The complex symptoms of chronic multiple sclerosis (MS) are due, in part, to widespread axonal pathology affecting lesioned and non-lesioned areas of the CNS. Here we describe an association between microglial activation and axon/ oligodendrocyte pathology at nodal and paranodal domains in normal appearing white matter (NAWM) of MS and experimental allergic encephalomyelitis (EAE). The extent of paranodal axo-glial (neurofascin-155+/Caspr1+) disruption correlated with the local degree of microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axo-glial alterations were seen in pre-symptomatic EAE, at a time-point characterised by microglia activation prior to the infiltration of immune cells. Disruption of the axo-glial unit in adjuvant immunised animals was reversible and coincided with the resolution of microglial inflammation, whereas paranodal damage and microglial inflammation persisted in chronic EAE. We were able to preserve axo-glial integrity by administering minocycline, which inhibited microglial activation, in actively immunised animals. Therefore, permanent disruption to axo-glial domains in an environment of microglial inflammation is an early indicator of axonal injury that would affect normal nerve conduction contributing to pathology outside of the demyelinated lesion.
Axon; demyelination; multiple sclerosis; neuroinflammation; neurofascin; sodium channel
Clinical biomarkers are urgently needed in the sudden infant death syndrome (SIDS) to identify living infants at risk because it because it occurs without occurs without clinical warning. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. Here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared to autopsy controls, as a first step towards their assessment as diagnostic biomarkers of medullary pathology. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high performance liquid chromatography in 57 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude use of 5-HIAA, HVA, Trp or Tyr measurements as CSF biomarkers of 5-HT medullary pathology in infants at risk. They provide, however, important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS.
5-hydroxyindoleacetic acid; brainstem; dopamine; high performance liquid chromatography; postmortem interval; tryptophan; tyrosine
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis
Recent clinical studies indicate that traumatic brain injury (TBI) produces chronic and progressive neurodegenerative changes leading to late neurological dysfunction but little is known about the mechanisms underlying such changes. Microglial-mediated neuroinflammation is an important secondary injury mechanism after TBI. In human studies, microglial activation has been found to persist for many years after the initial brain trauma, particularly after moderate-to-severe TBI. In the present study, adult C57Bl/6 mice were subjected to single moderate-level controlled cortical impact and were followed up by longitudinal T2-weighted magnetic resonance imaging in combination with stereological histological assessment of lesion volume expansion, neuronal loss and microglial activation for up to 1 year after TBI. Persistent microglial activation was observed in the injured cortex through 1 year post-injury, and was associated with progressive lesion expansion, hippocampal neurodegeneration, and loss of myelin. Notably, highly activated microglia that expressed major histocompatibility complex class II (CR3/43), CD68 and NADPH oxidase (NOX2) were detected at the margins of the expanding lesion at 1 year post-injury; biochemical markers of neuroinflammation and oxidative stress were significantly elevated at this time point. These data support emerging clinical TBI findings and provide a mechanistic link between TBI-induced chronic microglial activation and progressive neurodegeneration.
Chronic microglial activation; NADPH oxidase; Progressive neurodegeneration; Traumatic brain injury
High-resolution microscopic magnetic resonance imaging (μMRI) and diffusion tensor imaging (DTI) were performed to characterize brain structural abnormalities in a mouse model of mucopolysaccharidosis type VII (MPS VII). μMRI demonstrated a decrease in the volume of anterior commissure and corpus callosum and a slight increase in the volume of the hippocampus in MPS VII vs. wild-type mice. DTI indices were analyzed in gray and white matter. In vivo and ex vivo DTI demonstrated significantly reduced fractional anisotropy in the anterior commissure, corpus callosum, external capsule and hippocampus in MPS VII vs. control brains. Significantly increased mean diffusivity was also found in the anterior commissure and corpus callosum from ex-vivo DTI. Significantly reduced linear anisotropy was observed from the hippocampus from in-vivo DTI, whereas significantly decreased planar anisotropy and spherical anisotropy were observed in the external capsule from only ex-vivo DTI. There were corresponding morphological differences in the brains of MPS VII mice by hematoxylin and eosin staining. Luxol fast blue staining demonstrated less intense staining of the corpus callosum and external capsule; myelin abnormalities in the corpus callosum were also demonstrated quantitatively in toluidine blue-stained sections and confirmed by electron microscopy. These results demonstrate the potential for μMRI and DTI for quantitative assessment of brain pathology in murine models of brain diseases.
Diffusion tensor imaging; Live animal imaging; Lysosomal storage diseases; Microscopic MRI; Mucopolysaccharidosis; Myelination; Neuropathology
To test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating–Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating–Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.
Alzheimer disease; Cerebral amyloid angiopathy; Hippocampal sclerosis; Neuritic plaques; Neurofibrillary tangles; Small-vessel disease
Traumatic brain injury frequently causes traumatic axonal injury (TAI) in white matter tracts. Experimental TAI in the corpus callosum of adult mice was used to examine the effects on oligodendrocyte lineage cells and myelin in conjunction with neuroimaging. The injury targeted the corpus callosum over the subventricular zone, a source of neural stem/progenitor cells. TAI was produced in the rostral body of the corpus callosum by impact onto the skull at bregma. During the first week post-injury, magnetic resonance diffusion tensor imaging showed that axial diffusivity decreased in the corpus callosum and that corresponding regions exhibited significant axon damage accompanied by hypertrophic microglia and reactive astrocytes. Oligodendrocyte progenitor proliferation increased in the subventricular zone and corpus callosum. Oligodendrocytes in the corpus callosum shifted toward upregulation of myelin gene transcription. Plp/CreERT:R26IAP reporter mice showed normal reporter labeling of myelin sheaths 0 to 2 days post-injury but labeling was increased between 2 to 7 days post-injury. Electron microscopy revealed axon degeneration, demyelination and redundant myelin figures. These findings expand the cell types and responses to white matter injuries that inform diffusion tensor imaging evaluation and identify pivotal white matter changes following TAI that may affect axon vulnerability vs. recovery following brain injury.
Traumatic brain injury; Axonal damage; Corpus callosum; Diffusion tensor imaging; Oligodendrocyte progenitor; Redundant myelin; Regeneration
The recently developed Mcoln1−/− knockout mouse provides a novel model for analyzing mucolipin 1 (TRP-ML1) function and mucolipidosis type IV (MLIV) disease. Here we characterize the neuropathology of the Mcoln1−/− mouse at the end stage. Evidence of ganglioside accumulation, including increases in GM2, GM3, and GD3 and redistribution of GM1 was found throughout the central nervous system (CNS) independent of significant cholesterol accumulation. Unexpectedly, colocalization studies using immunofluorescence confocal microscopy revealed that GM1 and GM2 were present in separate vesicles within individual neurons. While GM2 was significantly colocalized with LAMP2, consistent with late endosomal/lysosomal processing, some GM2-immunoreactivity occurred in LAMP2-negative sites, suggesting involvement of other vesicular systems. P62/Sequestosome 1 (P62/SQSTM1) inclusions were also identified in the CNS of the Mcoln1−/− mouse, suggesting deficiencies in protein degradation. Glial cell activation was increased in brain and there was evidence of reduced myelination in cerebral and cerebellar white matter tracts. Autofluorescent material accumulated throughout the brains of the knockout mice. Finally, axonal spheroids were prevalent in white matter tracts and Purkinje cell axons. This neuropathological characterization of the Mcoln1−/− mouse provides an important step in understanding how TRP-ML1 loss of function affects the CNS and contributes to MLIV disease.
Axonal spheroids; Bis(monoacylglycero) phosphate; Gangliosides; Lysosomal disease; Mucolipin 1; P62/Sequestosome 1
Many neurodegenerative disorders involve the abnormal accumulation of proteins. In addition to the well-known findings of neurofibrillary tangles and β-amyloid plaques in Alzheimer’s disease, here we show that abnormal accumulations of gephyrin, an inhibitory receptor anchoring protein, are highly correlated with the neuropathologic diagnosis of AD (odds ratio of 72.7; p = 6.844 × 10−6 by Fisher’s exact test, n = 17 AD and n = 14 control cases). Furthermore, the gephyrin accumulations are specific for AD and not seen in other neurodegenerative diseases. Gephyrin accumulations overlap with β-amyloid plaques and, more rarely, neurofibrillary tangles. Follow-up biochemical and proteomic studies suggest alterations in the gephyrin solubility and reveal elevated levels of gephyrin lower-molecular-weight species in the AD insoluble fraction. Since gephyrin is involved in synaptic organization and synaptic dysfunction is an early event in AD, these findings point to a possible role for gephyrin in AD pathogenesis.
