Sufficient Conditions for Fast Switching Synchronization in Time Varying Network Topologies

In previous work, empirical evidence indicated that a time-varying network could propagate sufficient information to allow synchronization of the sometimes coupled oscillators, despite an instantaneously disconnected topology. We prove here that if the network of oscillators synchronizes for the static time-average of the topology, then the network will synchronize with the time-varying topology if the time-average is achieved sufficiently fast. Fast switching, fast on the time-scale of the coupled oscillators, overcomes the descychnronizing decoherence suggested by disconnected instantaneous networks. This result agrees in spirit with that of where empirical evidence suggested that a moving averaged graph Laplacian could be used in the master-stability function analysis. A new fast switching stability criterion here-in gives sufficiency of a fast-switching network leading to synchronization. Although this sufficient condition appears to be very conservative, it provides new insights about the requirements for synchronization when the network topology is time-varying. In particular, it can be shown that networks of oscillators can synchronize even if at every point in time the frozen-time network topology is insufficiently connected to achieve synchronization.Comment: Submitted to SIAD

Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease

Endogenous protein quality control machinery has long been suspected of influencing the onset and progression of neurodegenerative diseases characterized by accumulation of misfolded proteins. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) tract in the protein huntingtin (htt), which leads to its aggregation and accumulation in inclusion bodies. Here, we demonstrate in a mouse model of HD that deletion of the molecular chaperones Hsp70.1 and Hsp70.3 significantly exacerbated numerous physical, behavioral and neuropathological outcome measures, including survival, body weight, tremor, limb clasping and open field activities. Deletion of Hsp70.1 and Hsp70.3 significantly increased the size of inclusion bodies formed by mutant htt exon 1, but surprisingly did not affect the levels of fibrillar aggregates. Moreover, the lack of Hsp70s significantly decreased levels of the calcium regulated protein c-Fos, a marker for neuronal activity. In contrast, deletion of Hsp70s did not accelerate disease in a mouse model of infectious prion-mediated neurodegeneration, ruling out the possibility that the Hsp70.1/70.3 mice are nonspecifically sensitized to all protein misfolding disorders. Thus, endogenous Hsp70s are a critical component of the cellular defense against the toxic effects of misfolded htt protein in neurons, but buffer toxicity by mechanisms independent of the deposition of fibrillar aggregates

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

Amyloid-beta/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer’s Disease

Alzheimer\u27s disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn.Weshowed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded wholecell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders

BackgroundTherapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker.MethodsWe availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change.ResultsCompared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology.ConclusionsOur head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value

Psychotropic medication usage in sporadic versus genetic behavioral-variant frontotemporal dementia.

INTRODUCTION: Psychotropic medication (PM) use in behavioral-variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. METHODS: We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART). RESULTS: We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants. DISCUSSION: Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated. HIGHLIGHTS: We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

INTRODUCTION: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. METHODS: We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex. RESULTS: Females with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe. DISCUSSION: Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation. Highlights: Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.</p

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia

Introduction: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. Methods: We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex. Results: Females with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe. Discussion: Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation