White Matter Pallor Research Articles

Neuropathology of feral conures with bromethalin toxicosis.

Bromethalin is a widely used neurotoxic rodenticide sometimes affecting nontarget wildlife. However, the effects of bromethalin on avian species are largely unknown. Here, we report the neuropathology of 14 feral conures (Psittacara sp.) with bromethalin toxicosis. Clinically, all birds presented with different degrees of paraparesis that sometimes progressed to dysphagia, ataxia, and tetraparesis. Histologically, there was astrogliosis, pallor, and vacuolation of white matter in the brain. This was usually more prominent in the medial longitudinal fasciculus, pons, optic tectum, cerebellar peduncle, and ventral funiculus. In most affected areas, there was loss of oligodendrocytes, and axons had extensive myelin loss or marked intramyelinic edema with splitting of myelin sheaths at the intraperiod line. Conures with bromethalin toxicosis had neuropathological changes similar to those of mammals exposed to bromethalin but with a characteristic distribution, probably related to higher susceptibility to cytotoxic edema in certain regions of the avian brain.

An autopsy case of adult‐onset neuronal intranuclear inclusion disease with perivascular preservation in cerebral white matter

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by appearance of eosinophilic hyaline intranuclear inclusions. While the main symptoms of adult-onset NIID are dementia or limb weakness, some patients present with encephalitic episodes and transient neurological symptoms. The pathophysiology of these acute, transient symptoms, however, remains unknown. Here, we describe an autopsy case of adult-onset NIID with progressive dementia and transient hemiparesis. The patient was a 70-year-old man without a relevant family history, and initially presented with progressive dementia. He then exhibited transient left hemiparesis at 75 years of age and died of ureteral cancer at 77 years of age. Neuropathological examination revealed the presence of multiple areas of focal spongiosis in the subcortical white matter and patchy myelin pallor of the white matter, as in previous reports. However, perivascular areas were preserved even in the damaged white matter. In addition, dense glial fibrillary acidic protein (GFAP)-immunoreactive astrocytic processes were observed in these areas. [Correction added on 23 January 2022, after first online publication: the preceding sentence has been corrected to improve readability.] GFAP immunohistochemistry revealed decreased density and morphological abnormalities of astrocytes in the affected white matter. These pathological findings might reflect blood-brain barrier impairment and dysregulation of blood flow, which may be related to the pathophysiology of the acute, transient symptoms observed in NIID.

Spinal Arteriolosclerosis Is Common in Older Adults and Associated With Parkinsonism.

There are few studies of spinal microvascular pathologies in older adults. We characterized spinal cord microvascular pathologies and examined their associations with other spinal and brain postmortem indices and parkinsonism in older adults. We documented 3 features of microvascular pathologies in spinal cord and brain specimens from 165 deceased older participants. We also measured spinal white matter pallor. Parkinsonian signs were assessed with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale. We examined the associations of spinal arteriolosclerosis with other spinal and brain postmortem indices and parkinsonism proximate to death using regression models which controlled for age and sex. Microinfarcts and cerebral amyloid angiopathy were not observed within the spinal cord parenchyma. Spinal arteriolosclerosis was observed at all spinal levels (C7, T7, L4, S4) examined and was more severe posteriorly than anteriorly (posterior: 4.3, SD=0.72 versus anterior: 3.9, SD=0.74; t=14.58; P<0.001). Arteriolosclerosis was more severe in the spinal cord than in the brain (cord: 4.10, SD=0.70; brain: 3.5, SD=0.98; t=10.39; P<0.001). The severity of spinal arteriolosclerosis was associated with spinal white matter pallor (r=0.47; P<0.001). Spinal arteriolosclerosis accounted for ≈3% of the variation in parkinsonism in models controlling for age, sex, brain arteriolosclerosis, and cerebrovascular disease pathologies. Further models showed that the association of spinal arteriolosclerosis and parkinsonism was not mediated via spinal white matter pallor. Although the regional distribution of microvascular pathologies varies within the central nervous system, spinal arteriolosclerosis is common and may contribute to the severity of spinal white matter pallor and parkinsonism in older adults.

Creutzfeldt-Jakob disease.

