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Alzheimer Disease: HELP
Articles from Virginia
Based on 162 articles published since 2009

These are the 162 published articles about Alzheimer Disease that originated from Virginia during 2009-2019.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Editorial Neural computation for rehabilitation. 2014

Hu, Xiaoling / Wang, Yiwen / Zhao, Ting / Gunduz, Aysegul. ·Interdisciplinary Division of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. · Qiushi Academy for Advanced Studies, Zhejiang University, Zhejiang 310027, China. · Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, VA 20147, USA. · J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA. ·Biomed Res Int · Pubmed #25610868.

ABSTRACT: -- No abstract --

2 Editorial Alzheimer's be not proud. 2014

Narayan, Mary Curry. ·Mary Curry Narayan, MSN, RN, HHCNS-BC, is a Home Health Clinical Nurse Specialist and leads Narayan Associates, Vienna, Virginia. Narayan Associates provides quality, education, and consulting services and patient/clinician resources and tools to home healthcare agencies. ·Home Healthc Nurse · Pubmed #24492274.

ABSTRACT: -- No abstract --

3 Editorial Environmental exposures and the risk for Alzheimer disease: can we identify the smoking guns? 2014

Dekosky, Steven T / Gandy, Sam. ·Department of Medical Ethics and Health Policy, University of Pennsylvania Perelman School of Medicine, Philadelphia2Department of Neurology, University of Virginia School of Medicine, Charlottesville3Department of Psychiatry and Neurobehavioral Sciences. · Department of Neurology and Psychiatry (Dual Primaries), Center for Cognitive Health and NFL Neurological Care, Mount Sinai Alzheimer's Disease Research Center, New York, New York. ·JAMA Neurol · Pubmed #24473699.

ABSTRACT: -- No abstract --

4 Editorial Commentary on "a roadmap for the prevention of dementia II: Leon Thal symposium 2008." The megacommunity approach to Alzheimer's disease. 2009

Van Lee, Reggie / Meagher, Beth / Fritz, Patrick / Penfield, Susan. ·Booz Allen Hamilton, McLean, VA, USA. ·Alzheimers Dement · Pubmed #19328452.

ABSTRACT: There are many groups and organizations across the government, private, and nonprofit sectors that are passionately engaged in the fight against Alzheimer's disease (AD), but they have constraints on their funding and scope and, therefore, cannot tackle the problem holistically. Addressing the complexities of this epidemic strategically will require the collective efforts of committed stakeholders. Individuals and organizations must work together to identify mutual interests and forge new relationships and partnerships. Through this network of stakeholders, known as a megacommunity, individual members can support and expand their objectives and impact through the combined knowledge and resources in the megacommunity network. Leaders Engaged on Alzheimer's Disease (LEAD) is an example of a megacommunity tackling the toughest issues facing AD patients and their families. LEAD is currently comprised of more that thirty individuals and organizations committed to sharing information and coordinating action across organizational boundaries.

5 Review Therapeutic potentials of plant iridoids in Alzheimer's and Parkinson's diseases: A review. 2019

Dinda, Biswanath / Dinda, Manikarna / Kulsi, Goutam / Chakraborty, Ankita / Dinda, Subhajit. ·Department of Chemistry, Tripura University, Suryamaninagar, Agartala, Tripura, 799 022, India. Electronic address: dindabtu@gmail.com. · Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesvile, 1300 Jefferson Park Ave, VA, 22908, USA. · College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 151742, Republic of Korea. · Department of Chemistry, Tripura University, Suryamaninagar, Agartala, Tripura, 799 022, India. · Department of Chemistry, Dasaratha Deb Memorial College, Khowai, Tripura, 799201, India. ·Eur J Med Chem · Pubmed #30877973.

