Pattern Of White Matter Injury Research Articles

Machine‐learning derived white matter signatures and the risk of dementia, stroke and mortality: the Rotterdam Study

AbstractBackgroundWhite matter hyperintensities (WMH), loss of white matter (WM) volume and WM microstructural integrity are important risk indicators of stroke and dementia, albeit of heterogeneous nature. Use of machine learning techniques may unravel different patterns of white matter injury, with distinct underlying pathologies and disease risk.MethodWe measured WMH volume, WM volume, global fractional anisotropy (FA) and global mean diffusivity (MD) in 5205 participants (mean age 64.9 years, 56.0% women) of the population‐based Rotterdam study with brain MRI between 2005 and 2016. We performed hierarchical clustering on age‐standardized imaging parameters to identify separate clusters of white matter injury, and compare determinants across clusters. We then determined the association between clusters and risk of dementia, stroke and mortality, using Cox proportional hazard models adjusted for sex, education, APOE‐ε4 and cardiovascular risk factors.ResultWe identified four distinct white matter signatures: (i) cluster with above‐average microstructural integrity and little WM atrophy and WMH, (ii) cluster with above‐average microstructural integrity and little WMH, yet substantial WM atrophy, (iii) cluster with poor microstructural integrity and substantial WMH, yet little WM atrophy, and (iv) cluster with poor microstructural integrity, substantial WM atrophy, and average WMH load. There were no clear differences between clusters in APOE genotype and cardiometabolic risk factors, except for higher prevalence of hypertension in cluster (iv). Cluster (iii) contained more women, and participants in clusters (iii) and (iv) had more microbleeds and lacunes. During a median 10.7 years of follow‐up, 272, 210, and 844 cases of dementia, stroke, death occurred, respectively. In fully adjusted models, dementia risk was increased for clusters (ii) (HR 1.57 [95%CI:1.04‐2.37]), (iii) (HR 2.43 [95%CI:1.68‐3.52]) and (iv) (HR 1.78 [95%CI:1.22‐2.62], compared to cluster (i). Moderate associations of clusters (iii) and (iv) with incidence stroke attenuated and were no longer statistically significant after adjustment for cardiovascular risk factors, while only cluster (iii) was associated with a small increase in mortality (HR 1.30 [95%CI:1.07‐1.58]).ConclusionMachine‐learning derived white matter signatures are differentially associated with dementia, stroke and mortality. Further research is needed to pinpoint differences in underlying pathology, and assess potential benefit of clusters for risk stratification.

EEG and clinical characteristics of neonatal parechovirus encephalitis

RationaleHuman parechoviruses (HPeVs) are single -stranded ribonucleic (RNA) viruses belonging to the picornaviridae family with characteristics similar to enteroviruses. They either cause mild respiratory and gastrointestinal or no symptoms in older children and adults but can be a major cause of central nervous system (CNS) infection in the neonatal period and demonstrate a seasonal predilection. Starting in March 2022, we saw eight patients with polymerase chain reaction (PCR) proven HPeV encephalitis with seizures and some electroencephalographic (EEG) features raising concerns for neonatal genetic epilepsy. Although cerebrospinal fluid (CSF) and imaging findings have been previously described, there is little emphasis on seizure presentation and EEG findings of HPeV in the literature. We wish to highlight the EEG and seizure semiology of HPeV encephalitis that may mimic a genetic neonatal epilepsy syndrome. MethodsRetrospective chart review of all neonates seen at Children’s Health Dallas, UTSW Medical Center between 03/18/2022–06/01/2022 with HPeV encephalitis. ResultsTerm neonates (postmenstrual age 37–40 weeks) presented with a variable combination of fever, lethargy, irritability, poor oral intake, erythematous rash, and focal seizures. One patient with a single episode of limpness and pallor did not undergo EEG due to a low suspicion for seizures. CSF indices were normal in all patients. EEG was abnormal in all patients where performed (n = 7). EEG features included dysmaturity (7/7, 100 %); excessive discontinuity (6/7, 86 %); excessive asynchrony (6/7, 86 %); multifocal sharp transients (7/7, 100 %). Focal/multifocal seizures were captured in 6/7 (86 %); tonic in 3/7 (42 %) and described as migrating in 2 patients. Subclinical seizures were noted in 6/7 (86 %) with status epilepticus in 5/7 (71 %) patients. In 2/7 (28 %) the EEG showed a burst suppression pattern with poor state variation and voltages of < 5–10 uV/mm during the inter-burst intervals. Repeat EEG (3–11 days post initial EEG) showed improvement in 3 of 4 patients. No patient had ongoing seizures beyond day two of admission (22.5 h after EEG initiation). MRI showed extensive restricted diffusion in the supratentorial white matter, thalami, and less frequently the cortex, mimicking imaging findings of a metabolic or hypoxic-ischemic encephalopathy (7/8). Seizures responded within 36 h of presentation to treatment with acute bolus doses of medications. One patient died due to diffuse cerebral edema and status epilepticus. Six patients had a normal clinical exam at discharge. All patients started on maintenance antiseizure medication (ASM) were sent home on either a single medication or two medications (phenobarbital and levetiracetam) with plans to wean phenobarbital after discharge. ConclusionsHPeV is a rare cause of seizures and encephalopathy in neonates. Prior studies have emphasized specific patterns of white matter injury on imaging. We demonstrate that HPeV also commonly presents with clonic or tonic seizures with or without apnea and often subclinical multifocal and migrating focal seizures that could mimic a genetic neonatal epilepsy syndrome. Interictal EEG shows a dysmature background with excessive asynchrony, discontinuity, burst-suppression pattern, and multifocal sharp transients. However, we note that 100 % of patients responded quickly to standard ASM, and did not have seizures after hospital discharge- a factor that can help distinguish it from a genetic epilepsy syndrome.

