Journal Of Alzheimer's Disease And Parkinsonism[JOURNAL]
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52 papers
A Blood Screening Test for Dementia with Lewy Bodies for Primary Care.
Petersen M, Ferman TJ, Zhang F … +9 more , Pedraza O, Wszolek ZK, Ross OA, Como T, Julovich D, Johnson LA, Hall J, Graff-Radford NR, O'Bryant SE
J Alzheimers Dis Parkinsonism · 2023 · PMID 40688520
INTRODUCTION: We sought to cross-validate our previously published blood test for detecting Dementia with Lewy Bodies (DLB). METHOD: Plasma samples were analyzed on 428 individuals (DLB n=89, Parkinson's Disease (PD) wit...
INTRODUCTION: We sought to cross-validate our previously published blood test for detecting Dementia with Lewy Bodies (DLB). METHOD: Plasma samples were analyzed on 428 individuals (DLB n=89, Parkinson's Disease (PD) without dementia n=126, Alzheimer's Disease (AD) n=108, Normal Controls (NC) n=105). RESULTS: The proteomic profile discriminated DLB and PD from NC with an AUC (Area Under the Curve) of 0.96 with demographics of age, sex and education. The proteomic profile also distinguished DLB from the PD group with an AUC of 0.92 with demographics. It further distinguished DLB, PD and AD from NC with an AUC of 0.95 as well as DLB from AD with an AUC of 0.92 with demographics. DISCUSSION: This data provides additional evidence of the potential utility of a multi-tiered blood-based proteomic screening method for detecting DLB and distinguishing DLB from NC, PD and AD that can be implemented in primary care settings to aid in the referral process.
Risk of Developing Alzheimer's Disease and Related Dementias in ALLHAT Trial Participants Receiving Diuretic, ACE-Inhibitor, or Calcium-Channel Blocker with 18 Years of Follow-Up.
Du XL, Simpson LM, Osani MC … +2 more , Yama JM, Davis BR
J Alzheimers Dis Parkinsonism · 2022 · PMID 35571234
BACKGROUND: There is no any large randomized clinical trial of antihypertensive drug treatment with 18-year passive follow-up to examine the risk of Alzheimer's Disease (AD) or Related Dementias (ADRD). METHODS: Post-tri...
BACKGROUND: There is no any large randomized clinical trial of antihypertensive drug treatment with 18-year passive follow-up to examine the risk of Alzheimer's Disease (AD) or Related Dementias (ADRD). METHODS: Post-trial passive follow-up study of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants in 1994-1998 by linking with their Medicare claims data through 2017 among 17,158 subjects in 567 U.S. centers who were free of ADRD at baseline on January 1, 1999. Main outcome was the occurrence of ADRD over 18 years of follow-up. RESULTS: The 18-year cumulative incidence rates were 30.9% for AD, 59.2% for non-AD dementias, and 60.9% for any ADRD. The 18-year cumulative incidence of AD was almost identical for the 3 drug groups (30.5% for chlorthalidone, 31.1% for amlodipine, and 31.4% for lisinopril). The hazard ratios of AD, non-AD dementias and total ADRD were not statistically significantly different among the 3 drug groups. The adjusted hazard ratio of AD was 1.04 (95% CI: 0.94-1.14) for chlorthalidone amlodipine, 1.02 (0.92-1.13) for lisinopril amlodipine, and 0.98 (0.89-1.08) for lisinopril chlorthalidone, which were not significantly different. The risk of AD and non-AD dementias was significantly higher in older subjects, females, blacks, non-Hispanics, subjects with lower education, and subjects with vascular diseases. CONCLUSION: The risk of ADRD did not vary significantly by 3 antihypertensive drugs in ALLHAT trial participants with 18-years of follow-up. The risk of ADRD was significantly associated with age, gender, race/ethnicity, education, and history of vascular diseases.
Parkinson's Disease Blood Test for Primary Care.
O'Bryant SE, Petersen M, Zhang F … +3 more , Johnson L, German D, Hall J
J Alzheimers Dis Parkinsonism · 2022 · PMID 37006377
BACKGROUND: A blood-test that could serve as a potential first step in a multi-tiered neurodiagnostic process for ruling out Parkinson's disease (PD) in primary care settings would be of tremendous value. This study ther...
