Infections of the central nervous system: Neuropathology.

Encephalitides include a large variety of diseases with high morbidity and mortality. Although the majority of identified pathogens are viruses, the cause of the disease remains unexplained in more than half of the cases despite extensive testing. Neuropathology provides the bases of our understanding of the inflammatory lesions in the central nervous system. Brain biopsy proves to be necessary in cases of unknown etiology, which deteriorate despite treatment. Unexpected pathogens can be uncovered by untargeted transcriptomic analysis, based on deep sequencing of small quantities of pathological brain tissue. Combined with immunohistochemistry and in situ hybridization, using tailored antibodies and probes, this next generation sequencing method opens perspectives in the diagnosis of encephalitides with a high efficiency particularly in, but not limited to, immunocompromised patients.

SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis.

We have previously demonstrated that Sox17 expression is prominent at developmental stages corresponding to oligodendrocyte progenitor cell (OPC) cycle exit and onset of differentiation, and that Sox17 promotes initiation of OPC differentiation. In this study, we examined Sox17 expression and regulation under pathological conditions, particularly in two animal models of demyelination/remyelination and in post-mortem multiple sclerosis (MS) brain lesions. We found that the number of Sox17 expressing cells was significantly increased in lysolecithin (LPC)-induced lesions of the mouse spinal cord between 7 and 30 days post-injection, as compared with controls. Sox17 immunoreactivity was predominantly detected in Olig2(+) and CC1(+) oligodendrocytes and rarely in NG2(+) OPCs. The highest density of Sox17(+) oligodendrocytes was observed at 2 weeks after LPC injection, coinciding with OPC differentiation. Consistent with these findings, in cuprizone-treated mice, Sox17 expression was highest in newly generated and in maturing CC1(+) oligodendrocytes, but low in NG2(+) OPCs during the demyelination and remyelination phases. In MS tissue, Sox17 was primarily detected in actively demyelinating lesions and periplaque white matter. Sox17 immunoreactivity was co-localized with NOGO-A+ post-mitotic oligodendrocytes both in active MS lesions and periplaque white matter. Taken together, our data: (i) demonstrate that Sox17 expression is highest in newly generated oligodendrocytes under pathological conditions and could be used as a marker of oligodendrocyte regeneration, and (ii) are suggestive of Sox17 playing a critical role in oligodendrocyte differentiation and lesion repair.

Frontotemporal lobar degeneration: diversity of FTLD lesions.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group including both sporadic and familial diseases, characterized by a macroscopic alteration. It may correspond to various cognitive syndromes: behavioral variant of frontotemporal dementia (bvFTD), progressive nonfluent aphasia, and semantic dementia. The neuropathologic classification is now based on identification of the protein that accumulates in neurons and glia: Tau, TAR DNA Binding Protein 43 (TDP-43), and FUsed in Sarcoma (FUS). The disorders in which the corresponding proteins accumulate have been named FTLD-Tau, FTLD-TDP, and FTLD-FUS. FTLD-Tau includes sporadic cases (e.g. Pick's disease) and Tau mutations. FTLD-TDP are subdivided within four types (A, B, C, D) according to the shape and distribution of TDP-43 positive lesions within the associative frontal cortex. The FTLD-FUS group includes atypical FTLD with ubiquitinated lesions (FTLD-U), Neuronal Intermediate Filament Inclusion Disease (NIFID) and Basophilic Inclusion Body Disease (BIBD).

Elevated levels of IFNγ and LIGHT in the spinal cord of patients with sporadic amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a paralytic and fatal neurodegenerative disorder caused by the gradual loss of both upper and lower motoneurons. There is compelling evidence from ALS experimental models that neuroinflammation actively contributes to motoneuron damage. We recently proposed that interferon gamma (IFNγ), a potent proinflammatory cytokine, induces motoneuron death by eliciting the activation of the lymphotoxin beta receptor (LT-ßR) through its ligand LIGHT. Here, we explore the pertinence of this non-cell-autonomous mechanism in human ALS. METHODS: The levels and expression pattern of IFNγ, LIGHT, and LT-ßR were investigated by Western blot and immunohistochemical analysis in spinal cord of patients with sporadic ALS. RESULTS: We observed significant increased levels of IFNγ in human ALS spinal cords compared to control cases. We found that large ventral horn neurons as well as glial cells were immunoreactive for IFNγ in sporadic ALS spinal cord. We further observed that LIGHT and LT-ßR were expressed mainly by motoneurons in both ALS and control cases, and while LT-ßR levels remained constant between ALS and control cases, LIGHT levels were increased in human ALS spinal cords. CONCLUSION: These findings in sporadic ALS cases, which are consistent with the observation made in ALS experimental models, propose that the IFNγ-triggered LIGHT/LT-ßR-mediated death pathway may contribute to human ALS pathogenesis.

