Abstract Olfactory dysfunction is common in multiple sclerosis ( MS ). Olfactory bulb and tract pathology in MS and other demyelinating diseases remain unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease ( MS ; n = 17), neuromyelitis optica [( NMO ); n = 3] and acute disseminated encephalomyelitis [( ADEM ); n = 7] was compared to neuroinflammatory [herpes simplex virus encephalitis ( HSE ); n = 3], neurodegenerative [ A lzheimer's disease ( AD ); n = 4] and non‐neurologic (n = 8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons and inflammation. Inferior frontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases [ MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)] but was absent in HSE , AD and non‐neurologic controls. Inflammation was greater in the demyelinating diseases compared to non‐neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination ( r = 0.610, P = 0.009) and parenchymal inflammation ( r = 0.681, P = 0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the adjacent inferior frontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and is highly inflammatory, and is specific to demyelinating disease.
Multiple sclerosis (MS) susceptibility is characterized by maternal parent-of-origin effects and increased female penetrance.In 7796 individuals from 1797 MS families (affected individuals n 5 2954), we further implicate epigenetic modifications within major histocompatibility complex (MHC) class II haplotypes as mediating these phenomena.Affected individuals with the main MS-associated allele HLA-DRB1 * 15 had a higher female-to-male ratio versus those lacking it (P 5 0.00023).Distorted transmission of MHC haplotypes by both parent-of-origin and gender-of-affected-offspring was most evident in the maternal HLA-DRB1 * 15 transmission to affected female offspring (OR 5 3.31, 95% CI 5 2.59 -4.24) contrasting with similarity among maternal transmission to affected male offspring (OR 5 2.13, 95% CI 5 1.44 -3.14), paternal transmissions to affected female (OR 5 2.14, 95% CI 5 1.64 -2.78) and male (OR 5 2.16, 95% CI 5 1.37 -3.39) offspring.Significant parent-of-origin effects were observed in affected females (maternal: P 5 9.33 3 10 242 ; paternal: P 5 1.12 3 10 215 ; comparison: P 5 0.0014), but not in affected males (maternal: P 5 6.70 3 10 28 ; paternal: P 5 2.54 3 10 26 ; comparison: P 5 0.95).Conditional logistic regression analysis revealed further differential risk of HLA diplotypes.Risks for HLA-DRB1 * 15 and likely for other HLA-DRB1 haplotypes were restricted by (i) parent-of-origin, (ii) gender-of-offspring and (iii) trans epistasis in offspring.These findings may illuminate the gender bias characterizing autoimmunity overall.They raise questions about the concept of restricted antigen presentation in autoimmunity and suggest that gender-specific epigenetic interactions may be the driving forces behind the MHC haplotypic associations.Haplotype-specific epigenetic modifications at MHC class II and their decay appear to be at the heart of MS pathogenesis and inheritance of risk, providing the focus for gene -environment interactions that determine susceptibility and resistance.
The common complaint of headache usually has a benign cause, most often a primary headache syndrome. The history and neurologic and general physical examinations usually permit a definitive diagnosis. When in doubt, diagnostic testing is indicated. Certain historical and examination findings increase the likelihood of a secondary headache disorder and the need for diagnostic testing. These include (1) recent head or neck injury; (2) a new, worse, worsening, or abrupt onset headache; (3) headache brought on by Valsalva maneuver or cough; (4) headache brought on by exertion; (5) headache associated with sexual activity; (6) pregnancy; (7) headache in the patient over the age of ~50; (8) neurologic findings and/or symptoms; (9) systemic signs and/or symptoms; (10) secondary risk factors, such as cancer or human immunodeficiency virus (HIV) infection. Less worrisome are headaches that wake the patient from sleep at night, always occur on the same side, or show a prominent effect of change in posture on the patient's pain. Diagnostic studies include neuroimaging, cerebrospinal fluid (CSF) examination, and blood tests, which are selected depending on the patient's history and findings. For most patients, the diagnostic test of choice is a magnetic resonance imaging (MRI) brain scan. Computed tomography (CT) of the brain is usually obtained in the setting of trauma or the abrupt onset of headache. CSF examination is useful in diagnosing subarachnoid bleeding, infection, and high and low CSF pressure syndromes.
Traumatic brain injury (TBI) is a leading cause of death and disability, particularly among the young. Despite this, no disease-specific treatments exist. Recently, blood–brain barrier disruption and parenchymal fibrinogen deposition have been reported in acute traumatic brain injury and in long-term survival; however, their contribution to the neuropathology of TBI remains unknown. The presence of fibrinogen—a well-documented activator of microglia/macrophages—may be associated with neuroinflammation, and neuronal/axonal injury. To test this hypothesis, cases of human TBI with survival times ranging from 12 h to 13 years (survival <2 months, n = 15; survival >1 year, n = 6) were compared with uninjured controls (n = 15). Tissue was selected from the frontal lobe, temporal lobe, corpus callosum, cingulate gyrus, and brainstem, and the extent of plasma protein (fibrinogen and immunoglobulin G [IgG]) deposition, microglial/macrophage activation (CD68 and ionized calcium-binding adapter molecule 1 [Iba-1] immunoreactivity), neuronal density, and axonal transport impairment (β-amyloid precursor protein [βAPP] immunoreactivity) were assessed. Quantitative analysis revealed a significant increase in parenchymal fibrinogen and IgG deposition following acute TBI compared with long-term survival and control. Fibrinogen, but not IgG, was associated with microglial/macrophage activation and a significant reduction in neuronal density. Perivascular fibrinogen deposition also was associated with microglial/macrophage clustering and accrual of βAPP in axonal spheroids, albeit rarely. These findings mandate the future exploration of causal relationships between fibrinogen deposition, microglia/macrophage activation, and potential neuronal loss in acute TBI.
Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX
Abstract Background The majority of individuals with Alzheimer’s disease (AD) exhibit vascular damage in the brain including reduced cerebral blood flow (CBF) and blood‐brain‐barrier (BBB) breakdown. Growing evidence suggests pericytes, a vessel‐residing cell able to modulate CBF and BBB integrity, are a major contributor to vascular dysfunction in AD. The close spatial relationship between microglia and capillaries led us to explore the hypothesis that microglia and pericytes functionally interact to influence vessel function in the healthy brain and that this interaction may become pathological in AD. Methods We first characterized the spatial and functional relationship between microglia, capillaries and pericytes in the healthy central nervous system (CNS) in fixed tissue and using in vivo two‐photon microscopy through cranial windows in adult NG2DsRed x CX3CR1 +/GFP mice. We then assessed the spatial relationship between microglia, capillaries and pericytes in the human superior frontal gyrus (SFG) of 12 control and 11 AD cases. Results We discovered a subset of microglia dynamically interacting with pericytes in the healthy CNS, which we termed pe ricyte‐associated m icroglia (PEM). PEM are present throughout the capillary tree, often maintain their position for at least 28 days and frequently were found to associate with pericytes lacking astroglial endfeet coverage. The loss of PEM alters capillary width beneath pericytes, but deletion of the microglial fractalkine receptor (CX3CR1), which regulates the recruitment of microglia to sites of neuroinflammation, does not reduce the proportion of microglia that are PEM. In AD, we found the proportion of microglia associated with capillaries and pericytes declines in the superior frontal gyrus (SFG) and that this decline is exacerbated by the APOE ε3/ε4 genotype. This reduction occurs despite an overall increase in pericyte numbers in AD cases. Conclusion We identify microglia specifically associating with pericytes in the healthy CNS and find these associations are reduced in AD. The changing relationship between microglia, capillaries and pericytes may be a novel mechanism contributing to vascular dysfunction in AD.
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