Annals of Neurology: Volume 92, Number 3, September 2022

Spatial patterns of white matter injury in Dutch type Cerebral Amyloid Angiopathy (D‐CAA). A: FLAIR‐based white matter hyperintensity probability map in D‐CAA carriers showing a posterior predominance. Individual images were placed in Montreal Neurological Institute (MNI) space, and voxels are colored by the probability of a white matter lesion being present in this cohort. B: Diffusion based mean diffusivity (MD) in the white matter skeleton. Individual MD images were placed in MNI space, and voxels are colored by the average value across D‐CAA carriers in this cohort. See paper in this issue by Shirzadi et al. (pp. 358–363).

Modeling the Properties of White Matter Tracts Using Diffusion Tensor Imaging to Characterize Patterns of Injury in Aging and Neurodegenerative Disease.

Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that can provide valuable insight into the microstructure of white matter tracts of the brain. In this paper, we evaluated the reliability and reproducibility of deriving a semi-automated pseudo-atlas DTI tractography method vs. standard atlas-based analysis alternatives, for use in clinical cohorts with neurodegeneration and ventriculomegaly. We showed that the semi-automated pseudo-atlas DTI tractography method was reliable and reproducible across different cohorts, generating 97.7% of all tracts. However, DTI metrics obtained from both methods were significantly different across the majority of cohorts and white matter tracts (p < 0.001). Despite this, we showed that both methods produced patterns of white matter injury that are consistent with findings reported in the literature and with DTI profiles generated from these methodologies. Scatter plots comparing DTI metrics obtained from each methodology showed that the pseudo-atlas method produced metrics that implied a more preserved neural structure compared to its counterpart. When comparing DTI metrics against a measure of ventriculomegaly (i.e., Evans’ Index), we showed that the standard atlas-based method was able to detect decreasing white matter integrity with increasing ventriculomegaly, while in contrast, metrics obtained using the pseudo-atlas method were sensitive for stretch or compression in the posterior limb of the internal capsule. Additionally, both methods were able to show an increase in white matter disruption with increasing ventriculomegaly, with the pseudo-atlas method showing less variability and more specificity to changes in white matter tracts near to the ventricles. In this study, we found that there was no true gold-standard for DTI methodologies or atlases. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.

Radiographic and histologic characterisation of white matter injury in a sheep model of CHD.

Nearly one in five children with CHD is born with white matter injury that can be recognised on postnatal MRI by the presence of T1 hyperintense lesions. This pattern of white matter injury is known to portend poor neurodevelopmental outcomes, but the exact aetiology and histologic characterisation of these lesions have never been described. A fetal sheep was cannulated at gestational age 110days onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid environment for 14.5days. The fetus was supported under hypoxic conditions (mean oxygen delivery 16ml/kg/day) to simulate the inutero conditions of CHD. At necropsy, the brain was fixed, imaged with MRI, and then stained to histologically identify areas of injury. Under hypoxemic inutero conditions, the fetus developed a T1 hyperintense lesion in its right frontal lobe. Histologically, this lesion was characterised by microvascular proliferation and astrocytosis without gliosis. These findings may provide valuable insight into the aetiology of white matter injury in neonates with CHD.