ABSTRACT: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aβ) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroinflammation and mitochondrial dysfunction lead to various molecular events in brain neurons causing neuronal cell death in these neurodegenerative disorders. Currently used drugs for treatment of AD and PD only reduce the symptoms of these diseases, but unable to stop the process of neurodegeneration. Therefore, innovation of new synthetic drugs or discovery of natural drugs for the treatment of AD and PD, is a challenging task of basic science and clinical medicine. Plant iridoids such as catalpol and its 10-O-trans-p-coumaroyl derivative, geniposide, harpagoside, and loganin, and seco-iridoids, oleuropein and its aglycone and oleocanthal have been found to exhibit significant neuroprotective effect and the property of slowing down the process of neurogedeneration in AD and PD. These plant metabolites have been shown to ameliorate AD by increasing the expression of insulin degrading enzyme (IDE), neprilysin (NEP), PPAR-γ, and α-secretase, and decreasing the expression of β-secretase (BACE-1) to reduce the levels of Aβ oligomers (Aβ

6 Review Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis. 2018

Bloom, George S / Lazo, John S / Norambuena, Andrés. ·Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. Electronic address: gsb4g@virginia.edu. · Department of Pharmacology, University of Virginia, Charlottesville, VA, USA; Department of Chemistry, University of Virginia, Charlottesville, VA, USA. · Department of Biology, University of Virginia, Charlottesville, VA, USA. ·Neuropharmacology · Pubmed #28965829.

ABSTRACT: The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is "how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD?" The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive. Here we review recent findings that mechanistically link soluble forms of amyloid-β (Aβ) and tau, the respective building blocks of the amyloid plaques and neurofibrillary tangles that accumulate in the brains of AD patients, with neuronal decline that is associated with poor insulin responsiveness and may begin long before AD symptoms become evident. We discuss how Aβ and tau work coordinately to deprive neurons of functionally accessible insulin receptors and dysregulate normal signaling by the protein kinase, mTOR. Finally, we suggest how newly gained knowledge about pathogenic signaling caused by reduced brain insulin signaling might be exploited for improved early detection and therapeutic intervention for AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

7 Review The DRD2 Taq1A A1 Allele May Magnify the Risk of Alzheimer's in Aging African-Americans. 2018

Blum, Kenneth / Badgaiyan, Rajendra D / Dunston, Georgia M / Baron, David / Modestino, Edward J / McLaughlin, Thomas / Steinberg, Bruce / Gold, Mark S / Gondré-Lewis, Marjorie C. ·Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA. · Department of Psychiatry and Behavioral Sciences, Keck Medicine University of Southern California, Los Angeles, CA, USA. · Division of Applied Clinical Research & Education, Dominion Diagnostics, LLC, North Kingstown, RI, USA. · Department of Neurogenetics, Igene, LLC, Austin, TX, USA. · Division of Reward Deficiency Syndrome and Addiction Therapy, Nupathways, Inc., Innsbrook, MO, USA. · Department of Clinical Neurology, Path Foundation, New York, NY, USA. · Division of Neuroscience Based Addiction Therapy, The Shores Treatment & Recovery Center, Port Saint Lucie, FL, USA. · Eötvös Loránd University, Institute of Psychology, Budapest, Hungary. · Department of Psychiatry and Behavioral Health, Richmond University Medical Center, 355 Bard Avenue, Staten Island, NY, 10310, USA. · NeuroPsychoSocial Genomics Core, National Human Genome Center, Howard University, Washington, DC, USA. · Department of Psychology, Curry College, Milton, MA, USA. · Center for Psychiatric Medicine, North Andover, MA, USA. · Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. · NeuroPsychoSocial Genomics Core, National Human Genome Center, Howard University, Washington, DC, USA. mgondre-lewis@howard.edu. · Developmental Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, USA. mgondre-lewis@howard.edu. · Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA. mgondre-lewis@howard.edu. ·Mol Neurobiol · Pubmed #28965318.

ABSTRACT: Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.

8 Review Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. 2017

Louveau, Antoine / Plog, Benjamin A / Antila, Salli / Alitalo, Kari / Nedergaard, Maiken / Kipnis, Jonathan. ·Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia, USA. · Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA. · Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. · Center of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. ·J Clin Invest · Pubmed #28862640.

