Browsing by Subject "Neurodegenerative Diseases"
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Item Open Access Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.(PLoS Genet, 2014-01) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Arbeeva, Liubov; Ukraintseva, Svetlana V; Stallard, Eric; Christensen, Kaare; Schupf, Nicole; Province, Michael A; Yashin, Anatoli IEnduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.Item Open Access Analysis of the mouse transcriptome for genes involved in the function of the nervous system.(Genome Res, 2003-06) Gustincich, Stefano; Batalov, Serge; Beisel, Kirk W; Bono, Hidemasa; Carninci, Piero; Fletcher, Colin F; Grimmond, Sean; Hirokawa, Nobutaka; Jarvis, Erich D; Jegla, Tim; Kawasawa, Yuka; LeMieux, Julianna; Miki, Harukata; Raviola, Elio; Teasdale, Rohan D; Tominaga, Naoko; Yagi, Ken; Zimmer, Andreas; Hayashizaki, Yoshihide; Okazaki, Yasushi; RIKEN GER Group; GSL MembersWe analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored.A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders.Item Open Access Brain connectivity and visual attention.(Brain connectivity, 2013-01) Parks, Emily L; Madden, David JEmerging hypotheses suggest that efficient cognitive functioning requires the integration of separate, but interconnected cortical networks in the brain. Although task-related measures of brain activity suggest that a frontoparietal network is associated with the control of attention, little is known regarding how components within this distributed network act together or with other networks to achieve various attentional functions. This review considers both functional and structural studies of brain connectivity, as complemented by behavioral and task-related neuroimaging data. These studies show converging results: The frontal and parietal cortical regions are active together, over time, and identifiable frontoparietal networks are active in relation to specific task demands. However, the spontaneous, low-frequency fluctuations of brain activity that occur in the resting state, without specific task demands, also exhibit patterns of connectivity that closely resemble the task-related, frontoparietal attention networks. Both task-related and resting-state networks exhibit consistent relations to behavioral measures of attention. Further, anatomical structure, particularly white matter pathways as defined by diffusion tensor imaging, places constraints on intrinsic functional connectivity. Lastly, connectivity analyses applied to investigate cognitive differences across individuals in both healthy and diseased states suggest that disconnection of attentional networks is linked to deficits in cognitive functioning, and in extreme cases, to disorders of attention. Thus, comprehensive theories of visual attention and their clinical translation depend on the continued integration of behavioral, task-related neuroimaging, and brain connectivity measures.Item Open Access Caregivers of people with neurodegenerative diseases: profile and unmet needs from a population-based survey in South Australia.(J Palliat Med, 2010-06) Aoun, Samar; McConigley, Ruth; Abernethy, Amy; Currow, David CINTRODUCTION: Neurodegenerative diseases (NDD) are characterized by progressive decline and loss of function, requiring considerable third-party care. NDD carers report low quality of life and high caregiver burden. Despite this, little information is available about the unmet needs of NDD caregivers. METHODS: Data from a cross-sectional, whole of population study conducted in South Australia were analyzed to determine the profile and unmet care needs of people who identify as having provided care for a person who died an expected death from NDDs including motor neurone disease and multiple sclerosis. Bivariate analyses using chi(2) were complemented with a regression analysis. RESULTS: Two hundred and thirty respondents had a person close to them die from an NDD in the 5 years before responding. NDD caregivers were more likely to have provided care for more than 2 years and were more able to move on after the death than caregivers of people with other disorders such as cancer. The NDD caregivers accessed palliative care services at the same rate as other caregivers at the end of life, however people with an NDD were almost twice as likely to die in the community (odds ratio [OR] 1.97; 95% confidence interval [CI] 1.30 to 3.01) controlling for relevant caregiver factors. NDD caregivers reported significantly more unmet needs in emotional, spiritual, and bereavement support. CONCLUSION: This study is the first step in better understanding across the whole population the consequences of an expected death from an NDD. Assessments need to occur while in the role of caregiver and in the subsequent bereavement phase.Item Open Access Chronic Lyme disease: the controversies and the science.