gephyrin; Alzheimer’s disease; β-amyloid; presenilin; synapse; GABA
Kallikreins (KLKs) are a family of 15 secreted serine proteases with emerging roles in neurological disease. To illuminate their contributions to the pathophysiology of spinal cord injury (SCI) we evaluated acute through chronic changes in the immunohistochemical appearance of six kallikreins, KLK1, KLK5, KLK6, KLK7, KLK8 and KLK9 in post-mortem human traumatic SCI cases, quantified their RNA expression levels in experimental murine SCI, and assessed the impact of recombinant forms of each enzyme toward murine cortical neurons in vitro. Temporally and spatially distinct changes in kallikrein expression were observed with partially overlapping patterns between human and murine SCI, including peak elevations (or reductions) during the acute and subacute periods. KLK9 showed the most robust changes and remained elevated chronically. Importantly, a subset of kallikreins, KLK1, KLK5, KLK6, KLK7 and KLK9 were shown to be neurotoxic toward primary neurons in vitro. Kallikrein immunoreactivity was also observed in association with swollen axons and retraction bulbs in the human SCI materials examined. Together, these findings demonstrate that elevated levels of a significant subset of kallikreins are positioned to contribute to neurodegenerative changes in cases of CNS trauma and disease and therefore represent new targets for the development of neuroprotective strategies.
axonal injury; degeneration; inflammation; neural injury; spinal cord injury
A large fraction of hereditary demyelinating neuropathies, classified as Charcot-Marie-Tooth disease type IA (CMT 1A), is associated with misexpression of peripheral myelin protein 22. In this study we characterized morphological and biochemical changes that occur with disease progression in neuromuscular tissue of Trembler J mice, a spontaneous rodent model of CMT 1A. Using age-matched, 2- and 10-month-old wild type and Trembler J mice, we observed neuromuscular deficits that progress from distal to proximal regions. The impairments in motor performance are underlined by degenerative events at distal nerve segments and structural alterations at nerve-muscle synapses. Furthermore, skeletal muscle of affected mice showed reduced myofiber diameter, increased expression of the muscle atrophy marker muscle ring-finger protein 1 and fiber type switching. A dietary intervention of intermittent fasting attenuated these progressive changes and supported distal nerve myelination and neuromuscular junction integrity. In addition to the well-characterized demyelination aspects of this model, our investigations identified distinct degenerative events in distal nerves and muscle of affected neuropathic mice. Therefore, therapeutic studies aimed at slowing or reversing the neuropathic features of these disorders should include the examination of muscle tissue, as well as neuromuscular contact sites.
Charcot-Marie-Tooth; Demyelinating neuropathy; Intermittent fasting; Muscle atrophy; Neuromuscular junction; Peripheral myelin protein 22; Peripheral nerve
Astrocytes have emerged as active participants of synaptic transmission and are increasingly implicated in neurological disorders including epilepsy. Adult glial fibrillary acidic protein (GFAP)-positive hippocampal astrocytes are not known for ionotropic glutamate receptor expression under basal conditions. Using a chemoconvulsive status epilepticus (SE) model of temporal lobe epilepsy, we show by immunohistochemistry and colocalization analysis that reactive hippocampal astrocytes express kainate receptor (KAR) subunits following SE. In the CA1 region, GluK1, GluK2/3, GluK4, and GluK5 subunit expression was observed in GFAP-positive astrocytes during the seizure free or “latent” period 1 week following SE. At 8 weeks following SE, a time following SE when spontaneous behavioral seizures occur, the GluK1 and GluK5 subunits remained expressed at significant levels. KAR subunit expression was found in astrocytes in the hippocampus and surrounding cortex, but not in GFAP-positive astrocytes of striatum, olfactory bulb, or brainstem. To examine hippocampal KAR expression more broadly, astroglial-enriched tissue fractions were prepared from dissected hippocampi and were found to have greater GluK4 expression following SE than controls. These results demonstrate that astrocytes begin to express KARs following seizure activity and suggest that their expression may contribute to the pathophysiology of epilepsy.
Astrogliosis; Epilepsy; Glutamate receptor; Kainic acid
Caspase-6 (Casp6) activation in the brain is implicated early in the pathogenesis of Alzheimer disease (AD). In view of the need for early AD diagnosis, brain Casp6 activity was investigated by measuring Tau cleaved by Casp6 (TauΔCasp6) protein in postmortem cerebrospinal fluid (CSF) of 7 non-cognitively impaired, 5 mild cognitively impaired and 12 mild, moderate and severe AD patients. Levels of TauΔCasp6 in CSF accurately reflected the levels of active Casp6 and TauΔCasp6 detected using immunohistochemistry in hippocampal sections from the same individuals. Levels of CSF TauΔCasp6 significantly correlated with AD severity, and with lower global cognitive scores, mini mental state exam, and episodic, semantic, and working memory scores. Regression analyses suggested that the CSF TauΔCasp6 levels combined with TauΔCasp6 brain pathology predict cognitive performance. These results indicate that CSF TauΔCasp6 levels holds promise as a novel early biomarker of AD.
Alzheimer disease; Caspase-6; Cognitive scores; Memory scores; Tau cleaved by Caspase-6; TauΔCasp6
Vanishing white matter disease (VWM) is a genetic leukoencephalopathy linked to mutations in the eukaryotic translation initiation factor 2B (eIF2B). It is a disease of infants, children and adults, who experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress and eventually leading to death. Characteristic neuropathological findings include cystic degeneration of the white matter with scarce reactive gliosis, dysmorphic astrocytes, and paucity of myelin despite an increase in oligodendrocytic density. To assess whether a defective maturation of macroglia may be responsible for the feeble gliosis and lack of myelin, we investigated the maturation status of astrocytes and oligodendrocytes in the brains of 8 VWM patients, 4 patients with other white matter disorders and 6 age-matched controls with a combination of immunocytochemistry, histochemistry, scratch-wound assays, Western blot and quantitative PCR. We observed increased proliferation and a defect in the maturation of VWM astrocytes. They show an anomalous composition of their intermediate filament network with predominance of the δ-isoform of the glial fibrillary acidic protein and an increase in the heat shock protein αB-crystallin, supporting the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM. We also demonstrated a significant increase in numbers of pre-myelinating oligodendrocyte progenitors in VWM, which may explain the co-existence of oligodendrocytosis and myelin paucity in the patients’ white matter.
Astrocytes; GFAPδ; Glia maturation; Olig2 cytoplasmic translocation; Oligodendrocyte progenitor cells; Vanishing white matter
Dendritic spines are the site of the majority of excitatory synapses, the loss of which correlates with cognitive impairment in patients with Alzheimer disease. Substantial evidence indicates that amyloid-β (Aβ) peptide, either insoluble fibrillar Aβ deposited into plaques or soluble non-fibrillar Aβ species, can cause spine loss but the concurrent contributions of fibrillar Aβ and non-fibrillar Aβ to spine loss has not been previously assessed. We used multiple-label immunohistochemistry to measure spine density, size, and f-actin content surrounding plaques in the cerebral cortex in the PSAPP mouse model of Aβ deposition. Our approach allowed us to measure fibrillar Aβ plaque content and an index of non-fibrillar Aβ species concurrently. We found that spine density was reduced within 6 μm of the plaque perimeter, remaining spines were more compact, and f-actin content per spine was increased. Measures of fibrillar Aβ plaque content were associated with reduced spine density near plaques, whereas measures of non-fibrillar Aβ species were associated with reduced spine density and size, but not altered f-actin content. These findings suggest that strategies to preserve dendritic spines in AD patients may need to address both non-fibrillar and fibrillar forms of Aβ and that non-fibrillar Aβ may exert spine toxicity through pathways not mediated by depolymerization of f-actin.
Alzheimer disease; Amyloid beta; Dendritic spine; Genetic mouse models; Phalloidin; X-34
Much of the morbidity following traumatic brain injury (TBI) is associated with traumatic axonal injury (TAI). Although most TAI studies focus on corpus callosum white matter, the visual system has received increased interest. To assess visual system TAI, we developed a mouse model of optic nerve TAI. It is unknown, however, whether this TAI causes retinal ganglion cell (RGC) death. To address this issue, YFP-16 transgenic mice were subjected to mild TBI and followed from 2 to 28 days. Neither TUNEL-positive or cleaved caspase-3 immunoreactive RGCs were observed from 2 to 28 days post-TBI. Quantification of immunoreactivity of Brn3a, an RGC marker, demonstrated no RGC loss; parallel electron microscopic analysis confirmed RGC viability. Persistent RGC survival was also consistent with the finding of reorganization in the proximal axonal segments following TAI wherein microglia/macrophages remained inactive. In contrast, activated microglia/macrophages closely enveloped the distal disconnected, degenerating axonal segments at 7 to 28 days post-injury, thereby confirming that this model consistently evoked TAI followed by disconnection. Collectively, these data provide novel insight into the evolving pathobiology associated with TAI that will form a foundation for future studies exploring TAI therapy and its downstream consequences.