This review will explore the clinical and pathological findings of the various forms of Creutzfeldt-Jakob disease (CJD). Clinical findings of CJD are characterized by rapidly progressive cognitive dysfunction, diffusion-weighted magnetic resonance imaging (DWI) hyperintensity, myoclonus, periodic sharp-wave complexes on electroencephalogram and akinetic mutism state. Neuropathologic findings of CJD are characterized by spongiform changes in gray matter, gliosis-particularly hypertrophic astrocytosis-neuropil rarefaction, neuron loss and prion protein (PrP) deposition. The earliest pathological symptom observed by HE staining in the cerebral cortex is spongiform change. This spongiform change begins several months before clinical onset, and is followed by gliosis. Subsequently, neuropil rarefaction appears, followed by neuron loss. Regions showing fine vacuole-type spongiform change reflect synaptic-type PrP deposition and type 1 PrPSc deposition, whereas regions showing large confluent vacuole-type spongiform changes reflect perivacuolar-type PrP deposition and type 2 PrPSc deposition. Hyperintensities of the cerebral gray matter observed in DWI indicate the pathology of the spongiform change in CJD. The cerebral cortical lesions with large confluent vacuoles and type 2 PrPSc show higher brightness and more continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrPSc . CJD cases showing diffuse myelin pallor of cerebral white matter have been described as panencephalopathic-type, and this white matter pathology is mainly due to secondary degeneration caused by cerebral cortical involvement, particularly in regard to neuron loss. In conclusion, clinical and neuroimaging findings and neuropathologic observations are well matched in both typical and atypical cases in CJD. The clinical diagnosis of CJD is relatively easy for typical CJD cases such as the MM1-type. However, even in atypical cases it seems that clinical findings can be used for an accurate diagnosis.

POSTMORTEM CEREBROVASCULAR DISEASE AND WHITE MATTER PALLOR ARE ASSOCIATED WITH LOWER ANTEMORTEM CEREBRAL PERFUSION, INCREASED WHITE MATTER HYPERINTENSITIES, AND POOR LEARNING

POSTMORTEM CEREBROVASCULAR DISEASE AND WHITE MATTER PALLOR ARE ASSOCIATED WITH LOWER ANTEMORTEM CEREBRAL PERFUSION, INCREASED WHITE MATTER HYPERINTENSITIES, AND POOR LEARNING

Acute hypoxic-ischemia in cardiac arrest encephalopathy causes only minimal demyelination.

The underlying pathological process of "ischemic leukoencephalopathy" is not well studied in humans and "demyelination" is thought to represent a major component. We selected brains from autopsy cases with definite histories of recent cardiac arrest, in which the autopsy findings demonstrated gray matter ischemic changes consistent with the survival time. We excluded cases with clinical or pathological evidence of other diseases that may affect the white matter, specifically those with moderate-severe edema. The selected cases were then subjected to a review of the gross pathology (photographs) and microscopy. We used the normal white matter areas in the same brains as internal controls to exclude artefactual changes. Sixteen cases were selected. The pathological changes in acute ischemic leukoencephalopathy include: white matter pallor with separation of myelinated fibers and fine vacuoles, coarse vacuoles with or without attenuated axons, apoptotic nuclei, axonal abnormalities, focal scattered demyelinated axons and infarcts. The interpretation of these findings is controversial (i.e. ischemia, edema, artifact or combination) due to the postmortem nature of the specimens. However, these factors should not affect our interpretation of minimal demyelination in the pathological process. The major underlying pathological process in acute ischemic leukoencephalopathy is axonal degeneration, while demyelination represents only a minor component.

