Combined assessment of progressive apraxia of speech brain microstructure by diffusion tensor imaging tractography and multishell neurite orientation dispersion and density imaging.

BACKGROUND: Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure. METHODS: Twenty-two PAOS patients and 26 age- and sex-matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions. RESULTS: Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus. CONCLUSIONS: DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.

Diffusion tensor imaging-based multi-fiber tracking reconstructions can regionally differentiate phonetic versus prosodic subtypes of progressive apraxia of speech.

Two subtypes of progressive apraxia of speech (PAOS) have been recognized: phonetic PAOS (PAOS_ph) where speech output is dominated by distorted sound substitutions and prosodic PAOS (PAOS_pr) which is dominated by segmented speech. We investigate whether these PAOS subtypes have different white matter microstructural abnormalities measured by diffusion tensor tractography. Thirty-three patients with PAOS (21 PAOS_ph and 12 PAOS_pr) and 19 healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent diffusion MRI. Using a whole-brain tractography approach, fractional anisotropy (FA) and mean diffusivity (MD) were extracted for cortico-cortical, cortico-subcortical, cortical-projection, and cerebello-cortical white matter tracts. A hierarchical linear model was applied to assess tract-level FA and MD across groups. Both PAOS_ph and PAOS_pr showed degeneration of cortico-cortical, cortico-subcortical, cortical-projection, and cerebello-cortical white matter tracts compared to controls. However, degeneration of the body of corpus callosum, superior thalamic radiation, and superior cerebellar peduncle was greater in PAOS_pr compared to PAOS_ph, and degeneration of the inferior segment of the superior longitudinal fasciculus (SLF) was greater in PAOS_ph compared to PAOS_pr. Worse parkinsonism correlated with greater degeneration of cortico-cortical and cortico-subcortical tracts in PAOS_ph. Apraxia of speech articulatory error score correlated with degeneration of the superior cerebellar peduncle tracts in PAOS_pr. Phonetic and prosodic PAOS involve the compromise of a similar network of tracts, although there are connectivity differences between types. Whereas clinical parameters are the current gold standard to distinguish PAOS subtypes, our results allege the use of DTI-based tractography as a supplementary method to investigate such variants.

Clinicopathologic features of a novel star-shaped transactive response DNA-binding protein 43 (TDP-43) pathology in the oldest old.

Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-ß in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findings, and AD neuropathologic changes for TDP-43 pathology using anti-phospho-TDP-43 antibodies. Seven cases (5%) only showed atypical TDP-43 inclusions that could not be typed. Immunohistochemistry and immunofluorescence assessed the atypical star-shaped TDP-43 pathology including its distribution, species, cellular localization, and colocalization with tau. All 7 had died at an extremely old age (median: 100 years [IQR: 94-101]) from nonneurological causes and none had dementia (4 cognitively unimpaired, 3 with amnestic mild cognitive impairment). Neuroimaging showed mild medial temporal involvement. Pathologically, the star-shaped TDP-43-positive inclusions were found in medial (subpial) amygdala and, occasionally, in basolateral regions. Hippocampus only showed TDP-43-positive neurites in the fimbria and subiculum while the frontal lobe was free of TDP-43 inclusions. The star-shaped inclusions were better detected with antibodies against N-terminal than C-terminal TDP-43. Double-labeling studies confirmed deposition of TDP-43 within astrocytes and colocalization with tau. We have identified a novel TDP-43 pathology with star-shaped morphology associated with superaging, with a homogeneous clinicopathologic picture, possibly representing a novel, true aging-related TDP-43 pathology.

Comparative assessment of regional tau distribution by Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer's & frontotemporal lobar degeneration patients.

Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.

Optimum Differentiation of Frontotemporal Lobar Degeneration from Alzheimer Disease Achieved with Cross-Sectional Tau Positron Emission Tomography.

OBJECTIVE: This study was undertaken to assess cross-sectional and longitudinal [18 F]-flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC). METHODS: One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated. RESULTS: Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%). INTERPRETATION: There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029.

Diffusion tractography of superior cerebellar peduncle and dentatorubrothalamic tracts in two autopsy confirmed progressive supranuclear palsy variants: Richardson syndrome and the speech-language variant.

BACKGROUND: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP. OBJECTIVES: To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson's syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL). METHODS: We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer's disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups. RESULTS: The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson's Disease Rating Scale correlated with the DRTT (p = 0.014). CONCLUSIONS: Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL.

Preliminary examination of early neuroconnectivity features in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MRI.