BACKGROUND: A blood-test that could serve as a potential first step in a multi-tiered neurodiagnostic process for ruling out Parkinson's disease (PD) in primary care settings would be of tremendous value. This study therefore sought to conduct a large-scale cross-validation of our Parkinson's disease Blood Test (PDBT) for use in primary care settings. METHODS: Serum samples were analyzed from 846 PD and 2291 volunteer controls. Proteomic assays were run on a multiplex biomarker assay platform using Electrochemiluminescence (ECL). Diagnostic accuracy statistics were generated using area under the receiver operating characteristic curve (AUC), Sensitivity (SN), Specificity (SP) and Negative Predictive Value (NPV). RESULTS: In the training set, the PDBT reached an AUC of 0.98 when distinguishing PD cases from controls with a SN of 0.84 and SP of 0.98. When applied to the test set, the PDBT yielded an AUC of 0.96, SN of 0.79 and SP of 0.97. The PDBT obtained a negative predictive value of 99% for a 2% base rate. CONCLUSION: The PDBT was highly successful in discriminating PD patients from control cases and has great potential for providing primary care providers with a rapid, scalable and cost-effective tool for screening out PD.
SARS-CoV-2, the Angiotensin Converting Enzyme 2 (ACE2) Receptor and Alzheimer's disease.
Lukiw WJ
J Alzheimers Dis Parkinsonism · 2021 · PMID 34476120
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Gastrointestinal (GI)-Tract Microbiome Derived Neurotoxins and their Potential Contribution to Inflammatory Neurodegeneration in Alzheimer's Disease (AD).
Lukiw WJ, Arceneaux L, Li W … +2 more , Bond T, Zhao Y
J Alzheimers Dis Parkinsonism · 2021 · PMID 34457996
The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial com...
The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial complexity even amongst healthy individuals-this has made it difficult to link specific microbial abundance patterns with age-related neurological disease. GI-tract commensal microorganisms are generally beneficial to human metabolism and immunity, however enterotoxigenic forms of microbes possess significant potential to secrete what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include toxic glycolipids such as lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA. One major microbial species of the GI-tract microbiome, about ~100-fold more abundant than in deep GI-tract regions is , an anaerobic, rod-shaped Gram-negative bacterium. can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); and (ii) a zinc-metalloproteinase known as -toxin (BFT) or . Ongoing studies indicate that BF-LPS and/or BFT disrupt paracellular-and transcellular-barriers by cleavage of intercellular-proteins resulting in 'leaky' barriers. These barriers: (i) become defective and more penetrable with aging and disease; and (ii) permit entry of microbiome-derived neurotoxins into the systemic-circulation from which they next transit the blood-brain barrier and gain access to the CNS. Here LPS accumulates and significantly alters homeostatic patterns of gene expression. The affinity of LPS for neuronal nuclei is significantly enhanced in the presence of amyloid beta 42 (Aβ42) peptides. Recent research on the appearance of the brain thanatomicrobiome at the time of death and the increasing likelihood of a complex brain microbiome are reviewed and discussed. This paper will also highlight some recent advances in this extraordinary research area that links the pro-inflammatory exudates of the GI-tract microbiome with innate-immune disturbances and inflammatory-signaling within the CNS with reference to Alzheimer's disease (AD) wherever possible.
Case Study: A Precision Medicine Approach to Multifactorial Dementia and Alzheimer's Disease.
Ross MK, Raji C, Lokken KL … +7 more , Bredesen DE, Roach JC, Funk CC, Price N, Rappaport N, Hood L, Heath JR
J Alzheimers Dis Parkinsonism · 2021 · PMID 35237464
We report a case of a patient with mixed dementia successfully treated with a personalized multimodal therapy. Monotherapeutics are inadequate for the treatment of Alzheimer's disease (AD) and mixed dementia; therefore,...
