Blast-induced axonal degeneration in the rat cerebellum in the absence of head movement

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or permitted in the lateral plane. Blast was found to produce axonal injury even with strict prevention of head movement. This axonal injury was restricted to the cerebellum, with the exception of injury in visual tracts secondary to ocular trauma. The cerebellar axonal injury was increased in rats in which blast-induced head movement was permitted, but the pattern of injury was unchanged. These findings support the contentions that blast per se, independent of head movement, is sufficient to induce axonal injury, and that axons in cerebellar white matter are particularly vulnerable to direct blast-induced injury.

Circulation of Nor98 Atypical Scrapie in Portuguese Sheep Confirmed by Transmission of Isolates into Transgenic Ovine ARQ-PrP Mice

Portugal was among the first European countries to report cases of Atypical Scrapie (ASc), the dominant form of Transmissible Spongiform Encephalopathy (TSE) in Portuguese small ruminants. Although the diagnostic phenotypes observed in Portuguese ASc cases seem identical to those described for Nor98, unequivocal identification requires TSE strain-typing using murine bioassays. In this regard, we initiated characterization of ASc isolates from sheep either homozygous for the ARQ genotype or the classical scrapie-resistant ARR genotype. Isolates from such genotypes were transmitted to TgshpXI mice expressing ovine PrPARQ. Mean incubation periods were 414 ± 58 and 483 ± 107 days in mice inoculated with AL141RQ/AF141RQ and AL141RR/AL141RR sheep isolates, respectively. Both isolates produced lesion profiles similar to French ASc Nor98 ‘discordant cases’, where vacuolation was observed in the hippocampus (G6), cerebral cortex at the thalamus (G8) level, cerebellar white matter (W1) and cerebral peduncles (W3). Immunohistochemical PrPSc deposition was observed in the hippocampus, cerebellar cortex, cerebellar white matter and cerebral peduncles in the form of aggregates and fine granules. These findings were consistent with previously reported cases of ASc Nor98 transmitted to transgenic TgshpXI mice, confirming that the ASc strain present in Portuguese sheep corresponds to ASc Nor98.

Cerebellar hemorrhages in patients with Dutch-type hereditary cerebral amyloid angiopathy

Background Recent studies suggest that superficially located cerebellar intracerebral hemorrhage (ICH) and microbleeds might point towards sporadic cerebral amyloid angiopathy (CAA). Aims We investigated the proportion of cerebellar ICH and asymptomatic macro- and microbleeds in Dutch-type hereditary CAA (D-CAA), a severe and essentially pure form of CAA. Methods Symptomatic patients with D-CAA (defined as ≥1 symptomatic ICH) and presymptomatic D-CAA mutation-carriers were included. We assessed magnetic resonance imaging scans for symptomatic (cerebellar) ICH and asymptomatic cerebellar macro- and microbleeds according to the STRIVE-criteria. Location was assessed as superficial-cerebellar (cortex, vermis or juxta-cortical) or deep-cerebellar (white matter, pedunculi cerebelli and gray nuclei). Results We included 63 participants (mean age 58 years, 60% women, 42 symptomatic). In total, the 42 symptomatic patients with D-CAA had 107 symptomatic ICH (range 1–7). None of these ICH were located in the cerebellum. Six of 42 (14%, 95%CI 4–25%) symptomatic patients and none of the 21 (0%, 95%CI 0–0%) presymptomatic carriers had ≥ 1 asymptomatic cerebellar macrobleed(s). All macrobleeds were superficially located. Cerebellar microbleeds were found in 40 of 63 (64%, 95%CI 52–76) participants (median 1.0, range 0–159), 81% in symptomatic patients and 29% in presymptomatic carriers. All microbleeds were strictly or predominantly superficially (ratio superficial versus deep 15:1) located. Conclusions Superficially located asymptomatic cerebellar macrobleeds and microbleeds are common in D-CAA. Cerebellar microbleeds are already present in the presymptomatic stage. Despite the high frequency of cerebellar micro and macrobleeds, CAA pathology did not result in symptomatic cerebellar ICH in patients with D-CAA.

