Diffusion MRI marks progressive alterations in fiber integrity in the zQ175DN mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disease affecting motor and cognitive abilities. Multiple studies have found white matter anomalies in HD-affected humans and animal models of HD. The identification of sensitive white-matter-based biomarkers in HD animal models will be important in understanding disease mechanisms and testing the efficacy of therapeutic interventions. Here we investigated the progression of white matter deficits in the knock-in zQ175DN heterozygous (HET) mouse model of HD at 3, 6 and 11 months of age (M), reflecting different states of phenotypic progression. We compared findings from traditional diffusion tensor imaging (DTI) and advanced fixel-based analysis (FBA) diffusion metrics for their sensitivity in detecting white matter anomalies in the striatum, motor cortex, and segments of the corpus callosum. FBA metrics revealed progressive and widespread reductions of fiber cross-section and fiber density in myelinated bundles of HET mice. The corpus callosum genu was the most affected structure in HET mice at 6 and 11 M based on the DTI and FBA metrics, while the striatum showed the earliest progressive differences starting at 3 M based on the FBA metrics. Overall, FBA metrics detected earlier and more prominent alterations in myelinated fiber bundles compared to the DTI metrics. Luxol fast blue staining showed no loss in myelin density, indicating that diffusion anomalies could not be explained by myelin reduction but diffusion anomalies in HET mice were accompanied by increased levels of neurofilament light chain protein at 11 M. Altogether, our findings reveal progressive alterations in myelinated fiber bundles that can be measured using diffusion MRI, representing a candidate noninvasive imaging biomarker to study phenotype progression and the efficacy of therapeutic interventions in zQ175DN mice. Moreover, our study exposed higher sensitivity of FBA than DTI metrics, suggesting a potential benefit of adopting these advanced metrics in other contexts, including biomarker development in humans.

Longitudinal alterations in brain perfusion and vascular reactivity in the zQ175DN mouse model of Huntington's disease.

BACKGROUND: Huntington's disease (HD) is marked by a CAG-repeat expansion in the huntingtin gene that causes neuronal dysfunction and loss, affecting mainly the striatum and the cortex. Alterations in the neurovascular coupling system have been shown to lead to dysregulated energy supply to brain regions in several neurological diseases, including HD, which could potentially trigger the process of neurodegeneration. In particular, it has been observed in cross-sectional human HD studies that vascular alterations are associated to impaired cerebral blood flow (CBF). To assess whether whole-brain changes in CBF are present and follow a pattern of progression, we investigated both resting-state brain perfusion and vascular reactivity longitudinally in the zQ175DN mouse model of HD. METHODS: Using pseudo-continuous arterial spin labelling (pCASL) MRI in the zQ175DN model of HD and age-matched wild-type (WT) mice, we assessed whole-brain, resting-state perfusion at 3, 6 and 9 and 13 months of age, and assessed hypercapnia-induced cerebrovascular reactivity (CVR), at 4.5, 6, 9 and 15 months of age. RESULTS: We found increased perfusion in cortical regions of zQ175DN HET mice at 3 months of age, and a reduction of this anomaly at 6 and 9 months, ages at which behavioural deficits have been reported. On the other hand, under hypercapnia, CBF was reduced in zQ175DN HET mice as compared to the WT: for multiple brain regions at 6 months of age, for only somatosensory and retrosplenial cortices at 9 months of age, and brain-wide by 15 months. CVR impairments in cortical regions, the thalamus and globus pallidus were observed in zQ175DN HET mice at 9 months, with whole brain reactivity diminished at 15 months of age. Interestingly, blood vessel density was increased in the motor cortex at 3 months, while average vessel length was reduced in the lateral portion of the caudate putamen at 6 months of age. CONCLUSION: Our findings reveal early cortical resting-state hyperperfusion and impaired CVR at ages that present motor anomalies in this HD model, suggesting that further characterization of brain perfusion alterations in animal models is warranted as a potential therapeutic target in HD.

Resting-state fMRI reveals longitudinal alterations in brain network connectivity in the zQ175DN mouse model of Huntington's disease.

Huntington's disease is an autosomal, dominantly inherited neurodegenerative disease caused by an expansion of the CAG repeats in exon 1 of the huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result in the impairment of striatal and cortical circuits that affect the brain's large-scale network functionality. However, the evolution of these disease-driven, large-scale connectivity alterations is still poorly understood. Here we used resting-state fMRI to investigate functional connectivity changes in a mouse model of Huntington's disease in several relevant brain networks and how they are affected at different ages that follow a disease-like phenotypic progression. Towards this, we used the heterozygous (HET) form of the zQ175DN Huntington's disease mouse model that recapitulates aspects of human disease pathology. Seed- and Region-based analyses were performed at different ages, on 3-, 6-, 10-, and 12-month-old HET and age-matched wild-type mice. Our results demonstrate decreased connectivity starting at 6 months of age, most prominently in regions such as the retrosplenial and cingulate cortices, pertaining to the default mode-like network and auditory and visual cortices, part of the associative cortical network. At 12 months, we observe a shift towards decreased connectivity in regions such as the somatosensory cortices, pertaining to the lateral cortical network, and the caudate putamen, a constituent of the subcortical network. Moreover, we assessed the impact of distinct Huntington's Disease-like pathology of the zQ175DN HET mice on age-dependent connectivity between different brain regions and networks where we demonstrate that connectivity strength follows a non-linear, inverted U-shape pattern, a well-known phenomenon of development and normal aging. Conversely, the neuropathologically driven alteration of connectivity, especially in the default mode and associative cortical networks, showed diminished age-dependent evolution of functional connectivity. These findings reveal that in this Huntington's disease model, altered connectivity starts with cortical network aberrations which precede striatal connectivity changes, that appear only at a later age. Taken together, these results suggest that the age-dependent cortical network dysfunction seen in rodents could represent a relevant pathological process in Huntington's disease progression.

ADEPT: Accurate Diffusion Echo-Planar imaging with multi-contrast shoTs.

PURPOSE: To introduce a novel imaging and parameter estimation framework for accurate multi-shot diffusion MRI. THEORY AND METHODS: We propose a new framework called ADEPT (Accurate Diffusion Echo-Planar imaging with multi-contrast shoTs) that enables fast diffusion MRI by allowing diffusion contrast settings to change between shots in a multi-shot EPI acquisition (i.e., intra-scan modulation). The framework estimates diffusion parameter maps directly from the acquired intra-scan modulated k-space data, while simultaneously accounting for shot-to-shot phase inconsistencies. The performance of the estimation framework is evaluated using Monte Carlo simulation studies and in-vivo experiments and compared to that of reference methods that rely on parallel imaging for shot-to-shot phase correction. RESULTS: Simulation and real-data experiments show that ADEPT yields more accurate and more precise estimates of the diffusion metrics in multi-shot EPI data in comparison with the reference methods. CONCLUSION: ADEPT allows fast multi-shot EPI diffusion MRI without significantly degrading the accuracy and precision of the estimated diffusion maps.

Resting Brain Fluctuations Are Intrinsically Coupled to Visual Response Dynamics.

How do intrinsic brain dynamics interact with processing of external sensory stimuli? We sought new insights using functional magnetic resonance imaging to track spatiotemporal activity patterns at the whole brain level in lightly anesthetized mice, during both resting conditions and visual stimulation trials. Our results provide evidence that quasiperiodic patterns (QPPs) are the most prominent component of mouse resting brain dynamics. These QPPs captured the temporal alignment of anticorrelation between the default mode (DMN)- and task-positive (TPN)-like networks, with global brain fluctuations, and activity in neuromodulatory nuclei of the reticular formation. Specifically, the phase of QPPs prior to stimulation could significantly stratify subsequent visual response magnitude, suggesting QPPs relate to brain state fluctuations. This is the first observation in mice that dynamics of the DMN- and TPN-like networks, and particularly their anticorrelation, capture a brain state dynamic that affects sensory processing. Interestingly, QPPs also displayed transient onset response properties during visual stimulation, which covaried with deactivations in the reticular formation. We conclude that QPPs appear to capture a brain state fluctuation that may be orchestrated through neuromodulation. Our findings provide new frontiers to understand the neural processes that shape functional brain states and modulate sensory input processing.

Accelerating in vivo fast spin echo high angular resolution diffusion imaging with an isotropic resolution in mice through compressed sensing.