We report a case of a patient with mixed dementia successfully treated with a personalized multimodal therapy. Monotherapeutics are inadequate for the treatment of Alzheimer's disease (AD) and mixed dementia; therefore, we approach treatment through an adaptive personalized multimodal program. Many multimodal programs are pre-determined, and thus may not address the underlying contributors to cognitive decline in each particular individual. The combination of a targeted, personalized, precision medicine approach using a multimodal program promises advantages over monotherapies and untargeted multimodal therapies for multifactorial dementia. In this case study, we describe successful treatment for a patient diagnosed with AD, using a multimodal, programmatic, precision medicine intervention encompassing therapies targeting multiple dementia diastheses. We describe specific interventions used in this case that are derived from a comprehensive protocol for AD precision medicine. After treatment, our patient demonstrated improvements in quantitative neuropsychological testing, volumetric neuroimaging, PET scans, and serum chemistries, accompanied by symptomatic improvement over a 3.5-year period. This case outcome supports the need for rigorous trials of comprehensive, targeted combination therapies to stabilize, restore, and prevent cognitive decline in individuals with potentially many underlying causes of such decline and dementia. Our multimodal therapy included personalized treatments to address each potential perturbation to neuroplasticity. In particular, neuroinflammation and metabolic subsystems influence cognitive function and hippocampal volume. In this patient with a primary biliary cholangitis (PBC) multimorbidity component, we introduced a personalized diet that helped reduce liver inflammation. Together, all these components of multimodal therapy showed a sustained functional and cognitive benefit. Multimodal therapies may have systemwide benefits on all dementias, particularly in the context of multimorbidity. Furthermore, these therapies provide generalized health benefits, as many of the factors - such as inflammation - that impact cognitive function also impact other systems.
Identification of Dysregulated Genes for Late-Onset Alzheimer's Disease Using Gene Expression Data in Brain.
Arzouni N, Matloff W, Zhao L … +2 more , Ning K, Toga AW
J Alzheimers Dis Parkinsonism · 2020 · PMID 33282526
BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative complex brain disease that represents a public health concern. AD is considered the fifth leading cause of death in Americans who are older than 65 years which...
BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative complex brain disease that represents a public health concern. AD is considered the fifth leading cause of death in Americans who are older than 65 years which prioritizes the importance of understanding the etiology of AD in its early stages before the onset of symptoms. This study attempted to further understand Alzheimer's disease (AD) etiology by investigating the dysregulated genes using gene expression data from multiple brain regions. METHODS: A linear mixed-effects model for differential gene expression analysis was used in a sample of 15 AD and 30 control subjects, each with data from four different brain regions, in order to deal with the hierarchical multilevel data. Post-hoc Gene Ontology and pathway enrichment analyses provided insights on the biological implications in AD progression. Supervised machine learning algorithms were used to assess the discriminative power of the top 10 candidate genes in distinguishing between the two groups. RESULTS: Enrichment analyses revealed biological processes and pathways that are related to structural constituents and organization of the axons and synapses. These biological processes and pathways imply dysfunctional axon and synaptic transmission between neuronal cells in AD. Random Forest classification algorithm gave the best accuracy on the test data with F1-score of 0.88. CONCLUSION: The differentially expressed genes were associated with axon and synaptic transmissions which affect the neuronal connectivity in cognitive systems involved in AD pathophysiology. These genes may open ways to explore new effective treatments and early diagnosis before the onset of clinical symptoms.
Treating Alzheimer's Disease (AD) with Light and Sound.
Lukiw WJ
J Alzheimers Dis Parkinsonism · 2020 · PMID 32775038
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Alzheimer's Disease and Its Potential Alternative Therapeutics.
Kisby B, Jarrell JT, Agar ME … +5 more , Cohen DS, Rosin ER, Cahill CM, Rogers JT, Huang X
J Alzheimers Dis Parkinsonism · 2019 · PMID 31588368 · Full text
Alzheimer's Disease (AD) is a chronic neurodegenerative disease that affects over 5 million individuals in the United States alone. Currently, there are only two kinds of pharmacological interventions available for sympt...