During the last decades, advances in the understanding of genetic, cellular, and microstructural alterations associated to Huntington's disease (HD) have improved the understanding of this progressive and fatal illness. However, events related to early neuropathological events, neuroinflammation, deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown. Ultra-high field diffusion MRI (UHFD-MRI) techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD. In addition, it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers. Moreover, qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events, compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration. The application of ultra-high field diffusion-MRI technology in animal models, particularly the R6/1 mice (a common preclinical mammalian model of HD), provide the opportunity to analyze alterations in a physiologically intact model of the disease. Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented, further application of different diffusion MRI techniques used in combination like diffusion tensor imaging, and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter. Thus, the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.

New molecular insights, innovative technologies, and medical approaches in the "Exploration of mechanisms in cortical plasticity".

No abstract present.

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra-high field MRI and diffusion tensor metrics.

OBJECTIVE: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS. METHODS: Ultra-high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A-SOD1) mice. RESULTS: Changes in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL and CS values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A-SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI. CONCLUSIONS: Changes in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CS as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.

Multicomponent diffusion analysis reveals microstructural alterations in spinal cord of a mouse model of amyotrophic lateral sclerosis ex vivo.

The microstructure changes associated with degeneration of spinal axons in amyotrophic lateral sclerosis (ALS) may be reflected in altered water diffusion properties, potentially detectable with diffusion-weighted (DW) MRI. Prior work revealed the classical mono-exponential model fails to precisely depict decay in DW signal at high b-values. In this study, we aim to investigate signal decay behaviors at ultra-high b-values for non-invasive assessment of spinal cord alterations in the transgenic SOD1G93A mouse model of ALS. A multiexponential diffusion analysis using regularized non-negative least squares (rNNLS) algorithm was applied to a series of thirty DW MR images with b-values ranging from 0 to 858,022 s/mm2 on ex vivo spinal cords of transgenic SOD1G93A and age-matched control mice. We compared the distributions of measured diffusion coefficient fractions between the groups. The measured diffusion weighted signals in log-scale showed non-linear decay behaviors with increased b-values. Faster signal decays were observed with diffusion gradients applied parallel to the long axis of the spinal cord compared to when oriented in the transverse direction. Multiexponential analysis at the lumbar level in the spinal cord identified ten subintervals. A significant decrease of diffusion coefficient fractions was found in the ranges of [1.63×10-8,3.70×10-6] mm2/s (P = 0.0002) and of [6.01×10-6,4.20×10-5] mm2/s (P = 0.0388) in SOD1G93A mice. Anisotropic diffusion signals persisted at ultra-high b-value DWIs of the mouse spinal cord and multiexponential diffusion analysis offers the potential to evaluate microstructural alterations of ALS-affected spinal cord non-invasively.

Editorial for "Evaluating the Therapeutic Effect of Low-Intensity Transcranial Ultrasound on Traumatic Brain Injury With Diffusion Kurtosis Imaging".

LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4 J. Magn. Reson. Imaging 2020;52:532-533.

Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.

Detection of axonal degeneration in a mouse model of Huntington's disease: comparison between diffusion tensor imaging and anomalous diffusion metrics.

OBJECTIVE: The goal of this work is to study the changes in white matter integrity in R6/2, a well-established animal model of Huntington's disease (HD) that are captured by ex vivo diffusion imaging (DTI) using a high field MRI (17.6 T). MATERIALS AND METHODS: DTI and continuous time random walk (CTRW) models were used to fit changes in the diffusion-weighted signal intensity in the corpus callosum of controls and in R6/2 mice. RESULTS: A significant 13% decrease in fractional anisotropy, a 7% increase in axial diffusion, and a 33% increase in radial diffusion were observed between R6/2 and control mice. No change was observed in the CTRW beta parameter, but a significant decrease in the alpha parameter (- 21%) was measured. Histological analysis of the corpus callosum showed a decrease in axonal organization, myelin alterations, and astrogliosis. Electron microscopy studies demonstrated ultrastructural changes in degenerating axons, such as an increase in tortuosity in the R6/2 mice. CONCLUSIONS: DTI and CTRW diffusion models display quantitative changes associated with the microstructural alterations observed in the corpus callosum of the R6/2 mice. The observed increase in the diffusivity and decrease in the alpha CTRW parameter providing support for the use of these diffusion models for non-invasive detection of white matter alterations in HD.