PURPOSE: Echo planar imaging (EPI) is commonly used to acquire the many volumes needed for high angular resolution diffusion Imaging (HARDI), posing a higher risk for artifacts, such as distortion and deformation. An alternative to EPI is fast spin echo (FSE) imaging, which has fewer artifacts but is inherently slower. The aim is to accelerate FSE such that a HARDI data set can be acquired in a time comparable to EPI using compressed sensing. METHODS: Compressed sensing was applied in either q-space or simultaneously in k-space and q-space, by undersampling the k-space in the phase-encoding direction or retrospectively eliminating diffusion directions for different degrees of undersampling. To test the replicability of the acquisition and reconstruction, brain data were acquired from six mice, and a numerical phantom experiment was performed. All HARDI data were analyzed individually using constrained spherical deconvolution, and the apparent fiber density and complexity metric were evaluated, together with whole-brain tractography. RESULTS: The apparent fiber density and complexity metric showed relatively minor differences when only q-space undersampling was used, but deteriorate when k-space undersampling was applied. Likewise, the tract density weighted image showed good results when only q-space undersampling was applied using 15 directions or more, but information was lost when fewer volumes or k-space undersampling were used. CONCLUSION: It was found that acquiring 15 to 20 diffusion directions with a full k-space and reconstructed using compressed sensing could suffice for a replicable measurement of quantitative measures in mice, where areas near the sinuses and ear cavities are untainted by signal loss.

Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA.

BACKGROUND: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. METHODS: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load. RESULTS: Treatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. CONCLUSIONS: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.

Neuroplasticity in the cerebello-thalamo-basal ganglia pathway: A longitudinal in vivo MRI study in male songbirds.

Similar to human speech, bird song is controlled by several pathways including a cortico-basal ganglia-thalamo-cortical (C-BG-T-C) loop. Neurotoxic disengagement of the basal ganglia component, i.e. Area X, induces long-term changes in song performance, while most of the lesioned area regenerates within the first months. Importantly however, the timing and spatial extent of structural neuroplastic events potentially affecting other constituents of the C-BG-T-C loop is not clear. We designed a longitudinal MRI study where changes in brain structure were evaluated relative to the time after neurotoxic lesioning or to vocal performance. By acquiring both Diffusion Tensor Imaging and 3-dimensional anatomical scans, we were able to track alterations in respectively intrinsic tissue properties and local volume. Voxel-based statistical analyses revealed structural remodeling remote to the lesion, i.e. in the thalamus and, surprisingly, the cerebellum, both peaking within the first two months after lesioning Area X. Voxel-wise correlations between song performance and MRI parameters uncovered intriguing brain-behavior relationships in several brain areas pertaining to the C-BG-T-C loop supervising vocal motor control. Our results clearly point to structural neuroplasticity in the cerebellum induced by basal ganglia (striatal) damage and might point to the existence of a human-like cerebello-thalamic-basal ganglia pathway capable of modifying vocal motor output.

Volumetric development of the zebra finch brain throughout the first 200 days of post-hatch life traced by in vivo MRI.

The first months of life are characterized by massive neuroplastic processes that parallel the acquisition of skills and abilities vital for proper functioning in later life. Likewise, juvenile songbirds learn the song sung by their tutor during the first months after hatching. To date, most studies targeting brain development in songbirds exclusively focus on the song control and auditory pathways. To gain a comprehensive insight into structural developmental plasticity of the entire zebra finch brain throughout the different subphases of song learning, we designed a longitudinal study in a group of male (16) and female (19) zebra finches. We collected T2-weighted 3-dimensional anatomical scans at six developmental milestones throughout the process of song learning, i.e. 20, 30, 40, 65, 90 and 120 days post hatching (dph), and one additional time point well after song crystallization, i.e. 200 dph. We observed that the total brain volume initially increases, peaks around 30-40 dph and decreases towards the end of the study. Further, we performed brain-wide voxel-based volumetric analyses to create spatio-temporal maps indicating when specific brain areas increase or decrease in volume, relative to the subphases of song learning. These maps informed (1) that most areas implicated in song control change early, i.e. between 20 and 65 dph, and are embedded in large clusters that cover major subdivisions of the zebra finch brain, (2) that volume changes between consecutive subphases of vocal learning appear highly similar in males and females, and (3) that only more rostrally situated brain regions change in volume towards later ages. Lastly, besides detecting sex differences in local tissue volume that align with previous studies, we uncovered two additional brain loci that are larger in male compared to female zebra finches. These volume differences co-localize with areas related to the song control and auditory pathways and can therefore be associated to the behavioral difference as only male zebra finches sing. In sum, our data point to clear heterochronous patterns of brain development similar to brain development in mammalian species and this work can serve as a reference for future neurodevelopmental imaging studies in zebra finches.

