Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid.

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little-known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre-symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p-Tau and ß-amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of ß-amyloid, and restores cognitive function to that of wild-type counterparts. Any diagnostic and/or therapeutic strategy based on T14-NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much-needed fresh insights into the progression of cell loss underlying AD. HIGHLIGHTS: The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early-stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

A role for vessel-associated extracellular matrix proteins in multiple sclerosis pathology.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA-DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA-DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA-DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA-DRB*15-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA-DRB1*15-positive and 23 HLA-DRB1*15-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (-36.5%, p = 0.036 and - 24.7%, p = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA-DRB1*15-positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.

Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

AIMS: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields. METHODS: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. RESULTS: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways. CONCLUSIONS: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.

A potential protective role of the nuclear receptor-related factor 1 (Nurr1) in multiple sclerosis motor cortex: a neuropathological study.

Cerebral cortical inflammation and neurodegeneration are hallmark pathological features of multiple sclerosis that contribute to irreversible neurological disability. While the reason for nerve cell death is unknown, the pathogenic inflammatory role of infiltrating lymphocytes is likely an important contributor. The nuclear receptor-related factor 1 counteracts inflammation in animal models of multiple sclerosis, and protects against neuronal loss in other neurodegenerative disorders, but its expression in post-mortem multiple sclerosis tissue is not known. This study aims to investigate the nuclear receptor-related factor 1 expression in multiple sclerosis motor cortex and evaluate its relationship with motor cortical pathology. To accomplish this, an autopsy cohort of pathologically confirmed multiple sclerosis (n = 46), and control (n = 11) cases was used, where the nuclear receptor-related factor 1 expression was related to neuronal and lymphocytic densities. Motor cortical nuclear receptor-related factor 1 was overexpressed in multiple sclerosis compared to control cases. Increased nuclear receptor-related factor 1 expression positively associated with neuronal densities, especially when present in nucleus of neurons, and associated with decreased CD8+ cytotoxic lymphocyte density. Our findings expand the current knowledge on nuclear receptor-related factor 1 in neurological diseases, and support the hypothesis that nuclear receptor-related factor 1 may play a dual neuroprotective role in multiple sclerosis by influencing inflammatory and neurodegenerative processes. Future studies elucidating the influence of nuclear receptor-related factor 1 on these processes in multiple sclerosis may cast light onto novel targets that may be modulated to alter clinical outcome.

Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. METHODS: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates (M mulatta) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months). RESULTS: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, P=0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD (P<0.017), including age as a covariate and either clinical hypertension (P<0.030) or neuropathological SVD diagnosis (P<0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals (P=0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. CONCLUSIONS: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.

Anterior optic pathway pathology in CNS demyelinating diseases.

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.

Vasculocentric Axonal NfH in Small Vessel Disease.

Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology.

Main Role of Antibodies in Demyelination and Axonal Damage in Multiple Sclerosis.

Antibodies and oxidative stress are hallmarks of multiple sclerosis (MS) lesions. We aimed to clarify the relation between them, their role in MS patients and to investigate their specificity, comparing MS with classical neurodegenerative diseases (ND). Brain samples from 14 MS cases, 6 with ND and 9 controls (without neurological diseases). Immunohistochemistry assays were used to detect oxidized lipids (EO6), IgG and IgM, oligodendrocytes (Olig2), axons (NF, neurofilament) and cellular (TUNEL) and axonal damage (APP, amyloid precursor protein). We did not observe EO6 in controls. All samples from MS patients showed EO6 in oligodendrocytes and axons within lesions. We did not detect co-localization between EO6 and antibodies. Neither did we between EO6 and TUNEL or APP. 94.4% of TUNEL-positive cells in normal appearing white matter were also stained for IgG and 75.5% for IgM. IgM, but not IgG, co-localized with APP. EO6 was associated with axonal damage in amyotrophic lateral sclerosis (ALS). We did not observe association between antibodies and cellular or axonal damage in ND patients. MS patients showed a higher number of B cells and plasma cells in the lesions and meninges than controls. The number of B cells and plasma cells was associated with the presence of antibodies and with the activity of the lesions. We observed a main role of B lymphocytes in the development of MS lesions. Antibodies contribute to the oligodendrocyte and axonal damage in MS. Oxidative stress was associated with axonal damage in ALS.

The influence of HLA-DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter.

Cortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA-DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA-DRB1*15 on relationships between inflammation and neurodegeneration in MS. Human post-mortem MS cases (n = 47) and controls (n = 10) were used. Adjacent sections of motor cortex were stained for microglia (Iba1+, CD68+, TMEM119+), lymphocytes (CD3+, CD8+), GFAP+ astrocytes, and neurons (NeuN+). A subset of MS cases (n = 20) and controls (n = 7) were double-labeled for neurofilament and glutamic acid decarboxylase 65/67 (GAD+) to assess the extent of the inhibitory synaptic loss. In MS cases, microglial protein expression positively correlated with neuron density (Iba1+: r = 0.548, p < 0.001, CD68+: r = 0.498, p = 0.001, TMEM119+ r = 0.437, p = 0.003). This finding was restricted to MS cases not carrying HLA-DRB1*15. Evidence of a 14% reduction in inhibitory synapses in MS was detected (MS: 0.299 ± 0.006 synapses/µm2 neuronal membrane versus control: 0.348 ± 0.009 synapses/µm2 neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 µm2 versus control: 531 ± 29 µm2 , p = 0.001), a finding driven by HLA-DRB1*15+ cases (15+: 376 ± 21 µm2 vs. 15-: 432 ± 22 µm2 , p = 0.018). Taken together, our results demonstrate that HLA-DRB1*15 modulates the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.

Vascular disease and multiple sclerosis: a post-mortem study exploring their relationships.

Vascular comorbidities have a deleterious impact on multiple sclerosis clinical outcomes but it is unclear whether this is mediated by an excess of extracranial vascular disease (i.e. atherosclerosis) and/or of cerebral small vessel disease or worse multiple sclerosis pathology. To address these questions, a study using a unique post-mortem cohort wherein whole body autopsy reports and brain tissue were available for interrogation was established. Whole body autopsy reports were used to develop a global score of systemic vascular disease that included aorta and coronary artery atheroma, cardiac hypertensive disease, myocardial infarction and ischaemic stroke. The score was applied to 85 multiple sclerosis cases (46 females, age range 39 to 84 years, median 62.0 years) and 68 control cases. Post-mortem brain material from a subset of the multiple sclerosis (n = 42; age range 39-84 years, median 61.5 years) and control (n = 39) cases was selected for detailed neuropathological study. For each case, formalin-fixed paraffin-embedded tissue from the frontal and occipital white matter, basal ganglia and pons was used to obtain a global cerebral small vessel disease score that captured the presence and/or severity of arteriolosclerosis, periarteriolar space dilatation, haemosiderin leakage, microinfarcts, and microbleeds. The extent of multiple sclerosis-related pathology (focal demyelination and inflammation) was characterized in the multiple sclerosis cases. Regression models were used to investigate the influence of disease status on systemic vascular disease and cerebral small vessel disease scores and, in the multiple sclerosis group, the relationship between multiple sclerosis-related pathology and both vascular scores. We show that: (i) systemic cardiovascular burden, and specifically atherosclerosis, is lower and cerebral small vessel disease is higher in multiple sclerosis cases that die at younger ages compared with control subjects; (ii) the association between systemic vascular disease and cerebral small vessel disease is stronger in patients with multiple sclerosis compared with control subjects; and (iii) periarteriolar changes, including periarteriolar space dilatation, haemosiderin deposition and inflammation, are key features of multiple sclerosis pathology outside the classic demyelinating lesion. Our data argue against a common primary trigger for atherosclerosis and multiple sclerosis but suggest that an excess burden of cerebral small vessel disease in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversibility disability.

Cell Senescence and Cerebral Small Vessel Disease in the Brains of People Aged 80 Years and Older.

Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified senescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcortical white matter of older persons (age 80-96 years, n = 60) with minimal AD, using antibodies to 2 established senescence markers (H3K9me3, γH2AX) and a myocyte marker (hSMM). Within the walls of penetrating arteries (20-300 µm), we quantified senescence-associated heterochromatic foci (SAHF)-positive nuclei, cell density (nuclei/µm2), and sclerotic index (SI). Senescent-appearing mural cells were present in small arteries of all cases. cSVD cases exhibited a lower proportion of senescent-appearing cells and lower area fraction (AF%) of SAHF-positive nuclei compared to controls (p = 0.014, 0.016, respectively). cSVD severity and SI both correlated negatively with AF% (p = 0.013, 0.002, respectively). Mural cell density was lower (p < 0.001) and SI higher (p < 0.001) in cSVD, relative to controls. In conclusion, senescent myocyte-like cells were universal in penetrating arteries of an AD-free cohort aged 80 years and older. Senescent-appearing nuclei were more common in persons aged 80 years and older without cSVD compared to cSVD cases, indicating caution in senolytic drug prescribing. Myocyte senescence and cSVD may represent alternative vessel fates in the aging human brain.

Rapid neuroinflammatory changes in human acute intracerebral hemorrhage.

OBJECTIVE: Spontaneous intracerebral hemorrhage (ICH) is the commonest form of hemorrhagic stroke and is associated with a poor prognosis. Neurosurgical removal of intracerebral hematoma has limited benefit and no pharmacotherapies are available. In acute ICH, primary tissue damage is followed by secondary pathology, where the cellular and neuroinflammatory changes are poorly understood. METHODS: We studied histological changes in postmortem tissue from a cohort of spontaneous supra-tentorial primary ICH cases (n = 27) with survival of 1-12 days, compared to a matched control group (n = 16) examined in corresponding regions. Hematoxylin-eosin and microglial (Iba1) immunolabelled sections were assessed at 0-2, 3-5, and 7-12 days post-ICH. RESULTS: Peri-hematoma, the observed ICH-related changes include edema, tissue neutrophils and macrophages from day 1. Ischemic neurons and swollen endothelial cells were common at day 1 and universal after day 5, as were intramural erythrocytes within small vessel walls. Activated microglia were evident at day 1 post-ICH. There was a significant increase in Iba1 positive area fraction at 0-2 (threefold), 3-5 (fourfold), and 7-12 days post ICH (ninefold) relative to controls. Giant microglia were detected peri-hematoma from day 5 and consistently 7-12 days post-ICH. INTERPRETATION: Our data indicate that neuroinflammatory processes commence from day 1 post-ICH with changing microglial size and morphology following ICH and up to day 12. From day 5 some microglia exhibit a novel multiply nucleated morphology, which may be related to changing phagocytic function. Understanding the time course of neuroinflammatory changes, post-ICH may reveal novel targets for therapy and brain restoration.

Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis.

To investigate whether the observed anisotropic diffusion in cerebral cortex may reflect its columnar cytoarchitecture and myeloarchitecture, as a potential biomarker for disease-related changes, we compared postmortem diffusion magnetic resonance imaging scans of nine multiple sclerosis brains with histology measures from the same regions. Histology measurements assessed the cortical minicolumnar structure based on cell bodies and associated axon bundles in dorsolateral prefrontal cortex (Area 9), Heschl's gyrus (Area 41), and primary visual cortex (V1). Diffusivity measures included mean diffusivity, fractional anisotropy of the cortex, and three specific measures that may relate to the radial minicolumn structure: the angle of the principal diffusion direction in the cortex, the component that was perpendicular to the radial direction, and the component that was parallel to the radial direction. The cellular minicolumn microcircuit features were correlated with diffusion angle in Areas 9 and 41, and the axon bundle features were correlated with angle in Area 9 and to the parallel component in V1 cortex. This may reflect the effect of minicolumn microcircuit organisation on diffusion in the cortex, due to the number of coherently arranged membranes and myelinated structures. Several of the cortical diffusion measures showed group differences between MS brains and control brains. Differences between brain regions were also found in histology and diffusivity measurements consistent with established regional variation in cytoarchitecture and myeloarchitecture. Therefore, these novel measures may provide a surrogate of cortical organisation as a potential biomarker, which is particularly relevant for detecting regional changes in neurological disorders.

Contribution of Fibrinogen to Inflammation and Neuronal Density in Human Traumatic Brain Injury.

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 (ß-amyloid precursor protein [ßAPP] 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 ßAPP 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.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease.

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-ß (Aß)42 and of the ratio Aß42/Aß40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.

Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder.

Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex, few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- and gender-matched patients with autism spectrum disorder and control subjects ranging in age from 13 to 69 years. Patients with autism had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age-dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.

Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex.

OBJECTIVE: Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration. METHODS: A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen). RESULTS: Motor cortical fibrin(ogen) deposition was significantly over-represented in MS compared to control cases in all compartments studied (ie, extracellular [p = 0.001], cell body [p = 0.003], and neuritic/glial-processes [p = 0.004]). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI-1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally-relevant layer 5 (p = 0.001). INTERPRETATION: For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270.