(Expert Rev Anti Infect Ther, 2011-07) Lantos, Paul MThe diagnosis of chronic Lyme disease has been embroiled in controversy for many years. This is exacerbated by the lack of a clinical or microbiologic definition, and the commonality of chronic symptoms in the general population. An accumulating body of evidence suggests that Lyme disease is the appropriate diagnosis for only a minority of patients in whom it is suspected. In prospective studies of Lyme disease, very few patients go on to have a chronic syndrome dominated by subjective complaints. There is no systematic evidence that Borrelia burgdorferi, the etiology of Lyme disease, can be identified in patients with chronic symptoms following treated Lyme disease. Multiple prospective trials have revealed that prolonged courses of antibiotics neither prevent nor alleviate such post-Lyme syndromes. Extended courses of intravenous antibiotics have resulted in severe adverse events, which in light of their lack of efficacy, make them contraindicated.Item Open Access Distinct and atypical intrinsic and extrinsic cell death pathways between photoreceptor cell types upon specific ablation of Ranbp2 in cone photoreceptors.(PLoS Genet, 2013-06) Cho, Kyoung-In; Haque, Mdemdadul; Wang, Jessica; Yu, Minzhong; Hao, Ying; Qiu, Sunny; Pillai, Indulekha CL; Peachey, Neal S; Ferreira, Paulo ANon-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+ -apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders.Item Open Access Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease.(Dalton Trans, 2010-03-07) Perez, Lissette R; Franz, Katherine JNeurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.Item Open Access Minimally invasive versus open fusion for Grade I degenerative lumbar spondylolisthesis: analysis of the Quality Outcomes Database.(Neurosurgical focus, 2017-08) Mummaneni, Praveen V; Bisson, Erica F; Kerezoudis, Panagiotis; Glassman, Steven; Foley, Kevin; Slotkin, Jonathan R; Potts, Eric; Shaffrey, Mark; Shaffrey, Christopher I; Coric, Domagoj; Knightly, John; Park, Paul; Fu, Kai-Ming; Devin, Clinton J; Chotai, Silky; Chan, Andrew K; Virk, Michael; Asher, Anthony L; Bydon, MohamadOBJECTIVE Lumbar spondylolisthesis is a degenerative condition that can be surgically treated with either open or minimally invasive decompression and instrumented fusion. Minimally invasive surgery (MIS) approaches may shorten recovery, reduce blood loss, and minimize soft-tissue damage with resultant reduced postoperative pain and disability. METHODS The authors queried the national, multicenter Quality Outcomes Database (QOD) registry for patients undergoing posterior lumbar fusion between July 2014 and December 2015 for Grade I degenerative spondylolisthesis. The authors recorded baseline and 12-month patient-reported outcomes (PROs), including Oswestry Disability Index (ODI), EQ-5D, numeric rating scale (NRS)-back pain (NRS-BP), NRS-leg pain (NRS-LP), and satisfaction (North American Spine Society satisfaction questionnaire). Multivariable regression models were fitted for hospital length of stay (LOS), 12-month PROs, and 90-day return to work, after adjusting for an array of preoperative and surgical variables. RESULTS A total of 345 patients (open surgery, n = 254; MIS, n = 91) from 11 participating sites were identified in the QOD. The follow-up rate at 12 months was 84% (83.5% [open surgery]; 85% [MIS]). Overall, baseline patient demographics, comorbidities, and clinical characteristics were similarly distributed between the cohorts. Two hundred fifty seven patients underwent 1-level fusion (open surgery, n = 181; MIS, n = 76), and 88 patients underwent 2-level fusion (open surgery, n = 73; MIS, n = 15). Patients in both groups reported significant improvement in all primary outcomes (all p < 0.001). MIS was associated with a significantly lower mean intraoperative estimated blood loss and slightly longer operative times in both 1- and 2-level fusion subgroups. Although the LOS was shorter for MIS 1-level cases, this was not significantly different. No difference was detected with regard to the 12-month PROs between the 1-level MIS versus the 1-level open surgical groups. However, change in functional outcome scores for patients undergoing 2-level fusion was notably larger in the MIS cohort for ODI (-27 vs -16, p = 0.1), EQ-5D (0.27 vs 0.15, p = 0.08), and NRS-BP (-3.5 vs -2.7, p = 0.41); statistical significance was shown only for changes in NRS-LP scores (-4.9 vs -2.8, p = 0.02). On risk-adjusted analysis for 1-level fusion, open