Calcium-mediated proteolytic damage in white matter of hydrocephalic rats?

Hydrocephalus is a pathological dilatation of the cerebrospinal fluid (CSF)-containing ventricles of the brain. Damage to periventricular white matter is multifactorial with contributions by chronic ischemia and gradual physical distortion. Acute ischemic and traumatic brain injuries are associated with calcium-dependent activation of proteolytic enzymes. We hypothesized that hydrocephalus is associated with calcium ion accumulation and proteolytic enzyme activation in cerebral white matter. Hydrocephalus was induced in immature and adult rats by injection of kaolin into the cisterna magna and several different experimental approaches were used. Using the glyoxal bis (2-hydroxyanil) method, free calcium ion was detected in periventricular white matter at sites of histological injury. Western blot determinations showed accumulation of calpain I (mu-calpain) and immunoreactivity for calpain I was increased in periventricular axons of young hydrocephalic rats. Proteolytic cleavage of a fluorogenic calpain substrate was demonstrated in white matter. Immunoreactivity for spectrin breakdown products was detected in scattered callosal axons of young hydrocephalic rats. The findings support the hypothesis that periventricular white matter damage associated with experimental hydrocephalus is due, at least in part, to calcium-activated proteolytic processes. This may have implications for supplemental drug treatments of this disorder.     

Does white matter matter? Spatio-temporal dynamics of task switching in aging

Older adults often encounter difficulties in switching between tasks, perhaps because of age-related decreases in executive function. Executive function may largely depend on connections between brain areas-connections that may become structurally and functionally weaker in aging. Here we investigated functional and structural age-related changes in switching between a spatial and a verbal task. These tasks were chosen because they are expected to differentially use the two hemispheres. Brain measures included anatomical information about anterior corpus callosum size (CC; the major commissure linking the left and right hemisphere), and the event-related optical signal (EROS). Behavioral results indicated that older adults had greater task-switching difficulties, which, however, were largely restricted to switching to the spatial task and to individuals with smaller anterior CCs. The EROS data showed both general switching-related activity in the left middle frontal gyrus (with approximately 300-msec latency) and task-specific activity in the inferior frontal gyrus, lateralized to the left for the switch-to-verbal condition and to the right for the switch-to-spatial condition. This lateralization was most evident in younger adults. In older adults, activity in the switch-to-spatial condition was lateralized to the right hemisphere in individuals with large CC, and to the left in individuals with small CC. These data suggest that (a) task switching may involve both task-general and task-specific processes; and (b) white matter changes may underlie some of the age-related problems in switching. These effects are discussed in terms of the hypothesis that aging involves some degree of cortical disconnection, both functional and anatomical.     

Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter?

The targeted brain dysfunction that accompanies aging can have a devastating effect on cognitive and intellectual abilities. A significant proportion of older adults experience precipitous cognitive decline that negatively impacts functional activities. Such individuals meet clinical diagnostic criteria for dementia, which is commonly attributed to Alzheimer''s disease (AD). Structural neuroimaging, including magnetic resonance imaging (MRI), has contributed significantly to our understanding of the morphological and pathology-related changes that may underlie normal and disease-associated cognitive change in aging. White matter hyperintensities (WMH), which are distributed patches of increased hyperintense signal on T2-weighted MRI, are among the most common structural neuroimaging findings in older adults. In recent years, WMH have emerged as robust radiological correlates of cognitive decline. Studies suggest that WMH distributed in anterior brain regions are related to decline in executive abilities that is typical of normal aging, whereas WMH distributed in more posterior brain regions are common in AD. Although epidemiological, observational, and pathological studies suggest that WMH may be ischemic in origin and caused by consistent or variable hypoperfusion, there is emerging evidence that they may also reflect vascular deposition of (β-amyloid, particularly when they are distributed in posterior areas and are present in patients with AD. Findings from the literature highlight the potential contribution of small-vessel cerebrovascular disease to the pathogenesis of AD, and suggest a mechanistic interaction, but future longitudinal studies using multiple imaging modalities are required to fully understand the complex role of WMH in AD.     