ABSTRACT: Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

9 Review Effect of Chinese Herbal Medicine on Alzheimer's Disease. 2017

Howes, Melanie-Jayne R / Fang, Rui / Houghton, Peter J. ·Royal Botanic Gardens, Kew, Richmond, United Kingdom; King's College London, London, United Kingdom. Electronic address: m.howes@kew.org. · Royal Botanic Gardens, Kew, Richmond, United Kingdom. · King's College London, London, United Kingdom. ·Int Rev Neurobiol · Pubmed #28807163.

ABSTRACT: Alzheimer's disease (AD) is reaching epidemic proportions yet treatment strategies are limited and are restricted to providing symptomatic relief for the cognitive and behavioral and psychological symptoms of dementia (BPSD). Chinese herbal medicine (CHM) has been a valuable source of medicines for centuries and research has burgeoned in recent years to understand the scientific basis for their use. Some plants have been used in CHM for AD symptoms (e.g., Polygala tenuifolia), while others are CHMs for different conditions, but they show mechanistic effects relevant to AD (e.g., Salvia miltiorrhiza). Some CHMs (e.g., Ginkgo biloba extract, and huperzine A from Huperzia serrata) show pharmacological activities relevant to AD, and promising effects on cognitive functions in clinical trials. Other CHMs show effects relevant to BPSD (e.g., Crocus sativus). This chapter discusses available scientific evidence for CHM plants and formulae that have been used both traditionally for AD, and those that have been used traditionally but not specifically for AD symptoms, and encompasses chemical, pharmacological and clinical studies. The ethnopharmacological approach to understanding the use of CHMs for AD is also discussed.

10 Review Assessing the Current State of Cognitive Frailty: Measurement Properties. 2017

Sargent, L / Brown, R. ·L. Sargent, Candidate at Medical University of South Carolina, Faculty of Virginia Commonwealth University, School of Nursing, Richmond, VA, USA, lsargent@vcu.edu. ·J Nutr Health Aging · Pubmed #28112769.

ABSTRACT: BACKGROUND: Currently, an estimated 25-30% of people ages 85 or older have dementia, with a projected 115 million people worldwide living with dementia by 2050. With this worldwide phenomenon fast approaching, early detection of at-risk older adults and development of interventions focused on preventing loss in quality of life are increasingly important. A new construct defined by the International Consensus Group (I.A.N.A/I.A.G.G) as «cognitive frailty» combines domains of physical frailty with cognitive impairment and provides a framework for research that may provide a means to identify individuals with cognitive impairment caused by nonneurodegenerative conditions. Using the integrative review method of Whittemore and Knafl., 2005 this study examines and appraises the optimal measures for detecting cognitive frailty in clinical populations of older adults. METHODS: The integrative review was conducted using PubMed, CINAHL, Web of Science, PsycInfo, and ProQuest Dissertations and Theses. From the total 185 articles retrieved, review of titles and key words were conducted. Following the initial review, 168 articles did not meet the inclusion criteria for association of frailty and cognition. Of the 18 fulltext articles reviewed, 11 articles met the inclusion criteria; these articles were reviewed in-depth to determine validity and reliability of the cognitive frailty measures. RESULTS: Predictive validity was established by the studies reviewed in four main areas: frailty and type of dementia MCI (OR 7.4, 95% CI 4.2-13.2), vascular dementia (OR 6.7, 95% CI 1.6-27.4) and Alzheimer's dementia (OR 3.2, 95% CI 1.7-6.2), frailty and vascular dementia (VaAD) is further supported by the rate of change in frailty x macroinfarcts (r = 0.032, p < 0.001); frailty and the individual domains of cognitive function established with the relationship of neurocognitive speed and change in cognition using regression coefficients; individual components of frailty and individual domains of cognitive function associations inculded slow gait and executive function (β -0.20, p < 0.008 ), attention (β -0.25 p < 0.008), processing speed (β -0.16, p < 0.008), word recall (β - 0.18, p = 0.02), and logical memory (β = 0.04, p =0.04). Weak grip was predictive for changes in executive function (β - 0.16, p =0.008). Physical activity was associated with changes in executive function (β = -0.18, p= 0.02) and word recall (β = 0.17, p= 0.02), individual components of frailty and global cognitive function were found in several studies which included grip strength (r = - 0.51, p < 0.001), gait speed (r = - 0.067, p < 0.001), and exhaustion (β - 0.18, p < 0.008). CONCLUSIONS: This paper presents the first-known review of the measurement properties for the cognitive frailty construct since the published results from the International Consensus Group (I.A.N.A/I.A.G.G). Evidence presented in this review continues to support the link between physical frailty and cognition with developing validity to support distinct relationships between components of physical frailty and cognitive decline. Results call attention to inconsistencies in reporting of reliability, validity, and heterogeneity in the measurements and operational definition for cognitive frailty. Further research is needed to establish an operational definition and develop psychometrically appropriate clinical measures to construct an understanding of the relationship between physical frailty and cognitive decline.