Alzheimer's Disease (AD) is a chronic neurodegenerative disease that affects over 5 million individuals in the United States alone. Currently, there are only two kinds of pharmacological interventions available for symptomatic relief of AD; Acetyl Cholinesterase Inhibitors (AChEI) and N-methyl-D-aspartic Acid (NMDA) receptor antagonists and these drugs do not slow down or stop the progression of the disease. Several molecular targets have been implicated in the pathophysiology of AD, such as the tau (τ) protein, Amyloid-beta (Aβ), the Amyloid Precursor Protein (APP) and more and several responses have also been observed in the advancement of the disease, such as reduced neurogenesis, neuroinflammation, oxidative stress and iron overload. In this review, we discuss general features of AD and several small molecules across different experimental AD drug classes that have been studied for their effects in the context of the molecular targets and responses associated with the AD progression. These drugs include: Paroxetine, Desferrioxamine (DFO), N-acetylcysteine (NAC), Posiphen/-(-)Phenserine, JTR-009, Carvedilol, LY450139, Intravenous immunoglobulin G 10%, Indomethacin and Lithium Carbonate (LiCO).
The Down Syndrome-Associated Protein, Regulator of Calcineurin-1, is Altered in Alzheimer's Disease and Dementia with Lewy Bodies.
N M, AIBL Research Group, C F … +8 more , I V, Ca M, Rc K, Ai B, A R, Ma P, DI F, Pa A
J Alzheimers Dis Parkinsonism · 2019 · PMID 31263630 · Full text
There is a known relationship between Alzheimer's disease (AD) and Down syndrome (DS), with the latter typically developing AD-like neuropathology in mid-life. In order to further understand this relationship we examined...
There is a known relationship between Alzheimer's disease (AD) and Down syndrome (DS), with the latter typically developing AD-like neuropathology in mid-life. In order to further understand this relationship we examined intersectin-1 (ITSN1) and the regulator of calcineurin-1 (RCAN1), proteins involved in endosomal and lysosomal trafficking that are over-expressed in DS. We examined RCAN1 and ITSN1 levels (both long (-L) and short (-S) isoforms) and the level of endogenous metals in White Blood Cells (WBCs) collected from AD patients who were enrolled in the Australian Imaging, Biomarker and Lifestyle Study on Ageing (AIBL). We also examined RCAN1 and ITSN1-S and -L in post-mortem brain tissue in a separate cohort of patients with AD or other types of dementia including Dementia with Lewy Bodies (DLB) and non-Alzheimer's disease dementia. We found that RCAN1 was significantly elevated in AD and DLB brain compared with controls, but there was no difference in the level of RCAN1 in WBCs of AD patients. There were no differences in the levels of ITSN1-L and -S between AD and the control, nor between other types of dementia and the control. We found that there were no differences in the levels of metals between AD and the control WBCs. In conclusion, our data demonstrate that RCAN1 is differentially regulated between the peripheral and central compartments in AD and should be further investigated to understand its potential role in dementia of AD and DLB.
Aluminum in neurological disease - a 36 year multicenter study.
Lukiw WJ, Kruck TPA, Percy ME … +11 more , Pogue AI, Alexandrov PN, Walsh WJ, Sharfman NM, Jaber VR, Zhao Y, Li W, Bergeron C, Culicchia F, Fang Z, McLachlan DRC
J Alzheimers Dis Parkinsonism · 2019 · PMID 31179161 · Full text
Aluminum is a ubiquitous neurotoxin highly enriched in our biosphere, and has been implicated in the etiology and pathology of multiple neurological diseases that involve inflammatory neural degeneration, behavioral impa...
