Confluent White Matter Research Articles

TTR cardiac amyloidosis, polyneuropathy, and dementia at old age – bystander, cause or “smoking gun” guilty by association

AbstractBackgroundMixed dementia type – Alzheimer’s Disease (AD), cerebral amyloid angiopathy (CAA), and vascular ‐ is vastly recognized as a cause of dementia in older adults. Whereas CAA, primarily leptomeningeal, is a frequent complication in hereditary transthyretin cardiac amyloidosis (TTRCA), it is unusually reported in association with wild‐type TTR, with or without polyneuropathy. The knowledge of mixed dementia and wild‐type TTR association is even scarcer.MethodsCase Report. 81‐year‐old, Right‐handed man, with a 5‐year history of diagnosed wild‐type TTRCA and polyneuropathy, treated with Tafamidis, vascular risk factors, and remote history of benign head injuries, was seen in our Memory Disorders Clinic for evaluation of moderate dementia. MOCA score was 7/30 on the day of evaluation.ResultsOur patient had 2 brain MRIs over 5‐year follow‐up. The first MRI was performed at initial memory complaints of mild cognitive impairment (MCI) concurrent with the diagnosis of cardiac amyloidosis and polyneuropathy. A second brain MRI was performed during prolonged transient neurological deficit ‐ aphasia with prominent word‐finding difficulties – accompanying delirium following septic knee arthritis surgery. The second MRI revealed foci of susceptibility weighted imaging (swi) artifact in line with superficial cerebral hemosiderosis in the left frontal lobe, and within the bilateral thalami, all new from the first MRI, which only revealed one focus of right periventricular white matter SWI microhemorrhage and moderate confluent white matter hyperintensities, more prominent in the left frontal and parietal lobes, progressed on the second MRI. The cognitive impairment (MCI to moderate dementia) and supporting MRI brain imaging evolved over 5 years and we indicate contributory components of probable CAA, vascular, and AD pathology.ConclusionsWe report a rare association between probable AD, CAA, and vascular dementia, in a patient diagnosed with wild‐type TTRCA and polyneuropathy. We aim to increase awareness of dementia following the cardiac onset of wild TTRCA, possibly similar to the hereditary TTRCA. We inquire about the fortuitous or causative association of mixed dementia type and wild TTRCA, with or without polyneuropathy. We propose to study the intricately mixed etiology of cognitive impairment and its relationship to AD in wild TTRCA through a national registry.

Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study

CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition that predominantly affects white matter due to genetic alterations in the CSF1R gene, which is expressed by microglia. We studied an elderly man with a hereditary, progressive dementing disorder of unclear etiology. Standard genetic testing for leukodystrophy and other neurodegenerative conditions was negative. Brain autopsy revealed classic features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), including confluent white matter degeneration with axonal spheroids and pigmented glial cells in the affected white matter, consistent with CSF1R-RD. Subsequent long-read sequencing identified a novel deletion in CSF1R that was not detectable with short-read exome sequencing. To gain insight into potential mechanisms underlying white matter degeneration in CSF1R-RD, we studied multiple brain regions exhibiting varying degrees of white matter pathology. We found decreased CSF1R transcript and protein across brain regions, including intact white matter. Single nuclear RNA sequencing (snRNAseq) identified two disease-associated microglial cell states: lipid-laden microglia (expressing GPNMB, ATG7, LGALS1, LGALS3) and inflammatory microglia (expressing IL2RA, ATP2C1, FCGBP, VSIR, SESN3), along with a small population of CD44+ peripheral monocyte-derived macrophages exhibiting migratory and phagocytic signatures. GPNMB+ lipid-laden microglia with ameboid morphology represented the end-stage disease microglia state. Disease-associated oligodendrocytes exhibited cell stress signatures and dysregulated apoptosis-related genes. Disease-associated oligodendrocyte precursor cells (OPCs) displayed a failure in their differentiation into mature myelin-forming oligodendrocytes, as evidenced by upregulated LRP1, PDGFRA, SOX5, NFIA, and downregulated NKX2-2, NKX6.2, SOX4, SOX8, TCF7L2, YY1, ZNF488. Overall, our findings highlight microglia–oligodendroglia crosstalk in demyelination, with CSF1R dysfunction promoting phagocytic and inflammatory microglia states, an arrest in OPC differentiation, and oligodendrocyte depletion.

A novel CSF1R missense mutation in a Chinese family with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: A case report

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We report a case of a 41-year-old man with rapid decline in cognition within 7 months of onset. Magnetic resonance imaging showed periventricular confluent white matter changes and atrophy of the corpus callosum. Clinical exome sequencing showed a mutation (c.2390T>G) in exon 18 of the CSF1R gene. In conclusion, the differential diagnosis of adult-onset leukodystrophy is extensive. Neuroimaging and genetic analysis greatly aid in the differential diagnosis of leukoencephalopathy.

Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease.

Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia. In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors. A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P=0.032), executive function (β=0.287, P=0.027), and long-term memory (β=0.228, P=0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P<0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P<0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P=0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia. DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk.

The role of susceptibility-weighted imaging & contrast-enhanced MRI in the diagnosis of primary CNS vasculitis: a large case series.

Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.

Cephalalgic syndrome in autosomal dominant cerebral arteriopathy with subcortical infarctions and leucoencephalopathy

Background: Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is caused by mutations in NOTCH3 gene, classic symptoms include migraine with aura, ischemic strokes, apathy, depression and dementia. Headache is usually the first symptom, characterized by recurrent attacks of migraine with typical, hemiplegic or prolonged aura with unusual frequency. Material and methods: All the data were picked from the patient’s medical recordings. The patient had undergone a complete clinical exam, a contrast enhanced MRI-scan and a genetic test. Then a literature review was done based on the peculiarities of the case. Results: A 43-year-old woman presented with pulsatile, alternating, severe headache, accompanied by phono, and photophobia, nausea and vomiting, with an onset at 35 years and a frequency of 12/30, triggered by menstruation and stress, preceded by a day by a visual aura lasting 5-6 minutes. Family history revealed cases of stroke and migraine. Neurologic examination was normal, but a contrast enhanced MRI showed diffuse polymorph confluent subcortical white matter lesions, involving external capsule and anterior poles of the temporal lobes. NOTCH3 gene sequencing revealed the presence of a heterozygote missense c.421C&gt;T mutation, localized in the 4thexone. After establishing the diagnosis, the patient was prescribed a symptomatic treatment. Conclusions: Headache in CADASIL patients has well-defined diagnostic criteria in the International Classification of Headache Disorders, is being considered a secondary headache which may resemble or not migraine with aura. The patient presented a migraine-with-aura-like headache but with some peculiarities.

Prevalence and Risk Factors of Cerebral Small Vessel Disease from a Population-Based Cohort in China

Introduction: Cerebral small vessel disease (CSVD) is a significant burden of morbidity and mortality among elderly people around the world. Epidemiological data with complete CSVD evaluations and a large sample size in the general population are still limited. Methods: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study were included in this study from 2017 to 2019. All participants underwent 3 Tesla brain magnetic resonance images to assess CSVD imaging markers. Demographic and risk factor data were collected. The general and age-specific prevalence of lacune, confluent white matter hyperintensity (WMH), moderate-severe enlarged perivascular spaces (EPVS), cerebral microbleed (CMB), and total CSVD score (an ordinal scale from 0 to 4, counting the presence of four imaging markers of CSVD) was evaluated. Associations between vascular risk factors and these markers were analyzed by multivariable logistic regression. Results: A total of 3,063 participants were enrolled. The mean age was 61.2 years and 46.5% were men. The most prevalent CSVD marker was confluent WMH (16.7%), followed by CMB (10.2%), moderate-severe EPVS in the basal ganglia (BG-EPVS) (9.8%), and lacune (5.6%). 30.5% of the participants have at least one of the four markers (total CSVD score ≥1 points). The prevalence of CSVD markers increases as age increases. Age and hypertension were independent risk factors for four CSVD markers and the total CSVD score. Conclusions: In this Chinese cohort with community-based adults aged 50–75 years, our findings showed a prevalence of 30.5% for CSVD. The most prevalent CSVD marker was confluent WMH, followed by CMB, moderate-severe BG-EPVS, and lacune. The risk factors for CSVD must be strictly screened and controlled in adults living in the community.