Cognitive impairment in progressive supranuclear palsy-Richardson’s syndrome is related to white matter damage

IntroductionBeside motor symptoms, patients with progressive supranuclear palsy syndrome (PSPs) commonly present cognitive and behavioral disorders. In this study we aimed to assess the structural brain correlates of cognitive impairment in PSPs.MethodsWe enrolled 23 patients with probable PSP Richardson's syndrome and 15 matched healthy controls. Patients underwent an extensive clinical and neuropsychological evaluation. Cortical thickness measures and diffusion tensor metrics of white matter tracts were obtained. Random forest analysis was used to identify the strongest MRI predictors of cognitive impairment in PSPs at an individual patient level.ResultsPSPs patients were in a moderate stage of the disease showing mild cognitive deficits with prominent executive dysfunction. Relative to controls, PSPs patients had a focal, bilateral cortical thinning mainly located in the prefrontal/precentral cortex and temporal pole. PSPs patients also showed a distributed white matter damage involving the main tracts including the superior cerebellar peduncle, corpus callosum, corticospinal tract, and extramotor tracts, such as the inferior fronto-occipital, superior longitudinal and uncinate fasciculi, and cingulum, bilaterally. Regional cortical thinning measures did not relate with cognitive features, while white matter damage showed a significant impact on cognitive impairment (r values ranging from −0.80 to 0.74).ConclusionsPSPs patients show both focal cortical thinning in dorsolateral anterior regions and a distributed white matter damage involving the main motor and extramotor tracts. White matter measures are highly associated with cognitive deficits. Diffusion tensor MRI metrics are likely to be the most sensitive markers of extramotor deficits in PSPs.     

Notch signaling: Key role in intrauterine infection/inflammation,embryonic development,and white matter damage?

The mechanisms or pathophysiologies that lead to cerebral white matter damage during development are complex and not fully understood. It is postulated that exposure of the preterm brain to inflammatory cytokines during intrauterine infection/inflammation contributes to brain white matter damage, and this damage may affect the function and differentiation of progenitor oligodendrocyte cells under physiological conditions. The Notch pathway, an important signaling pathway controlling various cells' differentiation, functions in the timing of oligodendrocyte differentiation, and Notch signaling may contribute to white matter damage and may mediate neurogenesis in a pathophysiological phase. Recent studies have led to recognition of the role of the Notch pathway in neurogenesis in cerebral ischemic damage and in myelination and axonal damage of neurodegenerative diseases. Moreover, Notch plays a critical role in steering an immune response toward inflammation by regulating expression of various cytokines and proinflammatory cytokines resulting in the activation of Notch signaling. Thus, the Notch signaling pathway likely plays a key role in intrauterine infection/inflammation, brain development, and white matter damage, and future research directed toward understanding its role will be important. Insofar as Notch signaling could have an important effect on neurogenesis, mobilization of progenitor cells is one strategy for compensating for the neuronal losses seen in white matter damage after intrauterine infection/inflammation. © 2009 Wiley‐Liss, Inc.     

Preserved white matter microstructure in young patients with anorexia nervosa?

A massive but reversible reduction of cortical thickness and subcortical gray matter (GM) volumes in Anorexia Nervosa (AN) has been recently reported. However, the literature on alterations in white matter (WM) volume and microstructure changes in both acutely underweight AN (acAN) and after recovery (recAN) is sparse and results are inconclusive. Here, T1‐weighted and diffusion‐weighted MRI data in a sizable sample of young and medication‐free acAN (n = 35), recAN (n = 32), and age‐matched female healthy controls (HC, n = 62) were obtained. For analysis, a well‐validated global probabilistic tractography reconstruction algorithm including rigorous motion correction implemented in FreeSurfer: TRACULA (TRActs Constrained by UnderLying Anatomy) were used. Additionally, a clustering algorithm and a multivariate pattern classification technique to WM metrics to predict group membership were applied. No group differences in either WM volume or WM microstructure were detected with standard analysis procedures either in acAN or recAN relative to HC after controlling for the number of performed statistical tests. These findings were not affected by age, IQ, or psychiatric symptoms. While cluster analysis was unsuccessful at discriminating between groups, multivariate pattern classification showed some ability to separate acAN from HC (but not recAN from HC). However, these results were not compatible with a straightforward hypothesis of impaired WM microstructure. The current findings suggest that WM integrity is largely preserved in non‐chronic AN. This finding stands in contrast to findings in GM, but may help to explain the relatively intact cognitive performance of young patients with AN and provide the basis for the fast recovery of GM structures. Hum Brain Mapp 37:4069–4083, 2016. © 2016 Wiley Periodicals, Inc.     