Aluminum is a ubiquitous neurotoxin highly enriched in our biosphere, and has been implicated in the etiology and pathology of multiple neurological diseases that involve inflammatory neural degeneration, behavioral impairment and cognitive decline. Over the last 36 years our group has analyzed the aluminum content of the temporal lobe neocortex of 511 high quality coded human brain samples from 18 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Brodmann anatomical areas including the inferior, medial and superior temporal gyrus (A20-A22) were selected for analysis: (i) because of their essential functions in massive neural information processing operations including cognition and memory formation; and (ii) because subareas of these anatomical regions are unique to humans and are amongst the earliest areas affected by progressive neurodegenerative disorders such as Alzheimer's disease (AD). Coded brain tissue samples were analyzed using the analytical technique of: (i) Zeeman-type electrothermal atomic absorption spectrophotometry (ETAAS) combined with (ii) an experimental multi-elemental analysis using the advanced photon source (APS) ultra-bright storage ring-generated hard X-ray beam (7 GeV) and fluorescence raster scanning (XRFR) spectroscopy device at the Argonne National Laboratory, US Department of Energy, University of Chicago IL, USA. These data represent the largest study of aluminum concentration in the brains of human neurological and neurodegenerative disease ever undertaken. Neurological diseases examined were AD (N=186), ataxia Friedreich's type (AFT; N=6), amyotrophic lateral sclerosis (ALS; N=16), autism spectrum disorder (ASD; N=26), dialysis dementia syndrome (DDS; N=27), Down's syndrome (DS; trisomy21; N=24), Huntington's chorea (HC; N=15), multiple infarct dementia (MID; N=19), multiple sclerosis (MS; N=23), Parkinson's disease (PD; N=27), prion disease (PrD; N=11) including bovine spongiform encephalopathy (BSE; 'mad cow disease'), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Sheinker syndrome (GSS), progressive multifocal leukoencephalopathy (PML; N=11), progressive supranuclear palsy (PSP; N=24), schizophrenia (SCZ; N=21), a young control group (YCG; N=22) and an aged control group (ACG; N=53). Amongst these 18 common neurological conditions and controls we report a statistically significant trend for aluminum to be increased only in AD, DS and DDS compared to age- and gender-matched brains from the same anatomical region. The results continue to suggest that aluminum's association with AD, DDS and DS brain tissues may contribute to the neuropathology of these neurological diseases but appear not to be a significant factor in other common disorders of the human central nervous system (CNS).
Identification and Analysis of Alzheimer's Candidate Genes by an Amplitude Deviation Algorithm.
Pang C, Yang H, Hu B … +8 more , Wang S, Chen M, Cohen DS, Chen HS, Jarrell JT, Carpenter KA, Rosin ER, Huang X
J Alzheimers Dis Parkinsonism · 2019 · PMID 31080696 · Full text
BACKGROUND: Alzheimer's disease (AD) is the most common form of senile dementia. However, its pathological mechanisms are not fully understood. In order to comprehend AD pathological mechanisms, researchers employed AD-r...
BACKGROUND: Alzheimer's disease (AD) is the most common form of senile dementia. However, its pathological mechanisms are not fully understood. In order to comprehend AD pathological mechanisms, researchers employed AD-related DNA microarray data and diverse computational algorithms. More efficient computational algorithms are needed to process DNA microarray data for identifying AD-related candidate genes. METHODS: In this paper, we propose a specific algorithm that is based on the following observation: When an acrobat walks along a steel-wire, his/her body must have some swing; if the swing can be controlled, then the acrobat can maintain the body balance. Otherwise, the acrobat will fall. Based on this simple idea, we have designed a simple, yet practical, algorithm termed as the Amplitude Deviation Algorithm (ADA). Deviation, overall deviation, deviation amplitude, and 3δ are introduced to characterize ADA. RESULTS: 52 candidate genes for AD have been identified via ADA. The implications for some of the AD candidate genes in AD pathogenesis have been discussed. CONCLUSIONS: Through the analysis of these AD candidate genes, we believe that AD pathogenesis may be related to the abnormality of signal transduction (AGTR1 and PTAFR), the decrease in protein transport capacity (COL5A2 (221729_at), COL5A2 (221730_at), COL4A1), the impairment of axon repair (CNR1), and the intracellular calcium dyshomeostasis (CACNB2, CACNA1E). However, their potential implication for AD pathology should be further validated by wet lab experiments as they were only identified by computation using ADA.
What Promises the CJD Diagnosis in a Case of Rapidly Progressive Dementia?