Dynamic resting state fMRI analysis in mice reveals a set of Quasi-Periodic Patterns and illustrates their relationship with the global signal.

Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural activity. Although there has been considerable advancement in the development of mouse resting state fMRI (rsfMRI), very little remains known about its dynamic repertoire. Here, we report for the first time the detection of a set of recurring spatiotemporal Quasi-Periodic Patterns (QPPs) in mice, which show spatial similarity with known resting state networks. Furthermore, we establish a close relationship between several of these patterns and the global signal. We acquired high temporal rsfMRI scans under conditions of low (LA) and high (HA) medetomidine-isoflurane anesthesia. We then employed the algorithm developed by Majeed et al. (2011), previously applied in rats and humans, which detects and averages recurring spatiotemporal patterns in the LF BOLD signal. One type of observed patterns in mice was highly similar to those originally observed in rats, displaying propagation from lateral to medial cortical regions, which suggestively pertain to a mouse Task-Positive like network (TPN) and Default Mode like network (DMN). Other QPPs showed more widespread or striatal involvement and were no longer detected after global signal regression (GSR). This was further supported by diminished detection of subcortical dynamics after GSR, with cortical dynamics predominating. Observed QPPs were both qualitatively and quantitatively determined to be consistent across both anesthesia conditions, with GSR producing the same outcome. Under LA, QPPs were consistently detected at both group and single subject level. Under HA, consistency and pattern occurrence rate decreased, whilst cortical contribution to the patterns diminished. These findings confirm the robustness of QPPs across species and demonstrate a new approach to study mouse LF BOLD spatiotemporal dynamics and mechanisms underlying functional connectivity. The observed impact of GSR on QPPs might help better comprehend its controversial role in conventional resting state studies. Finally, consistent detection of QPPs at single subject level under LA promises a step forward towards more reliable mouse rsfMRI and further confirms the importance of selecting an optimal anesthesia regime.

A three-dimensional digital neurological atlas of the mustached bat (Pteronotus parnellii).

Substantial knowledge of auditory processing within mammalian nervous systems emerged from neurophysiological studies of the mustached bat (Pteronotus parnellii). This highly social and vocal species retrieves precise information about the velocity and range of its targets through echolocation. Such high acoustic processing demands were likely the evolutionary pressures driving the over-development at peripheral (cochlea), metencephalic (cochlear nucleus), mesencephalic (inferior colliculus), diencephalic (medial geniculate body of the thalamus), and telencephalic (auditory cortex) auditory processing levels in this species. Auditory researchers stand to benefit from a three dimensional brain atlas of this species, due to its considerable contribution to auditory neuroscience. Our MRI-based atlas was generated from 2 sets of image data of an ex-vivo male mustached bat's brain: a detailed 3D-T2-weighted-RARE scan [(59 × 63 x 85) µm3] and track density images based on super resolution diffusion tensor images [(78) µm3] reconstructed from a set of low resolution diffusion weighted images using Super-Resolution-Reconstruction (SRR). By surface-rendering these delineations and extrapolating from cortical landmarks and data from previous studies, we generated overlays that estimate the locations of classic functional subregions within mustached bat auditory cortex. This atlas is freely available from our website and can simplify future electrophysiological, microinjection, and neuroimaging studies in this and related species.

Exploring sex differences in the adult zebra finch brain: In vivo diffusion tensor imaging and ex vivo super-resolution track density imaging.

