Translational evidence for two distinct patterns of neuroaxonal injury in sepsis: a longitudinal, prospective translational study.

BACKGROUND: Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis. METHODS: We conducted a longitudinal, prospective translational study involving (1) experimental sepsis in an animal model; (2) postmortem studies of brain from patients with sepsis; and (3) a prospective, longitudinal human sepsis cohort study at university laboratory and intensive care units (ICUs). Thirteen ICU patients with septic shock, five ICU patients who died as a result of sepsis, fourteen fluid-resuscitated Wistar rats with fecal peritonitis, eleven sham-operated rats, and three human and four rat control subjects were included. Immunohistologic and protein biomarker analysis were performed on rat brain tissue at baseline and 24, 48, and 72 h after sepsis induction and in sham-treated rats. Immunohistochemistry was performed on human brain tissue from sepsis nonsurvivors and in control patients without sepsis. The clinical diagnostics of SAE comprised longitudinal clinical data collection and magnetic resonance imaging (MRI) and electroencephalographic assessments. Statistical analyses were performed using SAS software (version 9.4; SAS Institute, Inc., Cary, NC, USA). Because of non-Gaussian distribution, the nonparametric Wilcoxon test general linear models and the Spearman correlation coefficient were used. RESULTS: In postmortem rat and human brain samples, neurofilament phosphoform, ß-amyloid precursor protein, ß-tubulin, and H&E stains distinguished scattered ischemic lesions from diffuse neuroaxonal injury in septic animals, which were absent in controls. These two patterns of neuroaxonal damage were consistently found in septic but not control human postmortem brains. In experimental sepsis, the time from sepsis onset correlated with tissue neurofilament levels (R = 0.53, p = 0.045) but not glial fibrillary acidic protein. Of 13 patients with sepsis who had clinical features of SAE, MRI detected diffuse axonal injury in 9 and ischemia in 3 patients. CONCLUSIONS: Ischemic and diffuse neuroaxonal injury to the brain in experimental sepsis, human postmortem brains, and in vivo MRI suggest these two distinct lesion types to be relevant. Future studies should be focused on body fluid biomarkers to detect and monitor brain injury in sepsis. The relationship of neurofilament levels with time from sepsis onset may be of prognostic value. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02442986 . Registered on May 13, 2015.

Effect of active Aß immunotherapy on neurons in human Alzheimer's disease.

Amyloid ß peptide (Aß) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aß immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aß42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aß42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aß removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aß immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline.

BACKGROUND: Alzheimer disease is characterized by cognitive decline, senile plaques of ß-amyloid (Aß) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aß and τ are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death. METHODS: In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Aß, τ and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1-3 years and assessed using Mini-Mental State Examination scores. RESULTS: The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Aß42 levels. Confocal microscopy revealed that JNK3 was associated with Aß in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model. LIMITATIONS: The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis. CONCLUSION: We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation.

Loss of endoplasmic reticulum calcium pump expression in choroid plexus tumours.

AIMS: Sarco/Endoplasmic Reticulum Calcium ATPase-type calcium pumps (SERCA enzymes) control cell activation by sequestering calcium ions from the cytosol into the endoplasmic reticulum. Although endoplasmic reticulum calcium signalling plays an important role in the regulation of choroid plexus epithelial function, SERCA expression in the choroid plexus has not been investigated so far. METHODS: In this work we investigated the expression of the SERCA3-type calcium pump in choroid plexus epithelial cells grown in vitro, and in normal and hyperplastic choroid plexus tissue, in choroid plexus papillomas displaying various degrees of atypia, and in choroid plexus carcinoma by immunohistochemistry in situ. RESULTS: Whereas normal choroid plexus epithelial cells express SERCA3 abundantly, SERCA3 expression is strongly decreased in papillomas, and is absent in choroid plexus carcinoma, while expression in hyperplastic epithelium is high, similarly to normal epithelium. SERCA3 expression was detected also in normal primary choroid plexus epithelial cells grown in vitro, and expression was markedly enhanced by short-chain fatty acid-type cell differentiation inducing agents, including valproate. CONCLUSION: These observations show that SERCA3 is a new phenotypic marker of normal choroid plexus epithelial differentiation, and that SERCA3 constitutes an early tumour marker 'by loss of expression' in the choroid plexus that may be useful to distinguish hyperplastic processes from papillomas. Endoplasmic reticulum calcium homeostasis becomes anomalous, due to loss of SERCA3 expression, already in benign neoplastic lesions of the choroid plexus epithelium.

Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway.

Beta-site APP cleaving enzyme 1 (BACE1) is the rate limiting enzyme for accumulation of amyloid ß (Aß)-peptide in the brain in Alzheimer's disease (AD). Oxidative stress (OS) that leads to metabolic dysfunction and apoptosis of neurons in AD enhances BACE1 expression and activity. The activation of c-jun N-terminal kinase (JNK) pathway was proposed to explain the BACE1 mRNA increase under OS. However, little is known about the translational control of BACE1 in OS. Recently, a post-transcriptional increase of BACE1 level controlled by phosphorylation of eIF2α (eukaryotic translation initiation factor-2α) have been described after energy deprivation. PKR (double-stranded RNA dependant protein kinase) is a pro-apoptotic kinase that phosphorylates eIF2α and modulates JNK activation in various cellular stresses. We investigated the relations between PKR, eIF2α and BACE1 in AD brains in APP/PS1 knock-in mice and in hydrogen peroxide-induced OS in human neuroblastoma (SH-SY5Y) cell cultures. Immunoblotting results showed that activated PKR (pPKR) and activated eIF2α (peIF2α) and BACE1 levels are increased in AD cortices and BACE1 correlate with phosphorylated eIF2α levels. BACE1 protein levels are increased in response to OS in SH-SY5Y cells and specific inhibitions of PKR-eIF2α attenuate BACE1 protein levels in this model. Our findings provide a new translational regulation of BACE1, under the control of PKR in OS, where eIF2α phosphorylation regulates BACE1 protein expression.

CD8 encephalitis in HIV-infected patients receiving cART: a treatable entity.

BACKGROUND: Despite its overall efficacy, combined antiretroviral therapy (cART) has failed to control human immunodeficiency virus (HIV) infection of the central nervous system (CNS). New acute and chronic neurological complications continue to be reported. METHODS: We conducted a retrospective study of 14 HIV-infected patients with documented encephalitis, which was initially attributed to an undetermined origin. Brain magnetic resonance imaging (MRI) uniformly revealed unusual, multiple linear gadolinium-enhanced perivascular lesions. RESULTS: All patients had manifested acute or subacute neurological symptoms; the brain MRIs indicating diffuse brain damage. The mean duration of HIV infection was approximately 10 years, and 8 patients were immunovirologically stable. Cerebrospinal fluid abnormalities with mildly elevated protein and pleocytosis with >90% lymphocytes, predominantly CD8, were found in all but 1 patient. The mean cerebral spinal fluid HIV load was 5949 copies/mL. Six patients reported a minor infection a few days prior to neurological symptoms, 2 patients presented criteria for the immune reconstitution inflammatory syndrome of the CNS, 2 were in virological escape, and 1 developed encephalitis after interruption of cART. Brain biopsies revealed inflammatory encephalitis associated with astrocytic and microglial activation as well as massive perivascular infiltration by polyclonal CD8(+) lymphocytes. All patients had been treated with glucocorticosteroids. The long-term therapeutic response varied from excellent, with no sequalae (n = 5), to moderate, with cognitive disorders (n = 4). The mean survival time was 8 years; however, 5 patients died within 13 months of initiation of treatment. CONCLUSIONS: CD8 encephalitis in HIV-infected patients receiving cART is a clinical entity that should be added to the list of HIV complications.

A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy.

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5-4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML-IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML.

Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: The purpose of this study was to report the detection of infarcts of the cerebral cortex in a patient with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using high-resolution postmortem 7-T MRI in association with pathological examination. METHODS: Whole brain high-resolution MRI data were obtained postmortem at 7 T in a 53-year-old patient with CADASIL. These MRI data were used to guide the neuropathological examination of the cortex. RESULTS: Combined with neuropathology, MRI allowed the delineation of intracortical infarcts confirmed by histological examination in this case. These lesions were not visible on the last in vivo MRI obtained at 1.5 T and were difficult to detect on neuropathological examination only. CONCLUSIONS: Postmortem high-resolution MRI may help to detect intracortical infarcts in CADASIL and possibly in other small vessel diseases of the brain.

Hyperglycaemia and apoptosis of microglial cells in human septic shock.

INTRODUCTION: The effect of hyperglycaemia on the brain cells of septic shock patients is unknown. The objective of this study was to evaluate the relationship between hyperglycaemia and apoptosis in the brains of septic shock patients. METHODS: In a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for neuronal ischaemia, neuronal and microglial apoptosis, neuronal Glucose Transporter (GLUT) 4, endothelial inducible Nitric Oxide Synthase (iNOS), microglial GLUT5 expression, microglial and astrocyte activation. Blood glucose (BG) was recorded five times a day from ICU admission to death. Hyperglycaemia was defined as a BG 200 mg/dL g/l and the area under the BG curve (AUBGC) > 2 g/l was assessed. RESULTS: Median BG over ICU stay was 2.2 g/l. Neuronal apoptosis was correlated with endothelial iNOS expression (rho = 0.68, P = 0.04), while microglial apoptosis was associated with AUBGC > 2 g/l (rho = 0.70; P = 0.002). Neuronal and microglial apoptosis correlated with each other (rho = 0.69, P = 0.006), but neither correlated with the duration of septic shock, nor with GLUT4 and 5 expression. Neuronal apoptosis and ischaemia tended to correlate with duration of hypotension. CONCLUSIONS: In patients with septic shock, neuronal apoptosis is rather associated with iNOS expression and microglial apoptosis with hyperglycaemia, possibly because GLUT5 is not downregulated. These data provide a mechanistic basis for understanding the neuroprotective effects of glycemic control.

A cortical form of CADASIL with cerebral Aß amyloidosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was diagnosed by genetic testing in a 53-year-old patient, 10 years before death. Following two strokes with partial recovery, he developed rapidly progressive cognitive decline 3 years before death. Neuropathology confirmed CADASIL. Characteristic arteriolar changes were associated with subcortical infarcts, and status cribrosus in basal ganglia and the cortico-subcortical junctions. Leukoencephalopathy was very mild. Severe arteriolar changes in the cerebral cortex and leptomeninges were associated with numerous intracortical microinfarcts. There was abundant Abeta deposition throughout the cerebral cortex, mainly as Aß42 diffuse plaques, frequently periarteriolar. There was no cerebral amyloid angiopathy apart from rare Aß40 deposits around Notch3-positive deposits. Amyloid plaques were rare. Tau pathology was minimal. Alzheimer disease associated with CADASIL has been described, but the few reported cases had abundant amyloid plaques, amyloid angiopathy, fibrillar plaques and neurofibrillary tangles. Aß accumulation could result from abnormal Aß synthesis or impaired elimination due to the arteriolar changes of CADASIL. We did not find Aß deposits in our other CADASIL cases with milder cortical arteriolar changes. Additional genetic predisposing factors were not identified. This case suggests that besides the classical, purely subcortical form of CADASIL, a "cortical" form with numerous lacunar infarcts and Aß deposition in the cerebral cortex may occur and may be difficult to differentiate clinically from Alzheimer disease.

[Gliomatosis cerebri: a biopsy and autopsy case report]. / Gliomatose cérébrale diffuse: étude biopsique et autopsique d'un cas.