Monocyte Chemoattractant Protein (MCP)-1 in Rotavirus-Associated White Matter Injury in Newborns.

Recent reports have suggested an association between rotavirus infection and a distinctive pattern of white matter injury (WMI) in neonates with seizures; however, the connection between the two is not fully understood. To evaluate the underlying mechanism, we profiled and compared eight cytokines (IL [interleukin]-1β, IL-6, IL-8, IL-10, IFN-γ [interferon-γ ], MCP-1 [monocyte chemoattractant protein-1], MIP-1β [macrophage inflammatory protein-1β], and TNF-α [tumor necrosis factor-α]) in the cerebrospinal fluid (CSF) of 33 neonates with seizures who had no other well-known causes of seizures and 13 control patients (rotavirus-induced gastroenteritis but without seizures). Among the 33 neonates with seizures, 9 showed WMI and all were infected with rotavirus (R + W + ). Among the 24 patients without WMI, 11 were infected with rotavirus (R + W - ) and 13 were not (R - W - ).Only MCP-1 and MIP-1β were different between the groups. MCP-1 was increased in R+ W+ compared with R + W- (p < 0.01), R - W- (p < 0.01), and control (p = 0.03) patients. MIP-1β was decreased in R + W+ compared with R - W- (p < 0.01) and control (p < 0.01), but not R + W- (p = 0.23) patients. MCP-1 and MIP-1β are C-C chemokines that recruit immune cells to the site of inflammation. Our pilot study suggests MCP-1-mediated monocyte recruitment may be linked with this complication caused by rotavirus.

Spotlight on the January 6 Issue

#### Notable in Neurology This issue features 2 pediatric papers discussing the rotavirus infection and congenital myopathies. There are several articles on the topic of cerebrovascular stroke, detailing recurrence of stroke after TIA and optimal combination secondary drug treatment. ### Distinctive pattern of white matter injury in neonates with rotavirus infection![Graphic][1]</img> The authors found a distinctive pattern of white matter injury in 18 neonates with seizures or apnea. Neonates with these characteristic diffusion-weighted images had a high positive rate of rotavirus infection without evidence of other pathogens, with neurologic symptoms appearing on the fifth day after birth. ![Graphic][2]</img> See p. … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif

Distinctive pattern of white matter injury in neonates with rotavirus infection.

To report a consecutive series of neonates with seizures or apnea and displaying white matter injuries with distinctive magnetic resonance diffusion-weighted imaging (DWI) pattern, and to discuss the high positive rate of rotavirus infection seen in these patients. In a retrospective review of neonates who were admitted to a tertiary referral center with seizures or apnea, we found a distinctive pattern of white matter injury (symmetrical restricted diffusion in the periventricular white matter and white matter tracts including the corpus callosum) in 18 patients. We describe the clinical and laboratory features of these 18 neonates. Additional PCR analyses for rotaviruses and parechoviruses were performed on banked frozen samples of CSF of 4 patients and blood of 15 patients. All 18 patients were born at term and healthy until symptoms occurred 4-7 days after birth. No history of asphyxia was observed. Only 1 patient presented with fever, and no patient showed a rash. All patients except 1 (94.4%) were rotavirus-positive in stool samples. However, neither rotaviruses nor enteroviruses/parechoviruses were detected in the CSF and blood. Tissue loss was observed in 5 of 8 subjects on repeat MRI scans. Neonates with this distinctive DWI pattern had a high positive rate of rotavirus infection, without evidence of other pathogens, and were characterized as term newborns with neurologic symptoms arising approximately the fifth day after birth. Although the specificity of this pattern is unclear, rotavirus testing should be considered for neonates presenting with this DWI pattern.