11 Review Mitochondria in the pathophysiology of Alzheimer's and Parkinson's diseases. 2017

Onyango, Isaac G / Khan, Shaharyar M / Bennett, James P. ·Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903 USA, ionyango@genciabiotech.com. · Gencia Biotechnology, 706 B Forest St, Charlottesville, VA 22903 USA. · Neurodegeneration Therapeutics, 3050 A Berkmar Dr, Charlottesville, VA 22901. ·Front Biosci (Landmark Ed) · Pubmed #27814651.

ABSTRACT: Mitochondria are responsible for the majority of energy production in energy-intensive tissues like brain, modulate Ca

12 Review CSF Aβ 2017

Kuhlmann, Julia / Andreasson, Ulf / Pannee, Josef / Bjerke, Maria / Portelius, Erik / Leinenbach, Andreas / Bittner, Tobias / Korecka, Magdalena / Jenkins, Rand G / Vanderstichele, Hugo / Stoops, Erik / Lewczuk, Piotr / Shaw, Leslie M / Zegers, Ingrid / Schimmel, Heinz / Zetterberg, Henrik / Blennow, Kaj / Anonymous750869. ·European Commission, Joint Research Centre, Institute for Reference Materials and Measurements, Geel, Belgium. · Inst. of Neuroscience and Physiology Dept. of Psychiatry and Neurochemistry The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Clinical Neurochemistry LaboratorySahlgrenska University Hospital, MölndalSE-431 80 Mölndal Sweden. · Roche Diagnostics GmbH, Penzberg, Germany. · Perelman School of Medicine, University of Pennsylvania, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA. · Department of Chromatographic Sciences, PPD Laboratories, Richmond, VA, USA. · ADx NeuroSciences NV, Gent, Belgium. · Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland. · Inst. of Neuroscience and Physiology Dept. of Psychiatry and Neurochemistry The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Clinical Neurochemistry LaboratorySahlgrenska University Hospital, MölndalSE-431 80 Mölndal Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · Inst. of Neuroscience and Physiology Dept. of Psychiatry and Neurochemistry The Sahlgrenska Academy at University of Gothenburg Mölndal, Sweden; Clinical Neurochemistry LaboratorySahlgrenska University Hospital, MölndalSE-431 80 Mölndal Sweden. Electronic address: kaj.blennow@neuro.gu.se. ·Clin Chim Acta · Pubmed #27216941.

ABSTRACT: The 42 amino acid form of amyloid β (Aβ

13 Review Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer's Disease? 2016

Louveau, Antoine / Da Mesquita, Sandro / Kipnis, Jonathan. ·Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. · Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: kipnis@virginia.edu. ·Neuron · Pubmed #27608759.

ABSTRACT: Lymphatic vasculature drains interstitial fluids, which contain the tissue's waste products, and ensures immune surveillance of the tissues, allowing immune cell recirculation. Until recently, the CNS was considered to be devoid of a conventional lymphatic vasculature. The recent discovery in the meninges of a lymphatic network that drains the CNS calls into question classic models for the drainage of macromolecules and immune cells from the CNS. In the context of neurological disorders, the presence of a lymphatic system draining the CNS potentially offers a new player and a new avenue for therapy. In this review, we will attempt to integrate the known primary functions of the tissue lymphatic vasculature that exists in peripheral organs with the proposed function of meningeal lymphatic vessels in neurological disorders, specifically multiple sclerosis and Alzheimer's disease. We propose that these (and potentially other) neurological afflictions can be viewed as diseases with a neuro-lympho-vascular component and should be therapeutically targeted as such.