Gliomatosis cerebri is a rare glial neoplasm, characterized by diffuse brain infiltration with relative preservation of the underlying cytoarchitecture. Its clinical and radiologic features are not specific and its antemortem diagnosis is difficult. We report a case of gliomatosis cerebri in a 68-year-old woman presenting with gait disturbances and episodic seizures. MRI showed bilateral white matter hypersignal intensities on Flair sequences and brain biopsy revealed a poorly cellular proliferation of neoplasic glial cells strongly expressing OLIG-2, Ki-67 and occasionally GFAP, without alpha-internexin expression. The patient status worsened rapidly and she died 2 months after the initial symptoms. Postmortem brain examination confirmed gliomatosis cerebri and revealed a focal glioblastoma in the frontal cortex, with nuclear p53 expression in the highest malignant areas. Gliomatosis cerebri should be included in the differential diagnostic of diffuse brain lesions. Antemortem diagnosis, although difficult, can be assessed by IRM and careful biopsy examination. Progression to glioblastoma has been seldom reported, enhancing the controversy about the etiopathogenesis of this rare tumour.

Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.

The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKR(p))-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKR(p) signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKR(p)-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKR(p)-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.

Cerebral amyloid angiopathy with co-localization of prion protein and beta-amyloid in an 85-year-old patient with sporadic Creutzfeldt-Jakob disease.

We report on an 85-year-old woman with hypertensive cerebral arteriolosclerosis who presented with rapidly progressive encephalopathy leading to death within 4 months. Magnetic resonance imaging showed mild cortical atrophy consistent with her age and diffuse leukoaraiosis. Her CSF 14-3-3 protein was positive. Neuropathology showed severe spongiform change and gliosis in the grey matter and immunohistochemistry revealed diffuse prion protein deposition in a predominant synaptic pattern. She had no family history of neurological disorder and genotyping did not show any prion protein gene mutation, in keeping with a diagnosis of sporadic Creutzfeldt-Jakob disease. There was also diffuse amyloid angiopathy involving the cortical and leptomeningeal arterioles of the cerebral hemispheres and cerebellum and the capillaries of the grey matter. The amyloid angiopathy expressed beta-amyloid but also prion protein and double immunostaining confirmed co-localization of both proteins in many vessel walls. Alzheimer's type pathology was restricted to a few diffuse beta-amyloid plaques in the entorhinal cortex and rare tangles in the hippocampus. Deposition of prion protein in cerebral vessels has been reported in a single case of stop codon 145 mutation of the PRNP gene. Co-localization of beta-amyloid and prion protein in the same amyloid plaque has been described in elderly patients with Creutzfeldt-Jakob or Gerstmann-Sträussler-Scheinker diseases but only exceptionally in cerebral amyloid angiopathy. In this patient, hypertensive cerebrovascular disease may have contributed to the failure to eliminate both proteins from the brain.

Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

To test the hypothesis that an apoptotic process plays a role in the pathogenesis of cerebral lesions in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we examined samples from frontal, temporal, insular, and occipital regions, basal ganglia, and cerebellum from 4 patients with CADASIL, 2 with Binswanger disease, and 3 controls. Apoptotic cells were identified using in situ end labeling and activated caspase 3 immunostaining. Immunolabeling for Notch3, the beta-amyloid protein precursor, and phosphorylated neurofilament protein was performed on successive sections. Apoptosis of vascular cells was markedly increased in status cribrosus in CADASIL, both in basal ganglia and subcortical white matter, suggesting that concomitantly with Notch3 deposition it may play a causative role in the dilatation of Virchow-Robin spaces. Neuronal apoptosis was found in CADASIL, mostly in cortical layers 3 and 5. Its severity correlated semiquantitatively with the extent of ischemic lesions and axonal damage in the underlying white matter. It was more severe in demented patients. Only occasional apoptotic neurons were found in the Binswanger cases and none in the controls. This supports the view that neuronal apoptosis may contribute to cortical atrophy and cognitive impairment in patients with CADASIL and that it may, at least partly, result from axonal damage in the underlying white matter.

Neuropathologic contributions to understanding AIDS and the central nervous system.