Two rare cases of myelin oligodendrocyte glycoprotein antibody-associated disorder in children with leukodystrophy-like imaging findings

BackgroundChildren with acquired demyelinating syndromes (ADS) whose sera are positive for myelin oligodendrocyte glycoprotein (MOG) immunoglobulin (IgG) can be diagnosed with MOG-IgG associated disorder (MOGAD). Cases with leukodystrophy-like imaging findings with recurrent MOGAD have rarely been reported.Case presentationTwo children with MOGAD, whose onset age was 6 months and 3 years, respectively, were admitted to the hospital due to fever and altered consciousness. In both children, MOG-IgG was detected in the serum using live cell-based assay. Brain magnetic resonance imaging (MRI) revealed leukodystrophy-like lesions with diffuse bilateral white matter. Cerebrospinal fluid (CSF) analysis showed mild pleocytosis with normal or slightly increased protein levels and no oligoclonal bands. Metabolic and inflammatory blood/CSF markers were all negative. Full exon gene testing revealed normal results, and nuclear and mitochondrial DNA were normal. Despite regular immunotherapy and reduction of lesions based on brain MRI results, the patients repeatedly relapsed and had residual neurological dysfunction at 3–4 years of follow-up.ConclusionsAlthough MOGAD is a monophasic and benign condition, certain MOGAD patients can experience multiple relapses and residual neurologic deficits. The spectrum of clinical manifestations in MOGAD is wider in children than in previously reported cases, including cases with leukodystrophy-like imaging findings. Such imaging findings along with MOG-IgG may occur recurrently and result in severe neurological prognosis. Patients with extensive and confluent white matter lesions should undergo early testing of MOG-IgG to ensure early therapy. In refractory cases, MOGAD treatment may need to be escalated beyond the current therapy, which means second-line immunotherapy should be performed as early as possible and hormone levels should not be rapidly reduced. Early diagnosis and appropriate treatment may improve the prognosis of children with MOGAD.

Novel c.2654+1G&gt;A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy

AbstractBackgroundThe colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.MethodThe demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.ResultFour generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C&gt;A) in intron 20 of the CSF1R gene in four members (Figure 5).ConclusionWe identified a novel splicing mutation (c.2319+1C&gt;A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia caused by a novel mutation of CSF1R gene

AbstractBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder caused by mutations in the colony‐stimulating factor 1 receptor (CSF1R) gene. As of 2022, more than 100 different CSF1R mutations were reported in patients with CSF1R‐related leukoencephalopathy.MethodIn this case report, we described ALSP in a previously healthy 46‐year‐old woman. The patient underwent detailed neurological examinations including cognitive assessment, brain magnetic resonance imaging (MRI) and whole‐exome sequencing.ResultThe patient manifested as memory impairment, poor interpersonal behavior and decreased verbal fluency. Brain MRI showed confluent white matter changes and atrophy of the corpus callosum. Whole‐exome sequencing identified a novel splice site mutation (C.1858 + 5G &gt; A) in intron 13 of the CSF1R gene, which has not been reported worldwide.ConclusionALSP has a wide range of clinical manifestations and genetic heterogeneity. It should be considered when diagnosing rapidly progressive dementia with or without motor impairment. We recommend biopsy or genetic testing in these patients to avoid misdiagnosis and delayed diagnosis. We will continue to monitor this family in the future to improve our understanding of ALSP, so as to correctly diagnose ALSP in clinic and provide clinical data for better research on the pathogenesis and treatment of this disease.

Magnetic Resonance Imaging Brain Findings in Chikungunya Virus (CHIKV) Infection with Neurological Complication during Epidemic Outbreak.

The Chikungunya virus is an alphavirus RNA of the family Togaviridae transmitted by the Aedes mosquito. We aim to report magnetic resonance imaging (MRI) brain findings for neurological complications at our institute during epidemic outbreak. A total of 43 seropositive cases of Chikungunya infection underwent MRI brain. Out of 43 patients, 27 (63%) had discrete and confluent supra-tentorial T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) hyper-intense white matter foci. A total of 14 patients (33%) showed multiple foci/areas of diffusion restriction, and four of these patients had infra-tentorial T2 & FLAIR hyper-intense foci with restricted diffusion. In three pediatric age group patients including two neonates, the pattern of involvement was diffuse white matter changes with restricted diffusion. In 30% cases, MRI was normal. Detection of focal or confluent white matter hyper-intense foci with restricted diffusion on MRI in patients presenting with fever and neurological symptoms has potential to conclude the diagnosis of Chikungunya encephalitis, especially in epidemic settings.

Reversible Neuroimaging findings associated with Kratom use. (P12-5.021)

<h3>Objective:</h3> To report a case of reversible ischemic changes on MRI associated with chronic kratom use in a patient presenting with encephalopathy and seizures <h3>Background:</h3> Mitragyna speciosa, or kratom, is a psychoactive substance that targets multiple opioid receptors and has been an unregulated and under-reported substance of abuse. Its use has been reported to cause liver toxicity, respiratory depression, neuropsychiatric issues and even death. Its neurological side effects at this time are not well established. <h3>Design/Methods:</h3> We report a case of a 23-year-old male with a medical history significant for polysubstance abuse who presented for acute encephalopathy and seizure-like episode, requiring ICU admission and intubation for airway protection. <h3>Results:</h3> Patient initially presented with hypotension, leukocytosis, and lactic acidosis concerning sepsis. He was started on broad spectrum antibiotics for meningitis coverage and Keppra to prevent further seizures. Urine toxicology screen was negative. Once examined off sedation, the patient was noted to have right upper extremity weakness with babinski reflex on right concerning stroke therefore an MRI was obtained. It revealed small areas of confluent juxtacortical white matter abnormality high in the posterior frontal lobes bilaterally with some true diffusion restriction on the left suggestive of acute infarct. However, the appearance was unusual for a stroke. Further history from the family revealed that the patient uses Kratom on a daily basis for a number of years to help with anxiety. He had no further seizures and his mental status improved during the remainder of his hospitalization. Repeat MRI Brain 2 months after initial presentation showed resolution of the abnormalities. <h3>Conclusions:</h3> Kratom has been reported in the past to cause neurological issues like seizures or PRES. This case shows reversible ischemic neuroimaging findings of Kratom use in a patient with a stroke-like presentation. <b>Disclosure:</b> Dr. Pisati has nothing to disclose. Dr. Shah has nothing to disclose. Dr. Thaliath has nothing to disclose. Dr. Maryala has nothing to disclose. Dr. Allam has nothing to disclose.

Teaching Neuro Images : Vanishing white matter ovarioleukodystrophy

A 21-year-old Pakistani woman with a history of 2 seizures at 20 months of age and consanguineous parents was diagnosed with premature ovarian failure and hyperprolactinemia. Her neurologic examination was normal. Brain imaging showed confluent white matter T2/fluid-attenuated inversion recovery hyperintensities with periventricular cavitations (figure). Genetic testing showed homozygosity for a p.Lys273Arg missense mutation in the EIF2B2 gene (NM_014239.3: c.818A>G), which had previously been reported as disease-causing,1 and confirmed vanishing white matter (VWM) ovarioleukodystrophy. At 2-year follow-up, she remains neurologically asymptomatic with stable imaging. There is phenotypic variation in VWM disease and neurologic deterioration is associated with stressors (head trauma, fever).1,2

Report of A Family with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) Without Mutations in CSF1R, AARS1 or AARS2.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare neurodegenerative disorder with characteristic clinicopathological features. Identification of pathogenic mutations in CSF1R, AARS1, and AARS2 genes led to increased recognition and diagnosis of the ALSP. This paper presents the first family with typical clinical, radiological, and pathological features of ALSP, yet negative for CSF1R, AARS1, and AARS2 mutations. The index case was a 30-year-old male who presented with gait difficulty, followed by cognitive decline and incontinence. Neurological examination evidenced progressive dementia, dysarthria, spasticity, parkinsonism, and severe gait disturbances. Brain MRI showed confluent white matter abnormalities with scattered foci of restricted diffusion, and atrophy of the corpus callosum. He was suspected of ALSP; however, the extensive genetic work-up did not find pathogenic mutation. He died at 33 years, and brain autopsy was performed. He had myelin staining pallor and axonal swellings, spheroids, and pigmented glia in affected white matter. His father developed similar symptoms in his early 40s and died at 46 years. Neuropathological examination also confirmed ALSP diagnosis. We found two similar cases in the literature with typical ALSP features but negative for CSF1R mutation; however, none were tested for AARS1 and AARS2 mutations. We draw attention to a new entity within the ALSP disease spectrum that needs further investigation. As the disease-modifying therapy is already available for ALSP-CSF1R, there is a strong need to identify the genetic cause of patients such as these in the ALSP spectrum, enabling research toward implementing effective treatment.

Is Contrast-Enhanced Computed Tomography Redundant for Suspected Intracranial Infection in the Emergency Setting?

There are currently no guidelines for when to use intravenous contrast with head computed tomography (CT) when there is suspected acute intracranial infection. The purpose of our study was to determine the proportion of cases with enhancing findings on CT that also have conspicuous correlating associated findings on noncontrast CT, which would have on their own merited further evaluation with magnetic resonance imaging, the criterion standard for evaluating central nervous system pathology. A retrospective keyword search of the history and clinical information fields in radiology reports for CT examinations of the head without and with contrast from the period January 1, 2004, to October 31, 2021 was performed. Patients with prior head surgery or a history of cancer were excluded. For remaining patients, the noncontrast CT was reviewed for vasogenic edema or mass effect as markers of a possible acute infection, and the presence of background hypodense white matter changes was noted and graded as either absent, mild/scattered, or confluent. Subsequently, the companion contrast-enhanced CT was reviewed for an enhancing abnormality. Chart review was performed to confirm that an infectious process was the ultimate clinical diagnosis in patients with enhancing abnormalities. Of 343 patients meeting study inclusion/exclusion criteria, 39 had acute infections with an enhancing abnormality on CT (prevalence 11.3%). Thirty-two of these 39 patients also had correlative findings on the noncontrast CT. Noncontrast CT had a positive predictive value of 100%, negative predictive value of 97.7%, sensitivity of 82.1%, specificity of 100%, and accuracy of 98.0% for detecting markers (vasogenic edema and/or mass effect) associated with an enhancing abnormality. Vasogenic edema was the most common noncontrast CT finding in patients who had an infectious enhancing lesion (32 of 39), followed by mass effect (22 of 39). The 7 cases where the acute infection was occult on noncontrast CT were due to leptomeningitis (n = 3), confluent background white matter changes masking the vasogenic edema surrounding intra-axial lesions (n = 3), and a small 0.5 cm extra-axial abscess. Most acute intracranial infections with an enhancing CT finding also have a correlative conspicuous noncontrast finding that on its own would merit further evaluation with magnetic resonance imaging, the criterion standard for investigating central nervous system disease, and therefore, in the setting of suspected intracranial infection, contrast-enhanced CT is redundant in most cases. Contrast-enhanced CT primarily provides diagnostic benefit in patients with confluent background white matter changes that may mask vasogenic edema on noncontrast CT.

Vascular Brain Lesions, Cognitive Reserve, and Their Association with Cognitive Profile in Persons with Early-Stage Cognitive Decline.