Aslam S, Fritz MA, Cordes L … +1 more , Sabbagh MN
J Alzheimers Dis Parkinsonism · 2018 · PMID 30733890 · Full text
BACKGROUND: Developing methods for accurately diagnosing prion diseases has been a challenge in the search for successful diagnosis and treatment of rapidly progressive dementia. prion diseases are rare. However, they sh...
BACKGROUND: Developing methods for accurately diagnosing prion diseases has been a challenge in the search for successful diagnosis and treatment of rapidly progressive dementia. prion diseases are rare. However, they should be considered in the differential diagnosis. Despite their rarity, several other conditions are often misdiagnosed as prion diseases. Most Alzheimer's (AD) and Lewy Body Disease (LBD) patients also meet Creutzfeldt-Jakob Disease (CJD) criteria. The similarities in symptomology and pathology between these two patient groups complicates diagnosis and can compromise patient care. Prevalent methods for the diagnosis of CJD lack the heightened sensitivity to conclusively detect CJD. Of all currently available methods, real-time quaking induced conversion (RT-QuIC) analysis provides the highest sensitivity necessary to allow for an accurate diagnosis and yields early, quantitative results. CLINICAL CASE: A 75-year-old woman with rapidly progressing dementia, for which CJD could not be ruled out, appeared for care at a neurological center. Laboratory test results, Magnetic Resonance Imaging (MRI), Cerebrospinal Fluid (CSF) studies, Positron Emission Tomography (PET), and an Electroencephalogram (EEG) proved inadequate to confirm CJD. In addition to AD, LBD, or CJD, other potential, yet improbable, pathologies could have caused the patient's symptoms. The patient's diagnosis ultimately was limited to either LBD or prion disease. Spongiform encephalogy was confirmed by a brain biopsy, and further testing confirmed sporadic CJD. CONCLUSION: RT-QuIC offers higher sensitivity than currently prevalent diagnostic methods and appears most promising for CJD diagnosis.
The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration.
Derk J, MacLean M, Juranek J … +1 more , Schmidt AM
J Alzheimers Dis Parkinsonism · 2018 · PMID 30560011 · Full text
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The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders.
Irwin DJ, Hurtig HI
J Alzheimers Dis Parkinsonism · 2018 · PMID 30473927 · Full text
Parkinson's Disease (PD) and the closely related Dementia with Lewy Bodies (DLB) are due to the accumulation of pathogenic alpha-synuclein protein in brain cells manifest by heterogeneous motor and non-motor symptoms, in...
Parkinson's Disease (PD) and the closely related Dementia with Lewy Bodies (DLB) are due to the accumulation of pathogenic alpha-synuclein protein in brain cells manifest by heterogeneous motor and non-motor symptoms, including cognitive impairment and dementia. The majority of patients with Parkinson's Disease develop Dementia (PDD) in late stages of the disease and have widespread neocortical distribution of alpha-synuclein pathology at autopsy, compared with PD without dementia, in which neocortical synuclein pathology is less prevalent. These three entities PD, DLB and PDD comprise a clinical spectrum, collectively known as Lewy Body Disorders (LBD). Recent investigations into the neuropathological basis of LBD have demonstrated that while synuclein pathology is the defining feature of these disorders, it is often accompanied by other age-related neurodegenerative pathologies. In particular, amyloid plaque and tau tangle pathology characteristic of Alzheimer's Disease (AD) (~50% of all LBD patients have sufficient pathology at autopsy for a secondary neuropathologic diagnosis of AD), appear to contribute to cognitive impairment in LBD, and the combination is associated with a shorter interval between onset of motor symptoms and development of dementia and a shorter life span. Further, the co-occurrence of neocortical alpha-synuclein, tau and amyloid pathologies found at end-stage disease suggests a potential synergistic interaction of these individual pathologies in humans during life, mirroring experimental observations in animal and cell model systems that show how pathogenic species of synuclein fibrils can promote trans-synaptic spread of both tauopathy and synucleinopathy with strain-like properties. Newer post-mortem studies using digital methods to measure pathologic burden have highlighted distinct neocortical patterns of areas with relative higher density of tau pathology in LBD compared to AD that support these model data. The emerging field of cerebrospinal fluid and molecular imaging biomarkers of synuclein, amyloid and tau pathologies in LBD is contributing to a greater understanding of how the different pathologies evolve and interact to produce clinical heterogeneity in LBD. Future work to elucidate biologically meaningful clinical subgroups of synucleinopathy and its co-pathology must focus on the full clinicopathological spectrum of LBD and use validated biomarkers, when available, to design clinical trials based on the precise selection of homogeneous patient subgroups to maximize statistical power for detecting the impact of treatment.