This historical review describes the evolution of the pathogenetic concepts associated with infection by the Human Immunodeficiency Virus (HIV), with emphasis on the pathology of the nervous system. Although the first descriptions of damage to the nervous system in the acquired immunodeficiency syndrome (AIDS) only appeared in 1982, the dramatic diffusion of the epidemic worldwide and the invariably rapidly fatal outcome of the disease, before the introduction of efficient treatment, generated from the beginning an enormous amount of research with rethinking on a number of pathogenetic concepts. Less than 25 years after the first autopsy series of AIDS patients were published and the virus responsible for AIDS was identified, satisfactory definition and classification of a number of neuropathological complications of HIV infection have been established, leading to accurate clinical radiological and biological diagnosis of the main neurological complications of the disease, which remain a major cause of disability and death in AIDS patients. Clinical and experimental studies have provided essential insight into the pathogenesis of CNS lesions and natural history of the disease. The relatively recent introduction of highly active antiretroviral therapy (HAART) in 1995-1996 has dramatically improved the course and prognosis of HIV disease. However, there remain a number of unsolved pathogenetic issues, the most puzzling of which remains the precise mechanism of neuronal damage underlying the specific HIV-related cognitive disorders (HIV dementia). In addition, although HAART has changed the course of neurological complications of HIV infection, new issues have emerged such as the lack of improvement or even paradoxical deterioration of the neurological status in treated patients. Interpretation of these latter data remains largely speculative partly because of the small number of neuropathological studies related to the beneficial consequence of this treatment.

Brain lesions in septic shock: a magnetic resonance imaging study.

BACKGROUND: Understanding of sepsis-induced brain dysfunction remains poor, and relies mainly on data from animals or post-mortem studies in patients. The current study provided findings from magnetic resonance imaging of the brain in septic shock. METHODS: Nine patients with septic shock and brain dysfunction [7 women, median age 63 years (interquartile range 61-79 years), SAPS II: 48 (44-56), SOFA: 8 (6-10)] underwent brain magnetic resonance imaging including gradient echo T1-weighted, fluid-attenuated inversion recovery (FLAIR), T2-weighted and diffusion isotropic images, and mapping of apparent diffusion coefficient. RESULTS: Brain imaging was normal in two patients, showed multiple ischaemic strokes in two patients, and in the remaining patients showed white matter lesions at the level of the centrum semiovale, predominating around Virchow-Robin spaces, ranging from small multiple areas to diffuse lesions, and characterised by hyperintensity on FLAIR images. The main lesions were also characterised by reduced signal on diffusion isotropic images and increased apparent diffusion coefficient. The lesions of the white matter worsened with increasing duration of shock and were correlated with Glasgow Outcome Score. CONCLUSION: This preliminary study showed that sepsis-induced brain lesions can be documented by magnetic resonance imaging. These lesions predominated in the white matter, suggesting increased blood-brain barrier permeability, and were associated with poor outcome.

Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia.

OBJECTIVE: To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. METHODS: CPEO patients (n=13) with large size deletion of mitochondrial DNA and matching healthy controls (n=22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. RESULTS: Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath. CONCLUSION: CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. SIGNIFICANCE: This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.

Cortical neuronal apoptosis in CADASIL.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations of the NOTCH3 gene and is a model of pure vascular dementia. Cortical atrophy has been reported to be associated with cognitive decline in the disease, although the underlying mechanism is unknown. We postulated that apoptosis may be involved in this process. METHODS: We report the clinical history, magnetic resonance imaging findings, and pathologic examinations of 4 patients (2 of whom were demented) who died from complications of the disease. Apoptosis was evaluated in brain tissue using antibodies against activated caspase3 and in situ end labeling assays for DNA fragmentation. RESULTS: Widespread neuronal apoptosis in the cerebral cortex (predominantly in layers 3 and 5) was observed in all patients. This was not seen in 3 non-CADASIL controls. Semiquantitative analysis suggested that apoptosis was more extensive in the presence of larger load of subcortical ischemic lesions and smaller brain volumes. CONCLUSIONS: Neuronal apoptosis may be involved in cortical atrophy in CADASIL and appears related to the burden of subcortical ischemic lesions. These findings may have important implications in other small vessel diseases and may provide a potential target for future therapeutic interventions.