MRI-detected white matter lesions: do they really matter?

Despite extensive research over the last decades the clinical significance of white matter lesions (WMLs) is still a matter of debate. Here, we review current knowledge of the correlation between WMLs and cognitive functioning as well as their predictive value for future stroke, dementia, and functional decline in activities of daily living. There is clear evidence that age-related WMLs relate to all of these outcomes on a group level, but the inter-individual variability is high. The association between WMLs and clinical phenotypes exists particularly for early confluent to confluent changes, which are ischaemic in aetiology and progress quickly over time. One reason for the variability of the relationship between WMLs and clinic on an individual level is probably the complexity of the association. Numerous factors such as cognitive reserve, concomitant loss of brain volume, and ultrastructural changes have been identified as mediators between white matter damage and clinical findings, and need to be incorporated in the consideration of WMLs as visible markers of these detrimental processes.     

MRI quantification of gray and white matter damage in patients with early–onset multiple sclerosis

Background and objective Contrary to what happens in adult–onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal–appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS. Methods Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early–onset MS and 16 sex– and age–matched healthy volunteers. Results Compared with healthy volunteers, patients with early–onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p <0.0001) of the NAWM.Brain dual–echo lesion load was significantly correlated with average FA (r = –0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM. Conclusions This study confirms the paucity of the ‘occult’ brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.     

Do seizures cause neuronal damage in rat amygdala kindling?

Using unbiased stereology, we estimated total neuronal numbers in the lateral, basal and accessory basal nuclei of the amygdala and in the hilus of the dentate gyrus 6 months after the induction of amygdala kindling. In kindled rats, there was no decrease in the total number of neurons in the various amygdaloid regions or the hilus compared to sham-operated animals. Furthermore, there was no correlation between the total duration of afterdischarges or the number of electrical stimulations and the number of neurons. Our data indicate that when using unbiased stereological methods, total neuronal number in the amygdala or hilus are not reduced after few amygdala-induced seizures.     

Recovery from chemotherapy-induced white matter changes in young breast cancer survivors?

In a previous longitudinal diffusion tensor imaging (DTI) study, we observed cerebral white matter (WM) alterations (reduced fractional anisotropy (FA)) related to decreased cognitive performance 3–5 months after chemotherapy-treatment (t2) when compared to baseline (t1) (Deprez et al. in Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30(3), 274–281. doi:10.1200/JCO.2011.36.8571, 2012). The current study investigates the evolution and the nature of these previously observed microstructural changes. Twenty-five young women with early-stage breast cancer who received chemotherapy treatment (C+), 14 who did not receive chemotherapy (C-) and 15 healthy controls (HC) previously studied, underwent reassessment 3–4 years after treatment (t3). We assessed (1) longitudinal changes of cognitive performance and FA and (2) cross-sectional group differences in myelin-water-imaging and multishell diffusion MRI metrics at t3. MRI metrics were assessed on a voxel-by-voxel basis and in regions-of-interest (ROI) in which previous WM injury was detected. Longitudinal results: Mixed-effects modeling revealed significant group-time interactions for verbal memory and processing speed (p < 0.05) reflecting regained performance in the C+ group at t3. Furthermore, in chemotherapy-treated patients, FA returned to baseline levels at t3 in all ROIs (p < 0.002), whereas no FA changes were seen in controls. Additionally, FA increase from t2 to t3 correlated with time since treatment in two of the four regions (r = 0.40, p < 0.05). Cross-sectional results: Advanced diffusion MRI and myelin-water imaging metrics in the ROIs did not differ between groups. Similarly, no whole-brain voxelwise differences were detected. Initial WM alterations and reduced cognitive performance following chemotherapy-treatment were found to recover in a group of young breast cancer survivors three to four years after treatment.     