Blast-Induced Axonal Degeneration In The Rat Cerebellum In The Absence of Head Movement

Blast exposure can injure brain by multiple mechanisms, and injury attributable to direct effects of the blast wave itself have been difficult to distinguish from that caused by rapid head displacement and other secondary processes. To resolve this issue, we used a rat model of blast exposure in which head movement was either strictly prevented or permitted in the lateral plane. Blast was found to produce axonal injury even with strict prevention of head movement. This axonal injury was restricted to the cerebellum, with the exception of injury in visual tracts secondary to ocular trauma. The cerebellar axonal injury was increased in rats in which blast-induced head movement was permitted, but the pattern of injury was unchanged. These findings support the contentions that blast per se, independent of head movement, is sufficient to induce axonal injury, and that axons in cerebellar white matter are particularly vulnerable to direct blast - induced injury.

Cerebellar Cortex and Cerebellar White Matter Volume in Normal Cognition, Mild Cognitive Impairment, and Dementia

The cerebellum is commonly viewed as a structure that is primarily responsible for the coordination of voluntary movement, gait, posture, and speech. Recent research has shown evidence that the cerebellum is also responsible for cognition. We analyzed 28 participants divided into three groups (9 with normal cognition, 9 with mild cognitive impairment, and 10 with moderate/severe cognitive impairment) based on the Montreal Cognitive Assessment. We analyzed the cerebellar cortex and white matter volume and assessed differences between groups. Participants with normal cognition had higher average values in total cerebellar volume, cerebellar white matter volume, and cerebellar cortex volume in both hemispheres, but by performing the Kruskal–Wallis test, we did not find these values to be statistically significant.

Tract Profiles of The Cerebellar Peduncles In Children Who Stutter

Cerebellar-cortical loops comprise critical neural circuitry that supports self-initiated movements and motor adjustments in response to perceived errors, functions that are affected in stuttering. It is unknown whether structural aspects of cerebellar circuitry are affected in stuttering, in particular in children close to symptom onset. Here we examined white matter diffusivity characteristics of the three cerebellar peduncles (CP) based on diffusion MRI (dMRI) data collected from 41 children who stutter (CWS) and 42 controls in the 3-11 year range. We hypothesized that CWS would exhibit decreased fractional anisotropy (FA) in the right CPs given the contralateral connectivity of the cerebellar-cortical loops and past reports of structural differences in left cortical areas in stuttering speakers. Automatic Fiber Quantification (AFQ) was used to track and segment cerebellar white matter pathways and to extract diffusivity measures. We found significant group differences for FA in the right Inferior CP (ICP) only: controls showed significantly higher FA in the right ventral ICP compared to CWS, controlling for age, sex, and verbal IQ. Furthermore, FA of right ICP was negatively correlated with stuttering frequency in CWS. These results suggest an early developmental difference in the right ICP for CWS compared to age-matched peers, which may indicate an alteration in error processing, a function previously linked to the ICP. Lower FA here may impact error monitoring and sensory input processing to guide motor corrections. Further longitudinal investigations in children may provide additional insights into how CP development links to stuttering persistence and recovery.

Placental endocrine function shapes cerebellar development and social behavior

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

Mapping of long-term cognitive and motor deficits in pediatric cerebellar brain tumor survivors into a cerebellar white matter atlas