Symptomatic White Matter Changes in Mild Traumatic Brain Injury Resemble Pathologic Features of Early Alzheimer Dementia

To evaluate white matter integrity in patients with mild traumatic brain injury (TBI) who did not have morphologic abnormalities at conventional magnetic resonance (MR) imaging with diffusion-tensor imaging to determine any relationship between patterns of white matter injury and severity of postconcussion symptoms. The institutional review board approved this study, with waiver of informed consent. Diffusion-tensor images from 64 consecutive patients with mild TBI obtained with conventional MR imaging were evaluated retrospectively. Fractional anisotropy (FA) maps were generated as a measure of white matter integrity. All patients underwent a neurocognitive evaluation. Correlations between skeletonized FA values in white matter, total concussion symptom score, and findings of sleep and wake disturbances were analyzed with regression analysis that used tract-based spatial statistics. Total concussion symptom scores varied from 2 to 97 (mean ± standard deviation, 32.7 ± 24.4), with 34 patients demonstrating sleep and wake disturbances. Tract-based spatial statistics showed a significant correlation between high total concussion symptom score and reduced FA at the gray matter-white matter junction (P < .05), most prominently in the auditory cortex (P < .05). FA in the parahippocampal gyri was significantly decreased in patients with sleep and wake disturbances relative to patients without such disturbances (0.26 and 0.37, respectively; P < .05). The distribution of white matter abnormalities in patients with symptomatic mild TBI is strikingly similar to the distribution of pathologic abnormalities in patients with early Alzheimer dementia, a finding that may help direct research strategies.

Patterns of white matter injury in HIV infection after partial immune reconstitution: a DTI tract-based spatial statistics study

HIV-infected individuals with severe immune suppression are more likely to develop HIV-associated neurocognitive disorders than those with preserved immune function. While partial immune reconstitution occurs in those with severe immune suppression after starting combined antiretroviral therapy, it is not established whether improvement in immune function reverses or prevents injury to the central nervous system (CNS). To address this question, 50 participants (nadir CD4 counts ≤ 200 cells/mm(3), on a stable antiretroviral regimen for at least 12 consecutive weeks prior to study) and 13 HIV negative participants underwent a comprehensive neurological evaluation followed by diffusion tensor imaging (DTI). Eighty-four percent of the 50 HIV participants were neurologically asymptomatic (HIVNA) and 16 % had mild cognitive impairment (HIVCI). Tract-based spatial statistics (TBSS) on DTI data revealed that mean diffusivity (MD) increased significantly in the posterior aspect of both hemispheres in HIVNA compared to controls. In HIVCI, compared to controls and HIVNA, increased MD extended to prefrontal areas. Fractional anisotropy decreased only in HIVCI, compared to either controls or HIVNA. Furthermore, DTI showed significant correlations to duration of HIV infection and significant associations with multiple cognitive domains. This study highlights that in partial immune reconstitution, injury to the CNS is present even in those that are neurologically asymptomatic and there are discrete spatial patterns of white matter injury in HIVNA subjects compared to HIVCI subjects. Our results also show that quantitative analysis of DTI using TBSS is a sensitive approach to evaluate HIV-associated white matter disease and thus valuable in monitoring central nervous system injury.

Clinical contributors to cerebral white matter integrity in HIV-infected individuals

HIV-infected people frequently exhibit brain dysfunction characterized by preferential damage to the cerebral white matter. Despite suppressed viral load and reconstituted immune function afforded by combination antiretroviral therapy (CART), brain dysfunction continues to be observed even in medically stable individuals. To provide insight into the etiology of HIV-associated brain dysfunction in the CART era, we examined the effects of HIV disease markers, antiretroviral treatment, hepatitis C (HCV) coinfection, and age on DTI measures of white matter integrity in a cohort of 85 individuals aged 23 to 65 years with chronic HIV infection. Fractional anisotropy and mean diffusivity were derived from 29 cerebral white matter regions, which were segmented on each individual brain using a high-resolution T1-weighted image and registered to diffusion images. Significant effects of clinical variables were found on white matter abnormalities in nearly all brain regions examined. Most notably, HCV coinfection and older age were associated with decreased anisotropy or increased diffusivity in the majority of brain regions. Individuals with higher current CD4 levels exhibited higher anisotropy in parietal lobe regions, while those undergoing antiretroviral treatment exhibited higher anisotropy in temporal lobe regions. The observed diffuse pattern of white matter injury suggests that future neuroimaging studies should employ methodologies that are not limited to circumscribed regions of interest. The current findings underline the multifactorial nature of HIV-associated brain dysfunction in the CART era, and the importance of examining the effects of HIV disease in the context of other comorbidities, in particular HCV coinfection and aging.

Cranial Ultrasonography

Cranial Ultrasonography