Genetics of Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD), the most frequent neurodegenerative disorder with a presenile onset, presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. Familial aggregation is frequently reported, and about 10% of cases have an autosomal dominant transmission. Microtubule associated protein tau (MAPT) gene mutations have been the first ones identified and are associated with early onset behavioral variant frontotemporal dementia phenotype. More recently, progranulin gene (GRN) mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified. In this review, current knowledge about mutations at the basis of familial FTLD will be described, together with genetic risk factors influencing the susceptibility to FTLD

The role of amyloid-β in white matter damage: possible common pathogenetic mechanisms in neurodegenerative and demyelinating diseases

Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer's disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology

RhoA and ζ PKC Control Distinct Modalities of LFA-1 Activation by Chemokines

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Heparan sulfate proteoglycan induces the production of NO and TNF-α by murine microglia

BACKGROUND: A common feature of Alzheimer's disease (AD) pathology is the abundance of activated microglia in neuritic plaques containing amyloid-beta protein (Aβ) and associated molecules including heparan sulfate proteoglycan (HSPG). Besides the role as pathological chaperone favouring amyloidogenesis, little is known about whether or not HSPG can induce microglial activation. Cultures of primary murine microglia were used to assess the effect of HSPG on production of proinflammatory molecules that are known to be present in neuritic plaques of AD. RESULTS: HSPG stimulated up-regulation of tumor necrosis factor-alpha (TNF-α), production of inducible nitric oxide synthase (iNOS) mRNA and accumulation of TNF-α protein and nitrite (NO(2)(-)) in a time- and concentration-dependent manner. The effects of HSPG were primarily due to the property of the protein core as indicated by the lack of microglial accumulation of TNF-α and NO(2)(- )in response to denaturated HSPG or heparan sulfate GAG chains (HS). CONCLUSION: These data demonstrate that HSPG may contribute to chronic microglial activation and neurodegeneration seen in neuritic plaques of AD

Molecular Mechanisms Involved in Lymphocyte Recruitment in Inflamed Brain Microvessels: Critical Roles for P-Selectin Glycoprotein Ligand-1 and Heterotrimeric Gi-Linked Receptors

AbstractLymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-α or LPS, proteolipid protein 139–151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and α4 integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for Gi protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS

A Novel Study and Meta-Analysis of the Genetic Variation of the Serotonin Transporter Promoter in the Italian Population Do Not Support a Large Effect on Alzheimer's Disease Risk

Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A → G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S-allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk

Efficient Recruitment of Lymphocytes in Inflamed Brain Venules Requires Expression of Cutaneous Lymphocyte Antigen and Fucosyltransferase-VII

Abstract Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV−/− mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII−/− or Fuc-VII−/−FucT-IV−/− mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA+ vs integrin β7+) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA

Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis

Background: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated. Objectives: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. Methods: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was & LE; 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). Results: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95% CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). Conclusions: SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity , MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS

PRNP P39L variant is a rare cause of frontotemporal dementia in Iialian population

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%)