Microglia/macrophage; Retinal ganglion cell survival; Traumatic axonal injury; Traumatic brain injury; Visual system; YFP-16 transgenic mice
Cerebral ischemia induces neurogenesis including proliferation and differentiation of neural progenitor cells and migration of newly generated neuroblasts. microRNAs (miRNAs) are small non-coding RNAs that decrease gene expression through mRNA destabilization and/or translational repression. Emerging data indicate that miRNAs have a role in mediating processes of proliferation and differentiation of adult neural progenitor cells. This article reviews recent findings on miRNA profile changes in neural progenitor cells after cerebral infarction and the contributions of miRNAs to their ischemia-induced proliferation and differentiation. We highlight interactions between the miR-124 and the miR17-92 cluster and the Notch and Sonic hedgehog signaling pathways in mediating stroke-induced neurogenesis.
miRNAs; Neural progenitor cells; Neurogenesis; Stroke
The APOE ε4 allele correlates with increased risk of Alzheimer disease (AD) and increased parenchymal amyloid plaques. We tested how the APOE genotype correlated with cerebral amyloid angiopathy (CAA) by analyzing 371 brains for parenchymal and meningeal CAA in 4 brain regions (frontal, parietal, temporal, and occipital neocortex). The overall severity of CAA was highest in the occipital lobe. APOE-ε4/4 brains (n = 22) had the highest levels of CAA across regions. In the occipital lobe, nearly all APOE-ε4/4 cases were scored with the highest level of CAA (meninges, 95% of cases; parenchyma, 81%). In this brain region as in others, APOE-ε3/4 brains (n = 115) showed consistently less CAA that APOE-ε4/4 brains (meninges, 43%; parenchyma, 43%). APOE-ε3/3 brains (n = 182) showed even less CAA (meninges, 19%; parenchyma, 19%). Interestingly, APOE-ε2/3 cases (n = 42) had more CAA than APOE-ε3/3 (meninges, 44%; parenchyma, 32%), despite a reduced risk for AD in the APOE-ε2/3 individuals. APOE-ε4/4 brains also had the fewest regions without CAA, whereas APOE-ε3/3 brains had the most. Ordinal regression analyses demonstrated significant impacts of APOE-ε2 and APOE-ε4 on CAA in at least some brain region. These data demonstrate that APOE genotype correlations with Ab deposition in CAA only incompletely correspond to other AD-linked brain pathologies.
Alzheimer disease; Apolipoprotein; CAA; Dementia; Hemorrhagic stroke; Risk factor
Motoneuron death following spinal cord injury or disease results in muscle denervation, atrophy, and paralysis. We have previously transplanted embryonic ventral spinal cord cells into peripheral nerve to reinnervate denervated muscles and to reduce muscle atrophy, but reinnervation was incomplete. Here, our aim was to determine whether brief electrical stimulation of embryonic neurons in peripheral nerve changes motoneuron survival, axon regeneration, and muscle reinnervation and function because neural depolarization is crucial for embryonic neuron survival and may promote activity-dependent axon growth. At 1 week after denervation by sciatic nerve section, embryonic day 14-15 cells were purified for motoneurons, injected into the tibial nerve of adult Fischer rats, and stimulated immediately for up to 1 hour. More myelinated axons were present in tibial nerves when transplants had been stimulated at 1 Hz for 1 hour at 10 weeks following transplantation. More muscles were reinnervated if the stimulation treatment lasted for 1 hour. Reinnervation reduced muscle atrophy, with or without the stimulation treatment. These data suggest that brief stimulation of embryonic neurons promotes axon growth, which has a long-term impact on muscle reinnervation and function. Muscle reinnervation is important because it may enable the use of functional electrical stimulation to restore limb movements.
Axon growth cone initiation; Cell transplantation; Motoneuron survival; Muscle denervation
Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H–I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n = 14), HS-TLE (n = 35), and H–I (n = 20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H–I, and 0% of HS-TLE cases (p < 0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H–I, and 0% of HS-FTLD cases (p= 0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H–I, and 37% of HS-TLE cases (p = 0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H–I cases (p = 0.019). The proximal-middle CA1 was the only area affected in 50% of H–I, 29% of HS-TLE, and 0% of HS-FTLD cases (p = 0.004). These findings support heterogeneity in the pathogenesis of HS.