Cognitive reserve may protect against the effects of brain pathology, but few studies have looked at whether cognitive reserve modifies the adverse effects of vascular brain pathology. We determined if cognitive reserve attenuates the associations of vascular brain lesions with worse cognition in persons with subjective concerns or mild impairment. We analyzed 200 participants aged 50-90 years from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. Cognition was measured using the Montreal Cognitive Assessment and a neuropsychological test battery. High vascular lesion burden was defined as two or more supratentorial infarcts or beginning confluent or confluent white matter hyperintensity. Cognitive reserve proxies included education, occupational attainment, marital status, social activities, physical activity, household income, and multilingualism. Mean age was 72.8 years and 48% were female; 73.5% had mild cognitive impairment and 26.5% had subjective concerns. Professional/managerial occupations, annual household income≥$60,000 per year, not being married/common law, and high physical activity were independently associated with higher cognition. Higher vascular lesion burden was associated with lower executive function, but the association was not modified by cognitive reserve. Markers of cognitive reserve are associated with higher cognition. Vascular lesion burden is associated with lower executive function. However, cognitive reserve does not mitigate the effects of vascular lesion burden on executive function. Public health efforts should focus on preventing vascular brain injury as well as promoting lifestyle factors related to cognitive reserve, as cognitive reserve alone may not mitigate the effects of vascular brain injury.

Symptomatic care of late-onset Alexander disease presenting with area postrema-like syndrome with prednisolone; a case report

BackgroundAlexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone.Case presentationA normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting.ConclusionsThis study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease. Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation. Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members. Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

Familial Brain Calcifications With Leukoencephalopathy: A Novel PDGFB Variant.

ObjectiveTo describe a family with primary familial brain calcifications (PFBCs) and leukoencephalopathy associated with a novel variant in PDGFB.MethodsWe present 3 generations of a family with PFBC associated with a previously unreported variant in PDGFB.ResultsA 24-year-old woman with migraine, bipolar disorder, and functional neurologic disorder was found to have bilateral calcifications of the basal ganglia and frontally predominant periventricular white matter disease. Her father had mild cognitive impairment and action tremor of the hands with basal ganglia and cerebellar calcifications found incidentally on head CT. Her paternal grandmother had severe parkinsonism and dementia with calcifications of the basal ganglia and cerebellum and diffuse, confluent periventricular white matter disease. Genetic testing in both the proband and her father revealed a PDGFB variant (NM_002608.3:c.298C>T:p.Arg100Cys) not reported in publicly available databases. Multiple in silico analysis tools support pathogenicity.DiscussionOur report identifies a novel PDGFB variant associated with PFBC and highlights the rare association of leukoencephalopathy with PDGFB-associated PFBC.

MINocyclinE to Reduce inflammation and blood brain barrier leakage in small Vessel diseAse (MINERVA) trial study protocol.

Background:Cerebral small vessel disease (SVD) is a common cause of stroke and cognitive impairment. Recent data has implicated neuroinflammation and increased blood-brain barrier (BBB) permeability in its pathogenesis, but whether such processes are causal and can be therapeutically modified is uncertain. In a rodent model of SVD, minocycline was associated with reduced white matter lesions, inflammation and BBB permeability.Aims:To determine whether blood-brain barrier permeability (measured using dynamic contrast-enhanced MRI) and microglial activation (measured by positron emission tomography using the radioligand 11C-PK11195) can be modified in SVD.Design:Phase II randomised double blind, placebo-controlled trial of minocycline 100 mg twice daily for 3 months in 44 participants with moderate to severe SVD defined as a clinical lacunar stroke and confluent white matter hyperintensities.Outcomes:Primary outcome measures are volume and intensity of focal increases of blood-brain barrier permeability and microglial activation determined using PET-MRI imaging. Secondary outcome measures include inflammatory biomarkers in serum, and change in conventional MRI markers and cognitive performance over 1 year follow up.Discussion:The MINERVA trial aims to test whether minocycline can influence novel pathological processes thought to be involved in SVD progression, and will provide insights into whether central nervous system inflammation in SVD can be therapeutically modulated.