Neuropathological Correlates of Falling in the CC75C Population-Based Sample of the Older Old

Previous imaging studies have suggested links between brain pathologies and factors that are associated with falls such as gait, balance and daily function. Possible neuropathological correlates of older people's falls have been suggested based on brain imaging studies, but to date none have been examined in brain tissue. Falls data collected from repeated surveys of a population-based cohort of individuals aged at least 75 years old at baseline were related to neuropathological data collected from post-mortem examination of the study's associated brain donor collection (n=212). Amongst people without dementia, most cerebrovascular neuropathological features examined, particularly white matter pallor, microinfarcts and microscopic atherosclerosis, were increasingly common across the subgroups categorised by no reports of falling, only one or at least two reports of falling. The overall burden of pathology was greater in those with dementia, but only microinfarcts showed a similar increase with respect to reported falling status. Subclinical pathologies sharing a common vascular origin are associated with increased falling amongst people with no dementia, as are microinfarcts in those with dementia. Although further research is needed to address the mechanisms of falls and their neuropathological correlates, the findings from the current study would suggest that if cerebrovascular disease prevention reduces vascular neuropathology changes this may have direct benefits in reducing falls amongst older people with or without dementia.

Fragile X Dementia Parkinsonism Syndrome (FXDPS)

The fragile X-associated tremor/ataxia syndrome is characterized by intention tremor and ataxia in people who are premutation carriers of the Fragile X gene. Patients with this disorder might also demonstrate signs of dementia with parkinsonian features. We report a patient with dementia and parkinsonian signs who did not demonstrate an intention tremor or gait ataxia. A 58-year-old woman who had 2 sons with fragile X retardation syndrome and was a carrier, developed progressive dementia, including impaired memory, executive dysfunction, nonfluent speech, and parkinsonian signs, but had no action-intention tremor and no gait ataxia. Magnetic resonance imaging revealed extensive abnormalities of the white matter. On post-mortem examination, 7 years after this evaluation, she demonstrated extensive subcortical white matter pallor (spongiosis) and widespread ubiquitin-positive intranuclear inclusions in both neurons and in protoplasmic astrocytes characteristic of fragile X-associated tremor/ataxia syndrome, but no spongiosis in the cerebellar peduncles a defining feature of this tremor/ataxia syndrome. Patients who present with dementia and signs of Parkinson syndrome, even in the absence of ataxia or intention tremor should be evaluated for this fragile X dementia parkinsonism syndrome.

Neuropathological Correlates of Dementia in Over-80-Year-Old Brain Donors from the Population-Based Cambridge City over-75s Cohort (CC75C) Study

Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimer's disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimer's disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age.

Perils of Intravascular Methylprednisolone Injection into the Vertebral Artery

Intravascular injection of particulate steroids during cervical nerve root blocks has been postulated to be a source of catastrophic neurologic complications that might be avoided with the use of non-particulate steroids. The objective of this study was to compare the effects of direct intravascular injection of particulate and non-particulate steroids on the spinal cord and central nervous system. Eleven adult pigs underwent direct injection, under fluoroscopic guidance, into the vertebral artery while under general anesthesia. A particulate steroid (methylprednisolone) was injected into four animals (Group 1), whereas seven animals received a non-particulate steroid (dexamethasone in four animals [Group 2] and prednisolone in three [Group 3]). Following injection, the animals were assessed by direct observation of physical activity and with magnetic resonance imaging. After the animals were killed, brain and spinal cord material was retrieved, fixed in paraformaldehyde for one week, and then subjected to histopathologic analysis. All four animals in Group 1 failed to regain consciousness after the injection and required ventilatory support. The animals in Groups 2 and 3 recovered fully and demonstrated no evidence of neurologic injury. Magnetic resonance imaging revealed upper cervical cord and brain stem edema in Group 1, but not in Groups 2 and 3. Histologic analysis showed early evidence of hypoxic and ischemic damage-specifically, early eosinophilic neuronal necrosis, nuclear condensation, white-matter pallor, and extracellular edema-in Group 1 but not in Groups 2 and 3. These data suggest that one etiology of neurologic complications following cervical nerve blocks may be inadvertent intravascular injection of particulate steroids, as all animals injected with methylprednisolone had neurologic deficits while none of the controls injected with non-particulate steroids were affected. To our knowledge, this study is the first to demonstrate that particulate steroids cause neurologic deficits and to suggest that use of non-particulate steroids might prevent such complications.