[The neuropathology of sleep in human neurodegenerative diseases]. / Neuropathologie du sommeil des maladies neurodégénératives humaines.

The neuropathology of human sleep remains an ill-defined issue. The data concerning the main structures of human brain areas involved, or supposed to be implicated, in sleep organisation are reviewed. Five levels of organisation can be schematically recognized: (i) the ascending arousal system, (ii) the non REM and REM systems (iii) regulated by hypothalamic areas, (iv) and the biological clock, (v) modulated by a number of "allostatic" influences. These are briefly described, with emphasis on the location of structures involved in humans, and on the recently revised concepts. Current knowledge on the topography of lesions associated with the main sleep disorders in degenerative diseases is recalled, including REM sleep behavior disorders, restless legs syndrome and periodic leg movements, sleep apneas, insomnia, excessive daily sleepiness, secondary narcolepsy and disturbed sleep-wake rhythms. The lesions of sleep related structures observed in early and late stages of four degenerative diseases are then reviewed. Two synucleinopathies (Lewy lesions associated disorders, including Parkinson's disease and Dementia with Lewy bodies, and Multiple System Atrophy) and two tauopathies (Progressive Supranuclear Palsy and Alzheimer's disease) are dealt with. The distribution of lesions usually found in affected patients fit with that expected from the prevalence of different sleep disorders in these diseases. This confirms the current opinion that these disorders depend on the distribution of lesions rather than on their biochemical nature. Further studies might throw insight on the mechanism of normal and pathological sleep in humans, counterpart of the increasing knowledge provided by animal models. Specially designed prospective clinicopathological studies including peculiar attention to sleep are urgently needed.

Pathology of tumors of the pineal region.

Tumors of the pineal region are rare and relatively few centers around the world have published substantial numbers of carefully studied cases. This review gives a historical account of our understanding of the normal pineal and the evolution of the classification of tumors and other mass lesions of the pineal region in human beings. Based on our experience over the past 30 years, a working classification is proposed and recent advances in the neuropathology of these lesions are discussed.

Reversible encephalopathy associated with cholesterol embolism syndrome: magnetic resonance imaging and pathological findings.

We describe a patient found to have acute diffuse and reversible encephalopathy on magnetic resonance imaging (MRI) associated with cholesterol emboli syndrome (CES). The initial MRI showed extensive white matter, basal ganglia and cortical damage without evidence of brain infarction. Dramatic clinical and MRI improvement was observed with corticosteroids. Pathologically, cholesterol crystal emboli were found in the lumen of skin and brain arteries and were associated with varying degrees of inflammation of the arteriole wall. This case suggests that CES may be responsible for extensive, acute and reversible encephalopathy underlined by an inflammation of brain arteries.

Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.

Saltatory conduction in myelinated fibres depends on the specific molecular organization of highly specialized axonal domains at the node of Ranvier, the paranodal and the juxtaparanodal regions. Voltage-gated sodium channels (Na(v)) have been shown to be deployed along the naked demyelinated axon in experimental models of CNS demyelination and in multiple sclerosis lesions. Little is known about aggregation of nodal, paranodal and juxtaparanodal constituents during the repair process. We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions. Whereas in demyelinated lesions, paranodal and juxtaparanodal proteins are diffusely distributed on denuded axons, the distribution of Na(v) channels is heterogeneous, with a diffuse immunoreactivity but also few broad Na(v) channel aggregates in all demyelinated lesions. In contrast to the demyelinated plaques, all remyelinated lesions are characterized by the detection of aggregates of Na(v) channels, paranodin/Caspr, K(v) channels and Caspr2. Our data suggest that these aggregates precede remyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of paranodal and then juxtaparanodal axonal proteins. Remyelination takes place in multiple sclerosis tissue but myelin repair is often incomplete, and the reasons for this remyelination deficit are many. We suggest that a defect of Na(v) channel aggregation might be involved in the remyelination failure in demyelinated lesions with spared axons and oligodendroglial cells.

Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis.

A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.

Long-term survival after gene therapy for a recurrent glioblastoma.

A patient presenting with a recurrent glioblastoma (GBM) survived 3 years after suicide gene therapy and finally died of a disseminated breast cancer with no indication of tumor recurrence on MRI. Postmortem analysis showed no evidence of recurrence of the GBM, neither near the initial tumor localization nor in any other area of the brain. Such an evolution is unusual in the course of this disease and may suggest in this particular case a cure of the GBM.

HIV-1-associated cognitive/motor complex: absence of neuronal loss in the cerebral neocortex.

We performed a postmortem morphometric study in six AIDS patients and six controls to determine if a neocortical neuronal loss occurs in HIV-1-associated cognitive/motor complex. Patients were selected during a prospective study including psychometric evaluation and neuroimaging, and none had focal lesions. Two had HIV-1-associated myelopathy with mild cognitive impairment, and four had HIV-1-associated dementia complex. Planimetry did not show any cerebral atrophy. Cortical thickness, mean neuronal size, and mean neuronal densities in Brodmann's areas 4, 9, and 40 were not statistically different in patients and controls. There were no significant changes in neuronal densities of columnar and laminar samples, indicating that there was neither global nor selective neuronal loss. HIV-1-associated cognitive/motor complex is not necessarily related to neocortical neuronal loss, but could be due to subcortical lesions or metabolic dysfunction.

Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis.

BACKGROUND: Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients. METHODS: The association of hallucinations and REM sleep both at night and during the day was examined in 10 consecutive nondemented patients with long-standing levodopa-responsive PD and hallucinations. Seven patients presented with paranoia and paranoid delusions. Overnight sleep recordings and standard multiple daytime sleep latency test were performed. The results were compared to those of 10 similar patients with PD not experiencing hallucinations. RESULTS: RBD was detected in all 10 patients with hallucinations and in six without. Although nighttime sleep conditions were similar in both groups, hallucinators tended to be sleepier during the day. Delusions following nighttime REM period and daytime REM onsets were observed in three and eight of the hallucinators, and zero and two of the others. Daytime hallucinations, coincident with REM sleep intrusions during periods of wakefulness, were reported only by hallucinators. Postmortem examination of the brain of one patient showed numerous Lewy bodies in neurons of the subcoeruleus nucleus, a region that is involved in REM sleep control. CONCLUSION: The visual hallucinations that coincide with daytime episodes of REM sleep in patients who also experience post-REM delusions at night may be dream imagery. Psychosis in patients with PD may therefore reflect a narcolepsy-like REM sleep disorder.

Morphology of demyelination in the human central nervous system.

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.

AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. The French Study Group for HIV-Associated Tumors.

Fifty-one cases of acquired immunodeficiency syndrome (AIDS)-related primary brain lymphomas (AR-PBL) were investigated for clinical characteristics; human immunodeficiency virus (HIV)-associated disorders; histopathologic features; immunophenotype; Epstein-Barr virus (EBV) infection; and, when frozen tissue was available, oncogene rearrangements. AR-PBL occurred late in the course of AIDS and were usually associated with other systemic or cerebral disorders and with a low level of CD4 lymphocytes. All cases were high grade lymphomas according to the Working Formulation or updated Kiel classification, and often displayed a multifocal pattern. Thirty cases were classified as immunoblastic with plasmacytic differentiation, 18 cases were large cell lymphomas with an immunoblastic component or centroblastic polymorphic lymphomas, and 2 were small noncleaved non-Burkitt lymphomas (Working Formulation). This latter category is classified as Burkitt's-like lymphoma in the REAL nomenclature. One case could not be classified because of necrosis. AR-PBL showed a high level expression of activation and adhesion molecules. The presence of EBV was detected in most cases, and, when PCR was used, this was a constant finding. bcl-2 oncoprotein and latent membrane protein-1 (LMP-1) were strongly expressed. None of the tested cases expressed p53, or were rearranged for bcl-2 or c-myc oncogenes. This study confirms the immunophenotypic specificity of AR-PBL, which may reflect the special immune status of the brain.