14 Review The Knowledge of Memory Aging Questionnaire: Factor Structure and Correlates in a Lifespan Sample. 2016

Calamia, Matthew / Reese-Melancon, Celinda / Cherry, Katie E / Hawley, Karri S / Jazwinski, S Michal. ·Department of Psychology, Louisiana State University, Baton Rouge, Louisiana. · Department of Psychology, Oklahoma State University, Stillwater, Oklahoma. · Department of Behavioral Sciences, Liberty University, Lynchburg, Virginia. · Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana. ·Yale J Biol Med · Pubmed #27505021.

ABSTRACT: The authors examined the factor structure of the Knowledge of Memory Aging Questionnaire (KMAQ) [1] using confirmatory factor analysis in a lifespan sample of 933 individuals who ranged in age from 18 to 101. Participants were college students at Louisiana State University and adults from the community enrolled in the Louisiana Healthy Aging Study (LHAS). A two-factor solution was expected, consistent with the normal and pathological memory aging dimensions that comprise the KMAQ. A bi-factor solution with items loading on a general response bias factor and either a normal or pathological knowledge-specific factor showed good model fit. Knowledge scores were correlated with demographic and cognitive performance variables. Implications of these data for clinical settings and research are considered.

15 Review The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review. 2016

Mohan, Akansha / Roberto, Aaron J / Mohan, Abhishek / Lorenzo, Aileen / Jones, Kathryn / Carney, Martin J / Liogier-Weyback, Luis / Hwang, Soonjo / Lapidus, Kyle A B. ·Baylor College of Medicine, Houston, Texas. · Clinical fellow, Child and Adolescent Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. · Old Dominion University, Norfolk, Virginia. · Resident physician, Adult Psychiatry, Westchester Medical Center, New York Medical College, Westchester, New York. · Tulane University School of Medicine, New Orleans, Louisianna. · Neurosurgery resident physician, Department of Neurosurgery, Medical University of South Carolina, Charleston, South Carolina. · University of Nebraska Medical Center, Omaha, Nebraska. · Northwell Health, Zucker Hillside Hospital, Glen Oaks, New York. ·Yale J Biol Med · Pubmed #27505016.

ABSTRACT: The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment.

16 Review Common and Rare Genetic Variants Associated With Alzheimer's Disease. 2016

Marei, Hany E / Althani, Asmaa / Suhonen, Jaana / El Zowalaty, Mohamed E / Albanna, Mohammad A / Cenciarelli, Carlo / Wang, Tengfei / Caceci, Thomas. ·Biomedical Research Center, Qatar University, Doha, Qatar. · Department of Health Sciences, College of Arts and Science, Qatar University, Doha, Qatar. · Department of Neurology, Al-Ahli Hospital, Doha, Qatar. · Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar. · CNR-Institute of Translational Pharmacology, Via Fosso del Cavaliere, Roma-Italy. · Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee. · Department of Biomedical Sciences, Virginia Tech Carilion School of Medicine, Roanoke, Virginia. ·J Cell Physiol · Pubmed #26496533.

ABSTRACT: Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets.

17 Review Microglia as a critical player in both developmental and late-life CNS pathologies. 2014

Derecki, Noël C / Katzmarski, Natalie / Kipnis, Jonathan / Meyer-Luehmann, Melanie. ·Department of Neuroscience and Center for Brain Immunology and Glia (BIG), School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA, ncd3z@virginia.edu. ·Acta Neuropathol · Pubmed #25056803.

ABSTRACT: Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.

18 Review Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. 2014

Bloom, George S. ·Departments of Biology and Cell Biology, University of Virginia, Charlottesville. ·JAMA Neurol · Pubmed #24493463.

ABSTRACT: The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.

19 Review Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. 2014

Rosenblum, William I. ·VCU School of Medicine, Richmond, VA, USA; Icahn School of Medicine at Mt Sinai, Mt Sinai, NY, USA. Electronic address: wirosenb@aol.com. ·Neurobiol Aging · Pubmed #24210593.