Rounding up the usual suspects

Progressive age-related changes in the small vessels of the brain including intracerebral end-arteries and arterioles may result in white matter (WM) abnormalities and lacunar infarcts.1,2 WM lesions seen as unidentified bright objects (UBOs) in T2-weighted or fluid attenuated inversion recovery (FLAIR) sequences on MRI are mostly attributable to small vessel disease (SVD) in the absence of profound neurodegenerative changes. Upon histologic examination small vessel wall changes range from graded degeneration of vascular smooth muscle cells (becoming acellular) and hardening by hyalinosis with concentric accumulation of extracellular matrix components to increment of the intima leading to severe arteriosclerosis and fibroid necrosis. Loss of vessel wall elements impairs vascular tone and dysregulates cerebral perfusion. Lacunar infarcts may result from progressive stenosis of the small vessels in both WM and subcortical structures. SVD in a perforating artery may also cause regions of incomplete infarction, attenuation, or rarefaction usually recognized by WM pallor upon microscopic examination. These events are accompanied by edema and diffuse damage of the blood-brain barrier with chronic leakage of fluid and macromolecules. Several previous studies have attempted correlation between degree of white matter …

48 YEAR OLD MALE WITH SUDDEN ONSET OF RIGHT SIDED WEAKNESS

This 48 year-old male presented with sudden right sided weakness and hypertension, and on CT was found to have a deep left hemispheric intracerebral hematoma. There were accompanying bilateral hypointensities in the occipital lobes, unchanged 1 day later, when expansion of the hematoma and uncal herniation resulted in death. The past medical history included liver transplantation followed by long term cyclosporin, features of thrombotic thrombocytopenic purpura (TTP) attributed to cyclosporin, type 1 diabetes mellitus and acute renal failure attributed to diabetic nephropathy. There was a 2-month history of hypertension poorly responsive to therapy. The occipital lobes at autopsy showed focal cortical hemorrhages with bilateral discoloration of white matter sparing subcortical zones. Microscopy showed white matter pallor with parenchymal cysts, enlarged perivascular spaces and focal acute hemorrhages consistent with edema secondary to acute hypertension. Cortical hemorrhages were associated with intravascular thrombi and fibrin exudates, as well as an accompanying microinfarct, attributed to TTP. The occipital pathology reflects the posterior leukoencephalopathy syndrome (PLS) combined with cortical lesions of TTP. PLS is usually diagnosed radiologically by occipital hypointensities, and is reversible, so that autopsy pathology is rarely examined. TTP may predispose to the development of the PLS in certain cases.

White matter abnormalities in HIV-1 infection: A diffusion tensor imaging study

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been found to be particularly prominent in the advanced stages of the disease. The purpose of this study was to determine whether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo, using diffusion tensor imaging (DTI). DTI is a magnetic resonance imaging (MRI) technique that is uniquely suited for the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. The two groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobes and internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed proton density, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle white matter disruptions in HIV-1 disease.

Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders.

We report a unique longitudinal epidemiological study of cognitive decline in the elderly population of the city of Cambridge, UK. A population sample of people aged 75 and over was surveyed between 1984-1996 (n = 2,616) and followed 2.4, 6, and 9 years later. CAMDEX diagnostic criteria were used for clinical assessment, and the neuropathological protocol (in 101 cases) was based on the CERAD method, with additional features to allow Braak staging of neurofibrillary pathology. The main findings are of the heterogeneity of lesions to be found in very old populations, and the existence of considerable overlap in the pathologies found in the demented and nondemented. It seems that white matter (ischemic) pallor an amyloid angiopathy, as well as neuritic plaques, neurofibrillary tangles and Lewy body formation are all lesions that increase the likelihood of dementia.

Increased blood–brain barrier permeability in LP-BM5 infected mice is mediated by neuroexcitatory mechanisms

Serum protein levels in LP-BM5 infected mouse brains were investigated to gain insight into the contribution of blood–brain barrier (BBB) patency to the pathogenesis of retroviral encephalopathy. Evans blue uptake by the forebrain and cerebellum was significantly increased between 8–12 weeks post inoculation. Immunohistochemistry revealed foci of albumin, transferrin, α 2-macroglobulin and IgG transudation around blood vessels particularly in the cerebral cortex and cerebellar vermis. These leaks were often associated with astrocytosis and apoptotic cells. Unlike the other serum proteins, IgG immunoreactivity extended from the circumventricular organs and disseminated throughout the brain parenchyma, accumulating on the plasma membranes of hippocampal and cortical neurons. Consistent with the chronic elevation of free glutamate levels in LP-BM5 infected mice, the increase in Evans blue uptake into the forebrain was completely reversed following dizocilpine administration. Thus, the chronic increase in free glutamate levels in LP-BM5 infected mouse brain contributes to BBB disruption. Furthermore, the CNS accumulation of serum proteins, particularly IgG, observed in these mice may increase osmotic load, impair neuronal function, and cause white matter pallor. Administration of NMDA receptor antagonists may prove useful in managing BBB permeability in those neuropathologies, such as HIV-associated dementia/cognitive/motor complex, having a glutamatergic component.

Viral load and neuropathology in the SIV model.

To investigate neuropathological processes involved in HIV infection, a longitudinal analysis of central nervous system (CNS) changes was performed using the SIV-infected macaque model. Five animals were studied during the early phase and 13 during the asymptomatic and symptomatic phases. Histopathological analyses were performed on one cerebral fixed hemisphere whereas on the other frozen hemisphere in situ hybridisation, immunohistochemistry and RT-PCR were performed. Viral load was quantified by in situ hybridisation, CD4 and CD8 T cell infiltration by immunohistochemistry and mRNA cytokine expression (IL1beta, IL2, IL6, TNFalpha, IFNgamma and TGF-beta1) by semiquantitative RT-PCR. As reported for HIV-infected humans, the neuropathological analysis of SIV infected animals revealed four distinct lesion profiles: minimal changes, early encephalitis, leukoencephalopathy and encephalitis. No relationship was found between neuropathological findings, numbers of SIV replicating cells and T cell infiltration. CNS infection was found to be an early event characterised by glial activation, an increase in the level of IL1beta, TNFalpha and IL6 mRNA expression. During the asymptomatic and symptomatic phases, IL6 and IL1beta mRNAs increase coincided with gliosis and the development of myelin lesions. The absence of relationship between neuropathological findings and viral load suggests that cerebral lesions are caused by an indirect mechanism. Inflammatory cytokine pattern associated with severe lesions show the key role of glial activation in the SIV neuropathological process.

HIV neuropathogenesis and therapeutic strategies.

Human immunodeficiency virus (HIV)-1 neuropathogenesis can be divided into three important components: (i) virus entry into the nervous system; (ii) the role of viral proteins and/or cellular products in neural tissue damage; (iii) the mechanisms of neuronal injury/death. Both blood derived macrophages or trafficking HIV-1 infected T-lymphocytes have been implicated in viral entry to the central nervous system (CNS). The major cell type harboring productive HIV-1 infection in the nervous system is the perivascular macrophage/microglia. The HIV-1 infection of brain astrocytes, restricted to the expression of regulatory gene products, may cause astrocyte dysfunction and contribute to neuronal injury or to disruption of the blood-brain barrier (BBB). Studies of cerebrospinal fluid and postmortem tissues reveal chronic inflammation/immune activation in the nervous system during the later stages of HIV-1 infection associated with disruption of BBB integrity. Blood-brain barrier damage may underlie the white matter pallor described in HIV-1 infection and could result in further entry into the CNS of toxic viral or cellular products, or additional HIV-1 infected cells. The HIV infected and activated macrophages/microglia produce excessive amounts of pro-inflammatory cytokines, including tumor necrosis factor alpha, and platelet activating factor. These products are directly toxic to human neurons in vitro. The HIV-1 envelope glycoprotein, gp 120 may stimulate the release of toxic factors from brain macrophages. Blocking N-methyl-D-aspartate (NMDA; or AMPA) glutamate receptors can antagonize candidate toxins of both viral and cellular origin. It has been postulated that (weak) excitotoxicity leads to oxidative stress in neurons and ultimately to apoptosis. Neuronal apoptosis occurs in the brains of both children and adults with HIV-1 infection. This understanding of HIV neuropathogenesis implies that therapeutic strategies should include: (i) anti-retroviral medications to decrease systemic and CNS virus load, and possibly to prevent perinatal transmission of HIV; (ii) anti-inflammatory compounds to decrease the chronic immune activation in microglia and allow the restoration of BBB integrity; and (iii) neuroprotective compounds to reduce neuronal injury and apoptotic death.

CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY (CADASIL)

BACKGROUND Cerebral autosomal dominant arteriopathy with subcortical intarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain. The affected gene was mapped in 1993 to chromosome 19. This mapping was essential in defining the natural history of the disease. REVIEW SUMMARY CADASIL can start with attacks of migraine with aura occurring at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually observed between 40 and 50 years of age. The stroke events are sometimes associated with severe mood disturbances. The disease leads progressively to a subcortical dementia associated with pseudobulbar palsy and urinary incontinence. Mean age at death is 65 years. The severity of the clinical presentation is greatly variable between and within families. Magnetic resonance imaging (MRI) is always abnormal in symptomatic subjects. On T2-weighted images areas of increased signals in white matter and basal ganglia and on T1-weighted images, it shows a decreased signal in the same regions. Signal abnormalities can be observed a long time before the onset of clinical manifestations, as they are present in asymptomatic young family members. The severity of the MRI findings dramatically increases with age. Pathologic studies show a widespread pallor of white matter and multiple small intarcts in both the white matter and basal ganglia, associated with a small artery disease of the brain. Electron microscopy studies show that the medium of the small arteries is thickened by a granular, eosinophilic, and nonamyloid material of undetermined origin that surrounds the smooth muscle cells. These ultrastructural abnormalities have been observed in other arteries, particularly in muscular and skin arteries. The gene of CADASIL is mapped to chromosome 19 in close vicinity to the locus of familial hemiplegic migraine and to that of acetazolamicle-responsive cerebellar paroxysmal ataxia. CONCLUSION CADASIL should be suspected in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders, or subcortical dementia whenever they are associated with MRI signal abnormalities in white matter and basal ganglia. These findings should prompt a genealogical study including all first-and second-degree relatives. CADASIL is an underdiagnosed cause of subcortical strokes.

Virus load and neuropathology in the FIV model.

The FIV (feline immunodeficiency virus) induces in cats brain changes presenting similarities with those observed in human immunodeficiency virus infection. This FIV model was used to study the relationship between viral load in brain, in lymphoid organs and central nervous system (CNS) changes during the early and late stages of infection. Early brain changes were analyzed in animals experimentally infected with two different FIV isolates and sacrificed at 7 and 15 days, 1, 2, 6, and 12 months post inoculation (p.i.). Late CNS abnormalities were analyzed in naturally FIV-infected cats referred to the Veterinary School of Nantes. For each animal, one cerebral hemisphere was fixed and examined using routine techniques. The characterization of FIV replicating cells by in situ hybridization was performed on the other half frozen hemisphere on sections performed in the anterior and the median regions of the brain. During the early stages of infection, moderate gliosis with glial nodules and sometimes white matter pallor and meningitis were associated with few infected cells scattered in the brain. Infection was an early event as infected cells could be detected in brain at 7 p.i. For each cat, these findings were found identical in the two analyzed areas. During the late stages, brain lesions and the number of virus replicating cells increased especially in animals with perivascular infiltrates. The multinucleated giant cells encephalitis was never observed and the number of FIV replicating cells scattered in the whole brain was always low. This discrepancy between the number of replicating cells and the brain lesions, corroborates the hypotheses suggesting that brain injuries may be mediated via diffusive factors and amplification processes through cytokine cascades and cell activations.

Low susceptibility of resident microglia to simian immunodeficiency virus replication during the early stages of infection.

To assess the susceptibility of resident microglia to simian immunodeficiency virus (SIV) infection, we analysed the brains of rhesus macaques after intracerebral (i.c.) inoculation of the virus into the central region at 7 days, 1, 2 and 3 months post-inoculation (p.i.). The brains of animals showed the same moderate neuropathological changes in central, frontal and parietal regions of the brain, characterized by gliosis, microglial nodules, perivascular infiltrates and occasional white matter pallor and similar low numbers of infected cells detected by in situ hybridization. These results, showing that i.c. inoculation did not lead to preferential infection of brain tissue, even near the inoculation point at 7 days p.i., provide evidence for the low susceptibility of resident microglia to SIV replication during the early stages of infection.