PrP immunohistochemistry: different protocols, including a procedure for long formalin fixation, and a proposed schematic classification for deposits in sporadic Creutzfeldt-Jakob disease.

The use of immunohistochemistry on formalin-fixed and paraffin-embedded tissue has greatly improved the neuropathological diagnosis of Creutzfeldt-Jakob disease and the other subacute spongiform encephalopathies in human and animals. Two pitfalls of this technique, however, currently exist: low sensitivity after long formalin fixation and difficulties in interpreting some images. Here we review the protocols currently in use for the pretreatment of sections allowing PrP detection by immunohistochemistry. In addition, a technique useful after long formalin fixation is reported: enzymatic digestion with proteinase K (24 degrees C, 1/100 for 8 minutes) was employed in addition to the usual autoclaving (121 degrees C for 10 minutes) followed by formic acid (99% for 5 minutes) and 4M guanidine thiocyanate (4 degrees C for 2 hours). This allowed a substantial increase in the sensitivity of 3F4 immunohistochemistry on paraffin-embedded tissue, especially after prolonged formalin fixation. In addition, we suggest a simple method for classification of PrP immunolabelling in sporadic Creutzfeldt-Jakob disease that would allow easy comparisons.

ApoE immunoreactivity and microglial cells in Alzheimer's disease brain.

The spatial relationship of apolipoprotein E (apoE)-like immunoreactivity (IR) to amyloid beta-peptide (A beta), astrocytes and microglial cells in the brain of Alzheimer's disease was studied by double immunolabelling. Diffuse apoE-like IR was seen in A beta diffuse deposits, and markedly increased in the core of classic senile plaques. Microglial cells, sometimes immunoreactive for apoE, were frequent in areas of apoE-like IR, where they often grouped into clusters in the core of apoE-labelled senile plaques. Although astrocytic processes were seen within these senile plaques, the cell bodies were always at a distance from the core. None of these astrocytes expressed apoE-like IR. Microglial cells, some of them immunoreactive for apoE, were seen in the center of apoE-labelled senile plaques. These data suggest that microglial cells play a more significant role than astrocytes in apoE deposition in senile plaques of Alzheimer disease.

A brain bank in a neuropathology laboratory (with some emphasis on diagnostic criteria).

The Brain Bank of La Salpêtrière Hospital (Paris) is implanted in a neuropathology laboratory. It is multipurpose, prospective, and "free of charge" for the users. Protocols are prospectively established, in collaboration with the neuroscientists. One of our major difficulties in the collection of cases concerns presently the controls: the neurological status of patients coming from Neurology departments has usually been correctly assessed but those patients are bad controls. The normality of the neurological status of patients dying in other departments is difficult to assess retrospectively. A general autopsy is performed in each case. Several systematic sampling and fixation procedures are currently in use; their pros and cons are discussed. The main safety problem we are confronted with is the risk of HIV and Jakob-Creutzfeldt transmission. We try to standardize our diagnostic procedures; criteria used in Alzheimer's disease, Parkinson's disease, Huntington's chorea are briefly reviewed. We plan, in the future, to standardize our procedures for control cases. The Brain Bank has had a very positive impact on the way this neuropathology laboratory works: it introduced new techniques; on the other hand, the adequate processing and diagnosis of the samples was, in many aspects, simplified by the collaboration with the neuropathology department. The demand for human brain samples is steadily increasing in Neuroscience, for at least 2 reasons: 1. some diseases are specifically human and lack adequate animal models (Alzheimer's disease, multisystem atrophy), or animal models may appear irrelevant in some aspects (multiple sclerosis) or finally, results obtained in animal models may have to be confronted with human pathology (AIDS ...) 2. many aspects of human neuroanatomy can not be extrapolated from animal data There are many ways of organizing a brain bank and no golden standard (Swaab et al., 1989): the neuroscientist himself may collect the samples in a given pathology or the neuropathologists may modify their practice to provide adequate samples to the neuroscientists. When the neuroscientist himself collects his own samples, he obviously proceeds more rapidly. However, he is confronted with the difficult problem of the controls, which require both a clinical follow-up and a pathological check up of the tissues, both of which may be difficult to obtain in a research unit. In our opinion, the neuropathologists are the natural "brain bankers": they are indeed naturally "rich", their job being precisely to collect human samples, in connection with the clinicians.(ABSTRACT TRUNCATED AT 400 WORDS)

The neuropathologic diagnostic criteria of frontal lobe dementia revisited. A study of ten consecutive cases.

Ten successive cases from the Neuropathology Laboratory of La Salpêtrière Hospital in Paris, were selected on the presence of: dementia and prominent symptoms and signs of the frontal type; a degenerative disease without markers other than Pick cells, Pick bodies or ubiquitin-labelled non argyrophilic inclusions. We propose the following steps to diagnose the degenerative dementia associated with symptoms and signs of the frontal type: 1. If there is severe frontotemporal atrophy, severe neuronal loss and astrogliosis, many ballooned neurons and characteristic inclusions that are both tau and ubiquitin positive, the diagnosis is Pick disease. 2. If signs of motor involvement (sometimes unnoticed by the clinician) are present with mild cortical atrophy and mild spongiosis of layers II-III, the diagnosis of frontal lobe degeneration associated with motor neuron disease is warranted. Ubiquitin positive inclusions are useful, but non specific, markers. 3. When there are neither Pick inclusions nor motor neuron disease, the diagnosis may be frontal lobe atrophy lacking distinctive histology.

[Neuropathology of the cerebral vessels of centenarians]. / Neuropathologie des vaisseaux cérébraux des centenaires.

Neuropathological study of brain and brain vessels was performed in two series of 12 and 20 centenarians, focusing on the prevalence of small vessel lesions, infarction, Alzheimer's changes and mental status. These are discussed as a function of vascular risk factors. In the first series (12 cases), there was no correlation between the severity of small vessel lesions: hyalinosis (12/12), mineralisation (10/12), amyloid angiopathy (9/12), vascular risk factors (high blood pressure or diabetes), Alzheimer's lesions. However, there was a tendency for an association between amyloid angiopathy and high density of neurofibrillary tangles. In the second series (20 cases), small infarcts and lacunes were found in 9/20 cases, neurofibrillary tangles and diffuse deposits of A beta peptide were constant, senile plaques were very frequent (19/20). Five patients were demented (one vascular dementia, one Alzheimer dementia, and 3 mixed dementias). These data indicate that: 1) Lesions of the walls of small cerebral vessels do not seem linked to the vascular risk factors observed at the end of the life of centenarians. 2) Cerebral infarcts and lacunes are frequent in these patients, and are responsible, at least in part, for a high proportion of the cognitive dysfunctions. The study of larger series is needed for a better understanding of relationships between vascular and degenerative lesions in the oldest old.

[Fatal familial insomnia and prion diseases]. / Insomnie fatale familiale et maladies à prions.

Fatal familial insomnia has recently enlarged the group of prion diseases. The disease starts between 35 and 60 years of age, is inherited as an autosomic dominant trait, and leads to death within 7 to 32 months. Clinical symptoms and signs include insomnia dysautonomia, cognitive and motor alteration. The discrete topography of the lesions in fatal familial insomnia underlines the role of the thalamus in the regulation of the sleep-wake cycle. Atrophy, neuronal loss and gliosis are prominent in the anterior and dorsomedial nuclei of the thalamus. Spongiosis, which is usually found in prion diseases, is absent in fatal familial insomnia. An abnormal prion protein (PrPsc) is detected in the brain. There is a mutation at codon 178 of the gene encoding this protein. Fatal insomnia is distinct from Creutzfeldt-Jakob disease on clinical, histopathologic and molecular grounds. It provides new information about genetics of prion diseases which share the characteristics of being altogether inherited and, in most cases, transmissible. The recent finding of abnormal PrP in diffuse subcortical gliosis suggests that other degenerative disorders could actually be prion diseases.