ABSTRACT: Before amyloid formation, peptides cleaved from the amyloid precursor protein (APP) exist as soluble oligomers. These are extremely neurotoxic. Their concentration is strongly correlated with synaptic impairment in animals and parallel cognitive decline in animals and humans. Clinical trials have largely been aimed at removing insoluble beta amyloid in senile plaques and have not reduced soluble load. Even treatment that should remove soluble oligomers has not consistently reduced the load. Failure to significantly improve cognition has frequently been attributed to failure of the amyloid hypothesis or to irreversible alteration in the brain. Instead, trial failures may be because of failure to significantly reduce load of toxic Aβ oligomers. Moreover, targeting only synthesis of Aβ peptides, only the oligomers themselves, or only the final insoluble amyloid may fail to significantly reduce soluble load because of the interrelationship between these 3 points in the amyloid cascade. Thus, treatments may fail unless trials target simultaneously all 3 points in the equation-"triple therapy". Cerebrospinal fluid analysis and other monitoring tools may in the future provide reliable measurement of soluble load. But currently, only analysis of autopsied brains can provide this data and thus enable proper evaluation and explanation of the outcome of clinical trials. These data are essential before attributing trial failures to the advanced nature of the disease or asserting that failures prove that the theory linking Alzheimer's disease to products of amyloid precursor protein is incorrect.

20 Review The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. 2014

Swerdlow, Russell H / Burns, Jeffrey M / Khan, Shaharyar M. ·Departments of Neurology and Molecular and Integrative Physiology, and the University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA; Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS, USA. Electronic address: rswerdlow@kumc.edu. · Departments of Neurology and Molecular and Integrative Physiology, and the University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA. · Gencia Corporation, Charlottesville, VA, USA. ·Biochim Biophys Acta · Pubmed #24071439.

ABSTRACT: Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

21 Review Biomarkers in pharmacology and drug discovery. 2014

Anderson, D C / Kodukula, Krishna. ·Center for Advanced Drug Research, SRI International, Harrisonburg, VA 22802, USA. Electronic address: dave.anderson@sri.com. · Center for Advanced Drug Research, SRI International, Harrisonburg, VA 22802, USA; Departments of Biology, and Chemistry and Biochemistry, James Madison University, Harrisonburg, VA 22802, USA. ·Biochem Pharmacol · Pubmed #24001556.

ABSTRACT: Biomarkers, quantitatively measurable indicators of biological or pathogenic processes, once validated play a critical role in disease diagnostics, the prediction of disease progression, and/or monitoring of the response to treatment. They may also represent drug targets. A number of different methods can be used for biomarker discovery and validation, including proteomics methods, metabolomics, imaging, and genome wide association studies (GWASs) and can be analysed using receiver operating characteristic (ROC) plots. The relative utility of single biomarkers compared to biomarker panels is discussed, along with paradigms for biomarker development, the latter in the context of three large-scale biomarker consortia, the Critical Path Predictive Safety Testing Consortium (PSTC), the NCI Early Detection Research Network (EDRN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The importance of systematic optimization of many parameters in biomarker analysis, including validation, reproducibility, study design, statistical analysis and avoidance of bias are critical features used by these consortia. Problems including introduction of bias into study designs, data reporting or data analysis are also reviewed.

22 Review Alzheimer disease: a tale of two prions. 2013

Nussbaum, Justin M / Seward, Matthew E / Bloom, George S. ·Department of Biology, University of Virginia, Charlottesville, VA, USA. ·Prion · Pubmed #22965142.