Zebra finches are an excellent model to study the process of vocal learning, a complex socially-learned tool of communication that forms the basis of spoken human language. So far, structural investigation of the zebra finch brain has been performed ex vivo using invasive methods such as histology. These methods are highly specific, however, they strongly interfere with performing whole-brain analyses and exclude longitudinal studies aimed at establishing causal correlations between neuroplastic events and specific behavioral performances. Therefore, the aim of the current study was to implement an in vivo Diffusion Tensor Imaging (DTI) protocol sensitive enough to detect structural sex differences in the adult zebra finch brain. Voxel-wise comparison of male and female DTI parameter maps shows clear differences in several components of the song control system (i.e. Area X surroundings, the high vocal center (HVC) and the lateral magnocellular nucleus of the anterior nidopallium (LMAN)), which corroborate previous findings and are in line with the clear behavioral difference as only males sing. Furthermore, to obtain additional insights into the 3-dimensional organization of the zebra finch brain and clarify findings obtained by the in vivo study, ex vivo DTI data of the male and female brain were acquired as well, using a recently established super-resolution reconstruction (SRR) imaging strategy. Interestingly, the SRR-DTI approach led to a marked reduction in acquisition time without interfering with the (spatial and angular) resolution and SNR which enabled to acquire a data set characterized by a 78µm isotropic resolution including 90 diffusion gradient directions within 44h of scanning time. Based on the reconstructed SRR-DTI maps, whole brain probabilistic Track Density Imaging (TDI) was performed for the purpose of super resolved track density imaging, further pushing the resolution up to 40µm isotropic. The DTI and TDI maps realized atlas-quality anatomical maps that enable a clear delineation of most components of the song control and auditory systems. In conclusion, this study paves the way for longitudinal in vivo and high-resolution ex vivo experiments aimed at disentangling neuroplastic events that characterize the critical period for vocal learning in zebra finch ontogeny.

Adult auditory brain responses to nestling begging calls in seasonal songbirds: an fMRI study in non-parenting male and female starlings (Sturnus vulgaris).

The present study aims to investigate whether begging calls elicit specific auditory responses in non-parenting birds, whether these responses are influenced by the hormonal status of the bird, and whether they reflect biparental care for offspring in the European starling (Sturnus vulgaris). An fMRI experiment was conducted to expose non-parenting male and female European starlings to recordings of conspecific nestling begging calls during both artificially induced breeding and non-breeding seasons. This response was compared with their reaction to conspecific individual warbling song motifs and artificial pure tones, serving as social species-specific and artificial control stimuli, respectively. Our findings reveal that begging calls evoke a response in non-parenting male and female starlings, with significantly higher responsiveness observed in the right Field L and the Caudomedial Nidopallium (NCM), regardless of season or sex. Moreover, a significant seasonal variation in auditory brain responses was elicited in both sexes exclusively by begging calls, not by the applied control stimuli, within a ventral midsagittal region of NCM. This heightened response to begging calls, even in non-parenting birds, in the right primary auditory system (Field L), and the photoperiod induced hormonal neuromodulation of auditory responses to offspring's begging calls in the secondary auditory system (NCM), bears resemblance to mammalian responses to hunger calls. This suggests a convergent evolution aimed at facilitating swift adult responses to such calls crucial for offspring survival.

Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model.

BACKGROUND: Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery. METHODS: We characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks. RESULTS: The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes - one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans. CONCLUSION: Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research. HIGHLIGHTS: Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset. DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development. Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.

Identification and characterization of Huntington related pathology: an in vivo DKI imaging study.

An important focus of Huntington Disease (HD) research is the identification of symptom-independent biomarkers of HD neuropathology. There is an urgent need for reproducible, sensitive and specific outcome measures, which can be used to track disease onset as well as progression. Neuroimaging studies, in particular diffusion-based MRI methods, are powerful probes for characterizing the effects of disease and aging on tissue microstructure. We report novel diffusional kurtosis imaging (DKI) findings in aged transgenic HD rats. We demonstrate altered diffusion metrics in the (pre)frontal cerebral cortex, external capsule and striatum. Presence of increased diffusion complexity and restriction in the striatum is confirmed by an increased fiber dispersion in this region. Immunostaining of the same specimens reveals decreased number of microglia in the (pre)frontal cortex, and increased numbers of oligodendrocytes in the striatum. We conclude that DKI allows sensitive and specific characterization of altered tissue integrity in this HD rat model, indicating a promising potential for diagnostic imaging of gray and white matter pathology.

Microstructural changes observed with DKI in a transgenic Huntington rat model: evidence for abnormal neurodevelopment.