versus minimally invasive approach was not significant for 12-month PROs, LOS, and 90-day return to work. CONCLUSIONS Significant improvement was found in terms of all functional outcomes in patients undergoing open or MIS fusion for lumbar spondylolisthesis. No difference was detected between the 2 techniques for 1-level fusion in terms of patient-reported outcomes, LOS, and 90-day return to work. However, patients undergoing 2-level MIS fusion reported significantly better improvement in NRS-LP at 12 months than patients undergoing 2-level open surgery. Longer follow-up is needed to provide further insight into the comparative effectiveness of the 2 procedures.Item Open Access Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.(PLoS Biol, 2010-01-19) Neef, Daniel W; Turski, Michelle L; Thiele, Dennis JNeurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.Item Open Access Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.(Annals of clinical and translational neurology, 2022-02) Berger, Miles; Browndyke, Jeffrey N; Cooter Wright, Mary; Nobuhara, Chloe; Reese, Melody; Acker, Leah; Bullock, W Michael; Colin, Brian J; Devinney, Michael J; Moretti, Eugene W; Moul, Judd W; Ohlendorf, Brian; Laskowitz, Daniel T; Waligorska, Teresa; Shaw, Leslie M; Whitson, Heather E; Cohen, Harvey J; Mathew, Joseph P; MADCO-PC InvestigatorsObjective
Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aβ levels after non-cardiac, non-neurologic surgery in older adults.Methods
Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis.Results
There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aβ42 changes over this interval (p > 0.05 for each).Interpretation
Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p-tau-181p levels or the p-tau-181p/Aβ or tau/Aβ ratios).Trial registration
clinicaltrials.gov (NCT01993836).Item Open Access Quantitative susceptibility mapping of brain iron in healthy aging and cognition.(NeuroImage, 2023-11) Madden, David J; Merenstein, Jenna LQuantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique that can assess the magnetic properties of cerebral iron in vivo. Although brain iron is necessary for basic neurobiological functions, excess iron content disrupts homeostasis, leads to oxidative stress, and ultimately contributes to neurodegenerative disease. However, some degree of elevated brain iron is present even among healthy older adults. To better understand the topographical pattern of iron accumulation and its relation to cognitive aging, we conducted an integrative review of 47 QSM studies of healthy aging, with a focus on five distinct themes. The first two themes focused on age-related increases in iron accumulation in deep gray matter nuclei versus the cortex. The overall level of iron is higher in deep gray matter nuclei than in cortical regions. Deep gray matter nuclei vary with regard to age-related effects, which are most prominent in the putamen, and age-related deposition of iron is also observed in frontal, temporal, and parietal cortical regions during healthy aging. The third theme focused on the behavioral relevance of iron content and indicated that higher iron in both deep gray matter and cortical regions was related to decline in fluid (speed-dependent) cognition. A handful of multimodal studies, reviewed in the fourth theme, suggest that iron interacts with imaging measures of brain function, white matter degradation, and the accumulation of neuropathologies. The final theme concerning modifiers of brain iron pointed to potential roles of cardiovascular, dietary, and genetic factors. Although QSM is a relatively recent tool for assessing cerebral iron accumulation, it has significant promise for contributing new insights into healthy neurocognitive aging.Item Open Access Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.(Progress in molecular biology and translational science, 2012-01) Fullwood, Melissa J; Zhou, Wei; Shenolikar, ShirishThe unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and β-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2α phosphatases that prolong eIF2α phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.Item Open Access Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.(Rejuvenation Res, 2015-04) Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Ukraintseva, Svetlana V; Stallard, Eric; Province, Michael A; Yashin, Anatoli IThe lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.Item Open Access Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.(J Neurotrauma, 2010-11) Laskowitz, Daniel T; Song, Pingping; Wang, Haichen; Mace, Brian; Sullivan, Patrick M; Vitek, Michael P; Dawson, Hana NCognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.