ABSTRACT: Alzheimer disease (AD) has traditionally been thought to involve the misfolding and aggregation of two different factors that contribute in parallel to pathogenesis: amyloid-β (Aβ) peptides, which represent proteolytic fragments of the transmembrane amyloid precursor protein, and tau, which normally functions as a neuronally enriched, microtubule-associated protein that predominantly accumulates in axons. Recent evidence has challenged this model, however, by revealing numerous functional interactions between Aβ and tau in the context of pathogenic mechanisms for AD. Moreover, the propagation of toxic, misfolded Aβ and tau bears a striking resemblance to the propagation of toxic, misfolded forms of the canonical prion protein, PrP, and misfolded Aβ has been shown to induce tau misfolding in vitro through direct, intermolecular interaction. In this review we discuss evidence for the prion-like properties of both Aβ and tau individually, as well as the intriguing possibility that misfolded Aβ acts as a template for tau misfolding in vivo.

23 Review Providing quality palliative care in end-stage Alzheimer disease. 2013

Yeaman, Paul A / Ford, James L / Kim, Kye Y. ·Salem Veterans Affairs Medical Center, Jefferson College of Health Sciences, VA, USA. ·Am J Hosp Palliat Care · Pubmed #22811214.

ABSTRACT: Providing quality palliative care is a daunting task profoundly impacted by diminished patient capacity at the end of life. Alzheimer disease (AD) is a disorder that erases our memories and is projected to increase dramatically for decades to come. By the time the patients with AD reach the end stage of the disease, the ability of patients to provide pertinent subjective complaints of pain and discomfort would have vanished. Historical perspectives of palliative care, exploration of the AD process, ethical issues, and crucial clinical considerations are provided to improve the understanding of disease progression and quality of care for patients with end-stage AD.

24 Review The role of molecular simulations in the development of inhibitors of amyloid β-peptide aggregation for the treatment of Alzheimer's disease. 2012

Lemkul, Justin A / Bevan, David R. ·Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States. jalemkul@vt.edu ·ACS Chem Neurosci · Pubmed #23173066.

ABSTRACT: The pathogenic aggregation of the amyloid β-peptide (Aβ) is considered a hallmark of the progression of Alzheimer's disease, the leading cause of senile dementia in the elderly and one of the principal causes of death in the United States. In the absence of effective therapeutics, the incidence and economic burden associated with the disease are expected to rise dramatically in the coming decades. Targeting Aβ aggregation is an attractive therapeutic approach, though structural insights into the nature of Aβ aggregates from traditional experiments are elusive, making drug design difficult. Theoretical methods have been used for several years to augment experimental work and drive progress forward in Alzheimer's drug design. In this Review, we will describe how two common techniques, molecular docking and molecular dynamics simulations, are being applied in developing small molecules as effective therapeutics against monomeric, oligomeric, and fibrillated forms of Aβ. Recent successes and important limitations will be discussed, and we conclude by providing a perspective on the future of this field by citing recent examples of sophisticated approaches used to better characterize interactions of small molecules with Aβ and other amyloidogenic proteins.

25 Review Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies. 2011

Ha, Giang T / Wong, Ryan K / Zhang, Yan. ·Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, USA. ·Chem Biodivers · Pubmed #21766442.

ABSTRACT: Alzheimer's disease (AD) is the fourth leading cause of death in adults, characterized by hallmark neuritic plaques and neurofibrillary tangles. Current treatments focus only on symptom relief. As a possible new treatment option for AD, huperzine A's chemistry, pharmacology, and clinical effectiveness are assessed. The chemical synthesis of huperzine A has been optimized, while an in vitro technique has provided a renewable plant source. Pharmacological studies showed that the drug inhibits the enzyme acetylcholinesterase reversibly and selectively. Huperzine A also displayed good pharmacokinetics with a rapid absorption and a wide distribution in the body at a low to moderate rate of elimination. Presently, inadequate toxicity data in human have been reported, yet animal studies demonstrated mild to moderate cholinergic side effects at therapeutic doses. Previous clinical trials have shown improvement in memory function using MMSE, MQ, ADAS-COG, and ADL tests. In an unpublished phase II clinical trial, the ADAS-COG and MMSE tests indicated cognitive enhancement at a dose of 0.4 mg, yet no improvement was observed at a dose of 0.2 mg. The MMSE scores indicated cognitive enhancement at 0.4 mg. Promising data suggested that huperzine A is well tolerated at doses up to 0.4 mg for 24 weeks. Therefore, huperzine A seems to be a potential treatment option for AD.