Huntington Disease (HD) is a fatal neurodegenerative disorder, caused by a mutation in the Huntington gene. Although HD is most often diagnosed in mid-life, the key to its clinical expression may be found during brain maturation. In the present work, we performed in vivo diffusion kurtosis imaging (DKI) in order to study brain microstructure alterations in developing transgenic HD rat pups. Several developing brain regions, relevant for HD pathology (caudate putamen, cortex, corpus callosum, external capsule and anterior commissure anterior), were examined at postnatal days 15 (P15) and 30 (P30), and DKI results were validated with histology. At P15, we observed higher mean (MD) and radial (RD) diffusivity values in the cortex of transgenic HD rat pups. In addition, at the age of P30, lower axial kurtosis (AK) values in the caudate putamen of transgenic HD pups were found. At the level of the external capsule, higher MD values at P15 but lower MD and AD values at P30 were detected. The observed DKI results have been confirmed by myelin basic protein immunohistochemistry, which revealed a reduced fiber staining as well as less ordered fibers in transgenic HD rat pups. These results indicate that neuronal development in young transgenic HD rat pups occurs differently compared to controls and that the presence of mutant huntingtin has an influence on postnatal brain development. In this context, various diffusivity parameters estimated by the DKI model are a powerful tool to assess changes in tissue microstructure and detect developmental changes in young transgenic HD rat pups.

Altered basal forebrain function during whole-brain network activity at pre- and early-plaque stages of Alzheimer's disease in TgF344-AD rats.

BACKGROUND: Imbalanced synaptic transmission appears to be an early driver in Alzheimer's disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits.  METHODS: To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. RESULTS: At the pre-plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default mode-like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy, and alterations in a number of cholinergic, gaba-ergic, and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aß) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. In wild-type rats, at both time points, peak activity in the BFB preceded peak activity in other brain regions-indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. CONCLUSIONS: This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission, possibly by modulating astrogliosis in the BFB, might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD.

Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer's disease.

Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer's disease (AD). However, the underlying mechanisms remain unclear. Here, we aimed to investigate long-term neurological consequences of ovariectomy in a rodent AD model, TG2576 (TG), and wild-type mice (WT) that underwent an ovariectomy or sham-operation, using in vivo MRI biomarkers. An increase in osmoregulation and energy metabolism biomarkers in the hypothalamus, a decrease in white matter integrity, and a decrease in the resting-state functional connectivity was observed in ovariectomized TG mice compared to sham-operated TG mice. In addition, we observed an increase in functional connectivity in ovariectomized WT mice compared to sham-operated WT mice. Furthermore, genotype (TG vs. WT) effects on imaging markers and GFAP immunoreactivity levels were observed, but there was no effect of interaction (Genotype × Surgery) on amyloid-beta-and GFAP immunoreactivity levels. Taken together, our results indicated that both genotype and ovariectomy alters imaging biomarkers associated with AD.

A Unified Maximum Likelihood Framework for Simultaneous Motion and $T_{1}$ Estimation in Quantitative MR $T_{1}$ Mapping.

In quantitative MR T1 mapping, the spin-lattice relaxation time T1 of tissues is estimated from a series of T1 -weighted images. As the T1 estimation is a voxel-wise estimation procedure, correct spatial alignment of the T1 -weighted images is crucial. Conventionally, the T1 -weighted images are first registered based on a general-purpose registration metric, after which the T1 map is estimated. However, as demonstrated in this paper, such a two-step approach leads to a bias in the final T1 map. In our work, instead of considering motion correction as a preprocessing step, we recover the motion-free T1 map using a unified estimation approach. In particular, we propose a unified framework where the motion parameters and the T1 map are simultaneously estimated with a Maximum Likelihood (ML) estimator. With our framework, the relaxation model, the motion model as well as the data statistics are jointly incorporated to provide substantially more accurate motion and T1 parameter estimates. Experiments with realistic Monte Carlo simulations show that the proposed unified ML framework outperforms the conventional two-step approach as well as state-of-the-art model-based approaches, in terms of both motion and T1 map accuracy and mean-square error. Furthermore, the proposed method was additionally validated in a controlled experiment with real T1 -weighted data and with two in vivo human brain T1 -weighted data sets, showing its applicability in real-life scenarios.

Monitoring Blood-Brain Barrier Integrity Following Amyloid-ß Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model.

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-ß (Aß) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aßimmunotherapy may affect blood-brain barrier (BBB) integrity. OBJECTIVE: To examine vascular integrity in aged (12-16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies. METHODS: Mice were treated on a weekly basis using anti-Aßimmunotherapy (3D6) and follow up was done longitudinally from 1-12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1-weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA). RESULTS: A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls'Prussian blue histopathological analysis. CONCLUSION: Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool.