White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors. OBJECTIVE: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. METHODS: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. RESULTS: A small, negative association of CSF Aß42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. CONCLUSION: Despite an association of WMH volume with CSF Aß42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

Autophagy in white matter disorders of the CNS: mechanisms and therapeutic opportunities.

Autophagy is a constitutive process that degrades, recycles and clears damaged proteins or organelles, yet, despite activation of this pathway, abnormal proteins accumulate in neurons in neurodegenerative diseases and in oligodendrocytes in white matter disorders. Here, we discuss the role of autophagy in white matter disorders, including neurotropic infections, inflammatory diseases such as multiple sclerosis, and in hereditary metabolic disorders and acquired toxic-metabolic disorders. Once triggered due to cell stress, autophagy can enhance cell survival or cell death that may contribute to oligodendrocyte damage and myelin loss in white matter diseases. For some disorders, the mechanisms leading to myelin loss are clear, whereas the aetiological agent and pathological mechanisms are unknown for other myelin disorders, although emerging studies indicate that a common mechanism underlying these disorders is dysregulation of autophagic pathways. In this review we discuss the alterations in the autophagic process in white matter disorders and the potential use of autophagy-modulating agents as therapeutic approaches in these pathological conditions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Interleukin-6-Mediated Inflammation May Cause Methotrexate-Induced Leukoencephalopathy.

Children with leukemia treated with methotrexate (MTX) may develop MTX-induced leukoencephalopathy, which can present as seizures or focal neurological deficits. However, the precise pathophysiology has not been fully elucidated. Differences in cytokine/chemokine profiles in cerebrospinal fluid (CSF) between children with MTX-induced leukoencephalopathy and those with posterior reversible encephalopathy syndrome (PRES), an acute neurological condition associated with hypertension, were investigated. Interleukin (IL)-1ß, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, tumor necrosis factor-alpha, interferon-gamma, granulocyte monocyte colony-stimulating factor, granulocyte colony-stimulating factor, macrophage inflammatory protein-1ß, and monocyte chemoattractant protein-1 concentrations were measured in CSF supernatants from 3 children with acute leukemia with MTX-induced leukoencephalopathy, 3 children with acute leukemia with PRES, 6 children with acute leukemia without neurological complications, and 8 children with acute encephalopathy. CSF IL-6 concentrations were higher in children with MTX-induced leukoencephalopathy than in children with acute leukemia with PRES, with acute leukemia without neurological complications, and with acute encephalopathy. We concluded that IL-6 may be involved in the pathogenesis of MTX-induced leukoencephalopathy.

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]-1ß, IL-6, IL-8, IL-10, IFN-γ [interferon-γ ], MCP-1 [monocyte chemoattractant protein-1], MIP-1ß [macrophage inflammatory protein-1ß], 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-1ß 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-1ß 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-1ß 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.

Hypothermic neuroprotection during reperfusion following exposure to aglycemia in central white matter is mediated by acidification.

Hypoglycemia is a common iatrogenic consequence of type 1 diabetes therapy that can lead to central nervous system injury and even death if untreated. In the absence of clinically effective neuroprotective drugs we sought to quantify the putative neuroprotective effects of imposing hypothermia during the reperfusion phase following aglycemic exposure to central white matter. Mouse optic nerves (MONs), central white matter tracts, were superfused with oxygenated artificial cerebrospinal fluid (aCSF) containing 10 mmol/L glucose at 37°C. The supramaximal compound action potential (CAP) was evoked and axon conduction was assessed as the CAP area. Extracellular lactate was measured using an enzyme biosensor. Exposure to aglycemia, simulated by omitting glucose from the aCSF, resulted in axon injury, quantified by electrophysiological recordings, electron microscopic analysis confirming axon damage, the extent of which was determined by the duration of aglycemia exposure. Hypothermia attenuated injury. Exposing MONs to hypothermia during reperfusion resulted in improved CAP recovery compared with control recovery measured at 37°C, an effect attenuated in alkaline aCSF. Hypothermia decreases pH implying that the hypothermic neuroprotection derives from interstitial acidification. These results have important clinical implications demonstrating that hypothermic intervention during reperfusion can improve recovery in central white matter following aglycemia.

Brain comorbidities in normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: This cross-sectional study aims to compare gait changes after the cerebrospinal fluid (CSF) tap test between normal pressure hydrocephalus patients with and without brain comorbidities (NPH+ and NPH- respectively) and then to identify significant contributors to a poor CSF tap test amongst individuals with NPH+. METHODS: Gait changes (during the single task and the dual task of backward counting) were quantified before and 24 h after the CSF tap test with an optoelectronic system in 52 NPH patients (77.4 ± 6.0 years; 34.6% women). Changes after the CSF tap test in stride time variability (STV, %) were our main outcome. CSF Alzheimer's disease biomarkers, cerebrovascular white matter changes assessed with brain imaging and neurodegenerative diseases with parkinsonian syndrome represented the three individual brain comorbidities. RESULTS: Brain comorbidities were frequently identified, NPH+ patients representing 40 patients of our sample (76.9%). NPH- patients improved their STV better in the single task (delta of STV = -58.6% ± 54.3% vs. -14.1% ± 62.0%; P = 0.031) and in the dual task (delta of STV =-32.2% ± 33.7% vs. 6.3% ± 58.4%; P = 0.028) after the CSF tap test than NPH+ patients. Amongst NPH+ individuals, only comorbid Alzheimer's disease was associated with STV increase (i.e. deterioration of gait) in the dual task [ß 38.4; 95% confidence interval (5.64; 71.24); P = 0.023] after the CSF tap test, whilst it was borderline in the single task [ß 35.0; 95% confidence interval (-1.97; 71.90); P = 0.063]. CONCLUSIONS: Brain comorbidities affect gait improvement after the CSF tap test in NPH patients; this influence is driven by Alzheimer's disease-related pathology.

Type I interferon and proinflammatory cytokine levels in cerebrospinal fluid of newborns with rotavirus-associated leukoencephalopathy.

OBJECTIVE: The purpose of this study was to identify whether there is an increase in type I interferon and proinflammatory cytokine levels in the cerebrospinal fluid of newborns with rotavirus-associated leukoencephalopathy. METHODS: Levels of type I interferons (interferon-alpha and interferon-beta) and proinflammatory cytokines (interleukin-6 and interferon-gamma) were measured in the cerebrospinal fluid of 23 newborns with rotavirus-associated leukoencephalopathy (patient group) and 39 infants under 90 days-of-age (control group). RESULTS: Cerebrospinal fluid pleocytosis was not observed in either group. Cerebrospinal fluid interleukin-6 levels were significantly higher in the patient group (7.02 ±â€¯5.88 pg/mL) than in the control group (1.14 ±â€¯1.90 pg/mL) (p < .0001). The mean cerebrospinal fluid interferon-gamma levels of the patient group (24.43 ±â€¯40.16 pg/mL) were also significantly higher than those of the controls group (0.0 ±â€¯0.0 pg/mL) (p < .0001). Cerebrospinal fluid interferon-alpha was not detected in any patient (0%) from the patient group, but was detected in four (10.3%) of the controls. Interferon-beta was detected in only two patients (8.7%) from the patient group and in one (2.6%) of the controls. Cerebrospinal fluid interleukin-6 levels correlated positively with the extent of white matter lesions on diffusion-weighted magnetic resonance imaging (r = 0.607, p = .002). CONCLUSIONS: Significant increases in proinflammatory cytokine levels accompanied by very low detection rates of type I interferon in cerebrospinal fluid indicate that rotavirus-associated leukoencephalopathy in newborns can be correlated with central nervous system inflammatory processes without direct virus invasion into the central nervous system.

A novel autosomal dominant leukodystrophy with specific MRI pattern.

Etiologic diagnosis of adulthood leukodystrophy is challenging in neurologic practice. We describe here the clinico-radiological features of a novel autosomal dominant leukodystrophy in a single family. Clinical and MRI features were recorded in a three generation family. Exome sequencing was performed in two affected relatives and one healthy member. Four total relatives (3 women and 1 man, mean age at onset: 45, range 32-59) were followed: 2 for migraine and 2 for cognitive loss. MRI features were homogeneous in the four affected relatives: extensive and symmetrical white matter hyperintensities on T2-weighted images, with a posterior predominance, involvement of the middle cerebellar peduncles, corpus callosum and the posterior limb of the internal capsules. An extensive metabolic screening was negative. In addition, sequencing of pathogenic genes involved in dominant leukodystrophies (NOTCH3, LMNB1, GFAP, CSF1R) was negative. No mutation has been identified yet with exome sequencing. This report is peculiar because of dominant inheritance, adult onset, highly homogeneous white matter hyperintensities on T2-weighted MR images, predominant in the middle cerebellar peduncles and posterior part of internal capsule and absence of mutation of the genes involved in dominant leukodystrophies.

Leucoencefalopatía multifocal progresiva asociada al natalizumab: importancia de la resonancia magnética en el diagnóstico precoz / Progressive multifocal leukoencephalopathy associated to natalizumab: the importance of magnetic resonance imaging in its early diagnosis

Introducción. El natalizumab es un fármaco utilizado en la esclerosis múltiple (EM), cuyo principal efecto adverso es el desarrollo de una leucoencefalopatía multifocal progresiva (LMP). Como ésta es potencialmente mortal o discapacitante, el tratamiento debe suspenderse inmediatamente ante su sospecha, teniendo en cuenta el posible desarrollo posterior de un síndrome de reconstitución inmune o rebrote de la EM. Caso clínico. Se describe un caso de LMP, inicialmente asintomático, en el contexto del tratamiento con natalizumab en una paciente con EM. Como factores de riesgo se determinaron títulos altos de anticuerpos contra el virus John Cunningham (VJC) y más de dos años de tratamiento. La reacción en cadena de la polimerasa para el VJC en el líquido cefalorraquídeo resultó negativa en dos determinaciones. El período entre el diagnóstico radiológico y el inicio de la clínica fue de dos meses. Durante el curso de la enfermedad, la paciente desarrolló un síndrome inflamatorio de reconstitución inmune y rebrotes de su EM. Presentó una buena respuesta tras el inicio de tratamiento con fingolimod, una vez estabilizada la LMP. Conclusión. Este caso ilustra la importancia de una estrecha vigilancia clinicorradiológica en pacientes con EM tratados con natalizumab, sobre todo cuando presentan factores de riesgo para el desarrollo de LMP, así como su potencial incidencia en la supervivencia y estado funcional final (AU)

Introduction. Natalizumab is a drug used in multiple sclerosis (MS) and its main side effect is the development of progressive multifocal leukoencephalopathy (PML). Since this is potentially fatal or disabling, treatment must be stopped immediately if it is suspected, taking into account the possible later development of immune reconstitution syndrome or renewed exacerbation of MS. Case report. We report a case of initially asymptomatic PML within the context of treatment with natalizumab in a female patient with MS. High antibody titers to the John Cunningham virus (JCV) and over two years’ treatment were established as risk factors. The polymerase chain reaction for the JCV in cerebrospinal fluid was negative in two determinations. The interval between the radiological diagnosis and the onset of the clinical features was two months. During the course of the disease, the patient developed immune reconstitution inflammatory syndrome and relapses, or renewed exacerbation, of her MS. She responded well after beginning treatment with fingolimod, once the PML had become stabilised. Conclusions. This case indicates the importance of close clinico-radiological monitoring in patients with MS treated with natalizumab, especially when they present risk factors for the development of PML, as well as its potential incidence on survival and final functional status (AU)

Biochemical markers of neurodegeneration in hereditary diffuse leucoencephalopathy with spheroids.

Hereditary diffuse leucoencephalopathy with spheroids (HDLS) is a rare autosomal dominantly inherited disease with unknown pathophysiology. Diagnosis of neurodegenerative diseases is increasingly based on biomarkers. Although lumbar puncture is routinely performed during the diagnostic workup of HDLS, reports on alterations of neurodegeneration-specific biochemical markers have not been documented so far. We report a 35-year-old woman with clinical, radiological and neuropathological signs of HDLS. She suffered from a rapidly progressive frontal lobe syndrome. Brain MRI revealed diffuse leucoencephalopathy with predominant involvement of the periventricular white matter and corpus callosum. Although she was severely impaired and leucoencephalopathy was prominent, only cerebrospinal fluid total-τ was moderately elevated. Other markers of neuronal (NSE) and astrocytic (S100B) damage were within normal range. Therefore, biochemical markers of central nervous system damage are not helpful in the diagnosis of HDLS.

Dissociable effects of Alzheimer disease and white matter hyperintensities on brain metabolism.

IMPORTANCE: Cerebrovascular disease and Alzheimer disease (AD) frequently co-occur and seem to act through different pathways in producing dementia. OBJECTIVE: To examine cerebrovascular disease and AD markers in relation to brain glucose metabolism in patients with mild cognitive impairment. DESIGN AND SETTING: Cohort study among the Alzheimer Disease Neuroimaging Initiative clinical sites in the United States and Canada. PARTICIPANTS: Two hundred three patients having amnestic mild cognitive impairment (74 of whom converted to AD) with serial imaging during a 3-year follow-up period. MAIN OUTCOMES AND MEASURES: Quantified white matter hyperintensities (WMHs) represented cerebrovascular disease, and cerebrospinal fluid ß-amyloid represented AD pathology. Brain glucose metabolism in temporoparietal and frontal brain regions was measured using positron emission tomography with fluorodeoxyglucose F18. RESULTS: In converters, greater WMHs were associated with decreased frontal metabolism (-0.048; 95% CI, -0.067 to -0.029) but not temporoparietal metabolism (0.010; 95% CI, -0.010 to 0.030). Greater cerebrospinal fluid ß-amyloid (per 10-pg/mL increase) was associated with increased temporoparietal metabolism (0.005; 95% CI, 0.000-0.010) but not frontal metabolism (0.002; 95% CI, -0.004 to 0.007) in the same patients. In nonconverters, similar relationships were observed except for a positive association of greater WMHs with increased temporoparietal metabolism (0.051; 95% CI, 0.027-0.076). CONCLUSIONS AND RELEVANCE: The dissociation of WMHs and cerebrospinal fluid ß-amyloid in relation to regional glucose metabolism suggests that these pathologic conditions operate through different and independent pathways in AD that reflect dysfunction in different brain systems. The positive association of greater WMHs with temporoparietal metabolism suggests that these pathologic processes do not co-occur in nonconverters.

N-acetylaspartylglutamate in CNS hypomyelination.

CSF N-acetylaspartylglutamate (NAAG) has been found to be elevated in some hypomyelinating disorders. This study addressed the question whether it could be used as a marker for hypomyelination and as a means to distinguish between hypomyelinating disorders biochemically. We have measured CSF NAAG in a cohort of 28 patients with hypomyelination with known and unknown aetiology. NAAG was found to be elevated in 7 patients, but was normal in the majority, including patients with defined hypomyelinating disorders. CSF NAAG is not a universal marker of hypomyelination, and the mechanism of its elevation remains poorly understood.

White matter lesion load increases the risk of low CSF Aß42 in apolipoprotein E-ɛ4 carriers attending a memory clinic.

BACKGROUND: White matter lesions (WMLs) are age-related manifestations of ischemic cerebrovascular disease and increase the risk for Alzheimer's disease (AD). The apolipoprotein E (ApoE) ɛ4 allele is a risk factor for late onset AD and has been related to low cerebrospinal fluid (CSF) Aß42 levels and to cerebrovascular disease. The present study analyzed the relationship between WMLs, ApoE-ɛ4 genotype, and low CSF Aß42. METHODS: A total of 235 memory clinic attenders were stratified in 3 groups according to WML load. WMLs were rated on axial T2 magnetic resonance imaging images. Group 1 had no or only small amounts of periventricular (PV) or subcortical (SC) WMLs, WML group 2 had high amounts of PV WMLs and low amounts of SC WMLs, and WML group 3 had high amounts of both PV and SC WMLs. In each WML group, ApoE-ɛ4 genotype was used in logistic regression as a predictor for low CSF Aß42 (cutoff≤450 ng/L). RESULTS: The odds ratio (OR) of having low CSF Aß42 was significantly increased in the presence of ApoE-ɛ4 only in WML group 3 (OR 3.69, P=.009). CONCLUSION: A high WML load may interact with the ApoE-ɛ4 genotype and increase the risk for reduced CSF Aß42 in patients attending a memory clinic.

Leukoencephalopathy with brainstem and spinal cord involvement and normal lactate: a new mutation in the DARS2 gene.

Leukoencephalopathy with brainstem and spinal cord involvement and elevated brain lactate diagnosis is based on its highly characteristic pattern of abnormalities observed by magnetic resonance imaging and spectroscopy. Clinically, affected patients develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. In 2007, the pathophysiology of this disorder was elucidated with the discovery of mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals. Here, the authors present a case of leukoencephalopathy with brainstem and spinal cord involvement with normal brain lactate, in which genetic analysis revealed a new mutation in the DARS2 gene not previously described.