Brain ischemia; Frontotemporal dementia; Frontotemporal lobar degeneration; Hippocampal sclerosis; Mesial temporal sclerosis; Vascular dementia; ZNT3
Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed “asymptomatic AD subjects” (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.
Alzheimer disease; Immunoreactivity; Neuronal hypertrophy; Preserved cognition; Soluble β-amyloid; Tau
While it is clear that astrocytes and microglia cluster around dense-core amyloid plaques in Alzheimer disease (AD), whether they are primarily attracted to amyloid deposits or are just reacting to plaque-associated neuritic damage remains elusive. We postulate that astrocytes and microglia may differentially respond to fibrillar amyloid β (Aβ). Therefore, we quantified the size distribution of dense-core Thioflavin-S (ThioS)-positive plaques in the temporal neocortex of 40 AD patients and the microglial and astrocyte responses in their vicinity (≤50 μm), and performed correlations between both measures. As expected, both astrocytes and microglia were clearly spatially associated with ThioS-positive plaques (p = 0.0001, ≤50 μm vs. >50 μm from their edge), but their relationship to ThioS-positive plaque size differed; larger ThioS-positive plaques were associated with more surrounding activated microglia (p = 0.0026), but this effect was not observed with reactive astrocytes. Microglial response to dense-core plaques appears to be proportional to their size, which we postulate reflects a chemotactic effect of Aβ. By contrast, plaque-associated astrocytic response does not correlate with plaque size and seems to parallel the behavior of plaque-associated neuritic damage.
Alzheimer disease; Amyloid plaques; Apolipoprotein E; Astrocytes; Microglia
Traumatic coma is associated with disruption of axonal pathways throughout the brain but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging (HARDI) to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness – arousal and awareness – in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. HARDI tractography guided tissue sampling in the neuropathological analysis. HARDI tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical “awareness pathways.” Neuropathologic examination, which utilized β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of HARDI tract disruption. Axonal injury was also present within the grey matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain.
Ascending reticular activating system (ARAS); Coma; Consciousness; High angular resolution diffusion imaging (HARDI); Tractography; Traumatic axonal injury (TAI); Traumatic brain injury (TBI)
In progressive multifocal leukoencephalopathy, JC virus–infected oligodendroglia display 2 distinct patterns of intranuclear viral inclusions: full inclusions in which progeny virions are present throughout enlarged nuclei and dot-shaped inclusions in which virions are clustered in subnuclear domains termed “promyelocytic leukemia nuclear bodies” (PML-NBs). Promyelocytic leukemia nuclear bodies may serve a scaffolding role in viral progeny production. We analyzed the formation process of intranuclear viral inclusions by morphometry and assessed PML-NB alterations in the brains of 2 patients with progressive multifocal leukoencephalopathy. By immunohistochemistry, proliferating cell nuclear antigen was most frequently detected in smaller nuclei; cyclin A was detected in larger nuclei. This suggests an S-to-G2 cell cycle transition in infected cells associated with nuclear enlargement. Sizes of PML-NBs were variable, but they were usually either small speckles 200 to 400 nm in diameter or distinct spherical shells with a diameter of 1 μm or more. By confocal microscopy, JC virus capsid proteins were associated with both small and large PML-NBs, but disruption of large PML-NBs was observed by ground-state depletion fluorescence nanoscopy. Clusters of progeny virions were also detected by electron microscopy. Our data suggest that, in progressive multifocal leukoencephalopathy, JC virus produces progeny virions in enlarging oligodendrocyte nuclei in association with growing PML-NBs and with cell cycle transition through an S-to-G2-like state.
Cell cycle; Cell stress; Intranuclear viral inclusions; JC virus; PML-NBs; Progressive multifocal leukoencephalopathy
Although extensive evidence supports the role of amyloid-β (Aβ) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathological feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to Aβ deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75NTR saporin (mu p75-SAP). Intracerebroventricular lesions that removed ~50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (~3 months) and marked (~7 months of age) Aβ deposition. Cranial windows were implanted and Aβ deposition was monitored in vivo using multiphoton microscopy. Aβ deposition was increased as soon as 7 days after the lesion and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-Aβ antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (~7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger Aβ deposition and synergistically contribute to cognitive impairment in AD patients.
β-amyloid; Alzheimer disease; Basal forebrain; Cholinergic system; Murine p75NTR saporin; Senile plaques