were scanned on a 16.4T MRI scanner with UHF-DTI and neurite orientation dispersion imaging (NODDI). Finite element analysis (FEA) was performed to determine the pattern and extent of the physical impact on the brain tissue. MRI findings were correlated with histopathological analysis in a subset of mice. In the LC group, increased fractional anisotropy (FA) and decreased orientation dispersion index (ODI) but limited neurite density index (NDI) changes were found in the gray matter, and minimal changes to white matter (WM) were observed. The HC group presented increased mean diffusivity (MD), decreased NDI, and decreased ODI in the WM and gray matter (GM); decreased FA was also found in a small area of the WM. WM changes were associated with WM degeneration and neuroinflammation. FEA showed varying region-dependent degrees of stress, in line with the different imaging findings. This study provides evidence that UHF-DTI combined with NODDI can detect concussions of variable intensities. This has significant implications for the diagnosis of concussion in humans.

Contralesional White Matter Alterations in Patients After Hemispherotomy.

Cerebral lesions may cause degeneration and neuroplastic reorganization in both the ipsi- and the contralesional hemisphere, presumably creating an imbalance of primarily inhibitory interhemispheric influences produced via transcallosal pathways. The two hemispheres are thought to mutually hamper neuroplastic reorganization of the other hemisphere. The results of preceding degeneration and neuroplastic reorganization of white matter may be reflected by Diffusion Tensor Imaging-derived diffusivity parameters such as fractional anisotropy (FA). In this study, we applied Diffusion Tensor Imaging (DTI) to contrast the white matter status of the contralesional hemisphere of young lesioned brains with and without contralateral influences by comparing patients after hemispherotomy to those who had not undergone neurosurgery. DTI was applied to 43 healthy controls (26 females, mean age ± SD: 25.07 ± 11.33 years) and two groups of in total 51 epilepsy patients with comparable juvenile brain lesions (32 females, mean age ± SD: 25.69 ± 12.77 years) either after hemispherotomy (30 of 51 patients) or without neurosurgery (21 of 51 patients), respectively. FA values were compared between these groups using the unbiased tract-based spatial statistics approach. A voxel-wise ANCOVA controlling for age at scan yielded significant group differences in FA. A post hoc t-test between hemispherotomy patients and healthy controls revealed widespread supra-threshold voxels in the contralesional hemisphere of hemispherotomy patients indicating comparatively higher FA values (p < 0.05, FWE-corrected). The non-surgery group, in contrast, showed extensive supra-threshold voxels indicating lower FA values in the contralesional hemisphere as compared to healthy controls (p < 0.05, FWE-corrected). Whereas lower FA values are suggestive of pronounced contralesional degeneration in the non-surgery group, higher FA values in the hemispherotomy group may be interpreted as a result of preceding plastic remodeling. We conclude that, whether juvenile brain lesions are associated with contralesional degeneration or reorganization partly depends on the ipsilesional hemisphere. Contralesional reorganization as observed in hemispherotomy patients was most likely enabled by the complete neurosurgical deafferentation of the ipsilesional hemisphere and, thereby, the disinhibition of the neuroplastic potential of the contralesional hemisphere. The main argument of this study is that hemispherotomy may be seen as a major plastic stimulus and as a prerequisite for contralesional neuroplastic remodeling in patients with juvenile brain lesions.

CANINE DISTEMPER VIRUS IN THE SEA OTTER (ENHYDRA LUTRIS) POPULATION IN WASHINGTON STATE, USA.

Before 2001, all serosurveys for morbilliviruses in sea otters (Enhydra lutris) in California, Washington, and Alaska, US, documented a 0% seroprevalence. The first published serologic detections of morbillivirus in sea otters occurred in 2001-02 in live-captured Washington sea otters, with a documented 80% seroprevalence. We conducted a retrospective study of sea otter cases from 1989 to 2010 compiled at the US Geological Survey, National Wildlife Health Center to identify cases of morbilliviral disease in Washington sea otters and to characterize the disease using immunohistochemistry, reverse transcription (RT)-PCR, genetic sequencing, virus isolation, and serology. We identified six cases of morbilliviral disease and 12 cases of morbilliviral infection in this population of sea otters during 2000-10. Significant histologic findings included inflammation in the white and gray matter of the brain characterized by lymphoplasmacytic perivascular cuffing, neuronal necrosis, and satellitosis in gray matter and by spongiosis, myelin degeneration, spheroids, and gemistocytes in white matter. Intranuclear and intracytoplasmic viral inclusion bodies were found in neurons, Purkinje cells, and glia. Immunohistochemistry for canine distemper virus (CDV) showed positive staining in neurons, glial cells, and cell processes. A pan-morbillivirus RT-PCR with subsequent restriction endonuclease digestion or sequencing identified CDV. Virus isolation was not successful. Two sea otters with morbilliviral encephalitis showed greater antibody titers to CDV than phocine distemper virus. Histologic changes were confined to the central nervous system and resembled neurologic canine distemper in domestic dogs. Cases of sea otters with morbilliviral infection without histologic changes could represent early infections or incompletely cleared sublethal infections. We found that morbillivirus was present in the Washington sea otter population as early as 2000, and we provide a description of the pathology of canine distemper in sea otters.

Assessment of Cerebral and Cerebellar White Matter Microstructure in Spinocerebellar Ataxias 1, 2, 3, and 6 Using Diffusion MRI.

Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12–24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia.

Characterizing white matter connectivity in Alzheimer's disease and mild cognitive impairment: An automated fiber quantification analysis with two independent datasets

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia. Diffusion tensor imaging (DTI) has been widely used to show structural integrity and delineate white matter (WM) degeneration in AD. The automated fiber quantification (AFQ) method is a fully automated approach that can rapidly and reliably identify major WM fiber tracts and evaluate WM properties. The main aim of this study was to assess WM integrity and abnormities in a cohort of patients with amnestic mild cognitive impairment (aMCI) and AD as well as normal controls (NCs). For this purpose, we first used AFQ to identify 20 major WM tracts and assessed WM integrity and abnormalities in a cohort of 120 subjects (39 NCs, 34 aMCI patients and 47 AD patients) in a discovery dataset and 122 subjects (43 NCs, 37 aMCI patients and 42 AD patients) in a replicated dataset. Pointwise differences along WM tracts were identified in the discovery dataset and simultaneously confirmed in the replicated dataset. Next, we investigated the utility of DTI measures along WM tracts as features to distinguish patients with AD from NCs via multilevel cross validation using a support vector machine. Correlation analysis revealed the identified microstructural WM alterations and classification output to be highly associated with cognitive ability in the patient groups, suggesting that they may be a robust biomarker of AD. This systematic study provides a pipeline to examine WM integrity and its potential clinical application in AD and may be useful for studying other neurological and psychiatric disorders.