Purpose Diaschisis of cerebrocerebellar loops contributes to cognitive and motor deficits in pediatric cerebellar brain tumor survivors. We used a cerebellar white matter atlas and hypothesized that lesion symptom mapping may reveal the critical lesions of cerebellar tracts. Methods We examined 31 long-term survivors of pediatric posterior fossa tumors (13 pilocytic astrocytoma, 18 medulloblastoma). Patients underwent neuronal imaging, examination for ataxia, fine motor and cognitive function, planning abilities, and executive function. Individual consolidated cerebellar lesions were drawn manually onto patients’ individual MRI and normalized into Montreal Neurologic Institute (MNI) space for further analysis with voxel-based lesion symptom mapping. Results Lesion symptom mapping linked deficits of motor function to the superior cerebellar peduncle (SCP), deep cerebellar nuclei (interposed nucleus (IN), fastigial nucleus (FN), ventromedial dentate nucleus (DN)), and inferior vermis (VIIIa, VIIIb, IX, X). Statistical maps of deficits of intelligence and executive function mapped with minor variations to the same cerebellar structures. Conclusion We identified lesions to the SCP next to deep cerebellar nuclei as critical for limiting both motor and cognitive function in pediatric cerebellar tumor survivors. Future strategies safeguarding motor and cognitive function will have to identify patients preoperatively at risk for damage to these critical structures and adapt multimodal therapeutic options accordingly.

Characterization of white matter branching in human cerebella: quantitative morphological assessment and fractal analysis of skeletonized MR images

Introduction: The aim of the present study was to investigate branching characteristics of the human cerebellar white matter by the means of findings obtained from the quantitative morphological assessment and fractal analysis of the skeletonized MR images of the human cerebellum. Methods: Thirty individuals with no apparent brain pathology (15 males and 15 females, ranging from 18 - 30 years of age) participated in this study. Their normal T2-weighted MR images of the cerebellar vermis (midsagittal plane) were examined. The skeletonizing procedure and subsequent quantitative morphological assessment of the acquired skeletonized MR images were performed. The following parameters were determined: the number of branches, the number of junctions, the amount of end-point voxels, junction voxels and slab voxels, the average and maximum branch lengths, the longest-shortest patch length, and the number of triple and quadruple points. Additionally, the individual branches of the obtained digital skeletons of the cerebellar white matter were examined and the following parameters were assessed: branch length variability, Euclidean distance, and branch length/Euclidean distance ratio. A fractal analysis was performed using the box counting method prior to and after the MR image skeletonizing procedure. The values of the fractal dimensions (FD) of both skeletonized and non-skeletonized MR images were calculated. Results: It was established that the cerebella, which had the maximum values of the FD, possessed a large number of small branches approximately equal in length and which were connected by numerous junctions, forming numerous endpoints. Those cerebella, which had higher values of the average branch length and greater branch length variability, showed lower values of the FD. The key characteristics of the digital skeleton that determined the values of the FD of the cerebellum and its skeletonized MR images were the number of branches and the number of junctions that had the strongest correlational relationships with the FD of the skeletonized MR images. We submitted a proposition to consider the number of branches and amount of junctions as a diagnostic criterion in the determination of normal values of the FD. Conclusions: The obtained data can be used as diagnostic criteria in assessment of the morphofunctional state of the cerebellum using magnetic resonance imaging (MRI) technique.

Cerebellar White Matter Abnormalities in Patients with Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy. Brain volumetry and diffusion tensor imaging (DTI) were performed in CMT patients with PMP22 duplication, MFN2, GJB1, or NEFL mutations to investigate for structural changes of the cerebellum.Volume in cerebellar white matter (WM) was significantly reduced in CMT patients with NEFL mutations. Abnormal DTI findings ​​were observed in the superior, middle, and inferior cerebellar peduncles predominantly in NEFL mutations, and partly in GJB1 mutations. Cerebellar ataxia was more prevalent in the NEFL mutation (72.7%) than GJB1 mutation (9.1%), but not observed in other genotypic subtypes, which indicates that structural cerebellar abnormalities were associated with the presence of cerebellar ataxia. However, NEFL and GJB1 mutations did not affect cerebellar gray matter (GM), and neither cerebellar GM nor WM abnormalities were observed in PMP22 duplication or MFN2 mutations. We found structural evidence of cerebellar WM abnormalities in CMT patients with NEFL and GJB1 mutations and the association between cerebellar WM involvement and cerebellar ataxia in these genetic subtypes, especially in the NEFL subgroup. Therefore, we suggest that neuroimaging such as MRI volumetry or DTI in CMT patients could play an important role in detecting abnormalities of the cerebellar WM.