APOE ?2 is associated with white matter hyperintensity volume in CADASIL

Apolipoprotein E (APOE) increases the risk for Alzheimer’s disease (ɛ4 allele) and cerebral amyloid angiopathy (ɛ2 and ɛ4), but its role in small vessel disease (SVD) is debated. Here we studied the effects of APOE on white matter hyperintensity volume (WMHV) in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a nonamyloidogenic angiopathy and inherited early-onset form of pure SVD. Four hundred and eighty-eight subjects were recruited through a multicenter consortium. Compared with APOE ɛ3/ɛ3, WMHV was increased in APOE ɛ2 (P = 0.02) but not APOE ɛ4. The results remained significant when controlled for genome-wide genetic background variation. Our findings suggest a modifying influence of APOE ɛ2 on WMHV caused by pure SVD.     

Do sperm cells remember?

Spontaneous alternation behavior (SAB) is the universal tendency of animals, including unicellular organisms, to alternate directional choices at consecutive left/right branchings while traversing a maze. Occurrence of SAB implies short-term memory, as a current decision is statistically dependent on previous ones. We developed a procedure to assess SAB in human spermatozoa. A total of 1302 progressively motile spermatozoa from healthy donors were observed as they entered one of two mazes, both fabricated by eximer laser ablation. The control maze was a simple T-maze (width=depth=20 microm, distance between entrance and free choice T-intersection=600 microm). The experimental maze was identical to the control maze except for a forced right-turn 600 microm before the T-intersection. We recorded individual sperm cells' left/right decisions at the T-intersections in both mazes. Of the 714 spermatozoa entering the control maze, 49.1% turned to the left (not significantly different from the chance expectation of 50.0%). Of the 588 spermatozoa entering the experimental maze, 58.6% turned left after the initial forced right turn (significant SAB; P=0.041, Wilcoxon). The statistical dependency of a directional decision on a previous one suggests a physiological 'memory' in human spermatozoa. Among the possible underlying mechanisms are refractory processes in structures responsible for flagellar beating, a postulation which deserves further scrutiny with video-monitored single-cell testing.     

Do epileptic seizures damage the brain?

PURPOSE OF REVIEW: The possibility that recurrent seizures in patients with poorly controlled epilepsy may produce neuronal damage and contribute to progressive functional and cognitive declines observed in some patients with epilepsy has major clinical and therapeutic implications for urgency of treatment and effective intervention to achieve complete control. RECENT FINDINGS: Advances in magnetic resonance imaging techniques, technical and conceptual advances in experimental analysis of neuronal death at the cellular and molecular level, and long-term neuropsychological observations have provided substantial new data and insights into phenomena of seizure-induced plasticity in neural circuitry that address the question "Do epileptic seizures damage the brain?" SUMMARY: The emerging perspective is that seizure-induced damage should be regarded not only as neuronal loss but as adverse long-term behavioral and cognitive consequences. This perspective provides a strong rationale for development of neuroprotective treatments to forestall adverse long-term consequences of repeated seizures, and for the importance of prompt, effective intervention that achieves complete seizure control.     

Understanding aberrant white matter development in schizophrenia: an avenue for therapy?

Although historically gray matter changes have been the focus of neuropathological and neuroradiological studies in schizophrenia, in recent years an increasing body of research has implicated white matter structures and its constituent components (axons, their myelin sheaths and supporting oligodendrocytes). This article summarizes this body of literature, examining neuropathological, neurogenetic and neuroradiological evidence for white matter pathology in schizophrenia. We then look at the possible role that antipsychotic medication may play in these studies, examining both its role as a potential confounder in studies examining neuronal density and brain volume, but also the possible role that these medications may play in promoting myelination through their effects on oligodendrocytes. Finally, the role of potential novel therapies is discussed.     

Brain white matter lesions in migraine: what’s the meaning?

Migraine has been associated with structural brain damage. Several studies have reported an association between migraine and brain white matter lesions or clinically silent infarct-like abnormalities in the posterior circulation territory. The origin of these lesions is still unclear. The cause is commonly interpreted as ischemic, which is consistent with the association of migraine, particularly with aura, with vascular risk factors. The relationship between increased volume of white matter hyperintensities and a history of severe headache per se is under debate. The clinical relevance of this brain damage deserves further investigations even if an association between cognitive impairment and migraine or headache of any type is not confirmed.