Ultra-High Field Diffusion MRI Reveals Early Axonal Pathology in Spinal Cord of ALS mice.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease characterized by a progressive degeneration of motor neurons leading to paralysis. Our previous MRI diffusion tensor imaging studies detected early white matter changes in the spinal cords of mice carrying the G93A-SOD1 mutation. Here, we extend those studies using ultra-high field MRI (17.6 T) and fluorescent microscopy to investigate the appearance of early structural and connectivity changes in the spinal cords of ALS mice. METHODS: The spinal cords from presymptomatic and symptomatic mice (80 to 120 days of age) were scanned (ex-vivo) using diffusion-weighted MRI. The fractional anisotropy (FA), axial (AD) and radial (RD) diffusivities were calculated for axial slices from the thoracic, cervical and lumbar regions of the spinal cords. The diffusion parameters were compared with fluorescence microscopy and membrane cellular markers from the same tissue regions. RESULTS: At early stages of the disease (day 80) in the lumbar region, we found, a 19% decrease in FA, a 9% decrease in AD and a 35% increase in RD. Similar changes were observed in cervical and thoracic spinal cord regions. Differences between control and ALS mice groups at the symptomatic stages (day 120) were larger. Quantitative fluorescence microscopy at 80 days, demonstrated a 22% reduction in axonal area and a 22% increase in axonal density. Tractography and quantitative connectome analyses measured by edge weights showed a 52% decrease in the lumbar regions of the spinal cords of this ALS mice group. A significant increase in ADC (23.3%) in the ALS mice group was related to an increase in aquaporin markers. CONCLUSIONS: These findings suggest that the combination of ultra-high field diffusion MRI with fluorescent ALS mice reporters is a useful approach to detect and characterize presymptomatic white matter micro-ultrastructural changes and axonal connectivity anomalies in ALS.

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis.

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro- and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High-field MRI data were acquired using a 9.4-T animal scanner to examine the spinal cord of an ALS mouse model at pre- and post-symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A-SOD1 mouse strain. DTI maps of diffusion-weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.

Diffusion tensor imaging identifies presymptomatic axonal degeneration in the spinal cord of ALS mice.

Extensive pathological evidence indicates that axonal degeneration represents an early and critical event in amyotrophic lateral sclerosis (ALS). Unfortunately, few MRI studies have focused in the early detection of white matter (WM) alterations in the spinal cord region. To unveil these WM changes, we performed high resolution diffusion tensor imaging (DTI) and correlated the results with histological analysis of adjacent slices taken from the spinal cords of presymptomatic mice. The DTI studies demonstrated a significant reduction in fractional anisotropy (FA) as well as axial diffusivities (AD) and an increase in radial diffusivity (RD), predominantly at lower segments of the spinal cord. Increases in FA and a reduction in AD and RD were observed in spinal cord (SC) gray matter (GM). Diffusion changes are associated with early and progressive alterations in axonal connectivity following a distal to proximal progression. Histological data tagging neuronal, axonal and glial cell markers demonstrated presymptomatic alterations in spinal cord WM and GM. This study demonstrates that DTI methods are optimal preclinical imaging tools to detect structural anomalies in WM and GM spinal cord during early stages of the disease.

Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington's disease.

Cumulative evidence indicates that the onset and severity of Huntington's disease (HD) symptoms correlate with connectivity deficits involving specific neuronal populations within cortical and basal ganglia circuits. Brain imaging studies and pathological reports further associated these deficits with alterations in cerebral white matter structure and axonal pathology. However, whether axonopathy represents an early pathogenic event or an epiphenomenon in HD remains unknown, nor is clear the identity of specific neuronal populations affected. To directly evaluate early axonal abnormalities in the context of HD in vivo, we bred transgenic YFP(J16) with R6/2 mice, a widely used HD model. Diffusion tensor imaging and fluorescence microscopy studies revealed a marked degeneration of callosal axons long before the onset of motor symptoms. Accordingly, a significant fraction of YFP-positive cortical neurons in YFP(J16) mice cortex were identified as callosal projection neurons. Callosal axon pathology progressively worsened with age and was influenced by polyglutamine tract length in mutant huntingtin (mhtt). Degenerating axons were dissociated from microscopically visible mhtt aggregates and did not result from loss of cortical neurons. Interestingly, other axonal populations were mildly or not affected, suggesting differential vulnerability to mhtt toxicity. Validating these results, increased vulnerability of callosal axons was documented in the brains of HD patients. Observations here provide a structural basis for the alterations in cerebral white matter structure widely reported in HD patients. Collectively, our data demonstrate a dying-back pattern of degeneration for cortical projection neurons affected in HD, suggesting that axons represent an early and potentially critical target for mhtt toxicity.