Targeting Prion-like Cis Phosphorylated Tau Pathology in Neurodegenerative Diseases.
Albayram O, Angeli P, Bernstein E … +4 more , Baxley S, Gao Z, Lu KP, Zhou XZ
J Alzheimers Dis Parkinsonism · 2018 · PMID 30197831 · Full text
Tau is a microtubule-associated protein heavily implicated in neurodegenerative diseases collectively known as tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Phosphorylation of tau at Th...
Tau is a microtubule-associated protein heavily implicated in neurodegenerative diseases collectively known as tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Phosphorylation of tau at Thr231 allows for the isomerization of phosphorylated tau (p-tau) into distinct cis and trans conformations. Cis, but not trans, p-tau is detectable not only in Alzheimer's disease and chronic traumatic encephalopathy, but also right after traumatic brain injury depending on injury severity and frequency both in humans and animal models. Cis p-tau is not only neurotoxic but also spreads from a neuron to another in a prion-like fashion, functioning as a primary driver of neurodegeneration, which can be effectively neutralized by cis p-tau antibody. This represents an exciting new opportunity for understanding disease development and developing early biomarkers and effective therapies of tauopathies.
The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Alzheimer's Disease.
Rohn TT, Kim N, Isho NF … +1 more , Mack JM
J Alzheimers Dis Parkinsonism · 2018 · PMID 30090689 · Full text
Despite a wealth of knowledge gained in the past three decades concerning the molecular underpinnings of Alzheimer's disease (AD), progress towards obtaining effective, disease modifying therapies has proven to be challe...
Despite a wealth of knowledge gained in the past three decades concerning the molecular underpinnings of Alzheimer's disease (AD), progress towards obtaining effective, disease modifying therapies has proven to be challenging. In this manner, numerous clinical trials targeting the production, aggregation, and toxicity of beta-amyloid, have failed to meet efficacy standards. This puts into question the beta-amyloid hypothesis and suggests that additional treatment strategies should be explored. The recent emergence of CRISPR/Cas9 gene editing as a relatively straightforward, inexpensive, and precise system has led to an increased interest of applying this technique in AD. CRISPR/Cas9 gene editing can be used as a direct treatment approach or to help establish better animal models that more faithfully mimic human neurodegenerative diseases. In this manner, this technique has already shown promise in other neurological disorders, such as Huntington's disease. The purpose of this review is to examine the potential utility of CRISPR/Cas9 as a treatment option for AD by targeting specific genes including those that cause early-onset AD, as well as those that are significant risk factors for late-onset AD such as the apolipoprotein E4 (APOE4) gene.
Towards a circuit-level understanding of hippocampal CA1 dysfunction in Alzheimer's disease across anatomical axes.
Masurkar AV
J Alzheimers Dis Parkinsonism · 2018 · PMID 29928558
The hippocampus has been a primary region of study with regards to synaptic and functional changes in Alzheimer’s disease (AD) due to its involvement in early stages, specifically area CA1. However, most work in this are...
The hippocampus has been a primary region of study with regards to synaptic and functional changes in Alzheimer’s disease (AD) due to its involvement in early stages, specifically area CA1. However, most work in this area has treated CA1 as a homogeneous structure comprised of uniform neural circuits. Yet, there is a plethora of evidence that CA1 varies in its structure and function across anatomical axes. Here I review the heterogeneity of the functional and circuit architecture of hippocampal area CA1 across three primary anatomical axes. I also summarize evidence that AD differentially affects these subregions, as well as hypotheses as to why this may occur.
microRNAs in Neurodegeneration: Current Findings and Potential Impacts.
Sharma S, Lu HC
J Alzheimers Dis Parkinsonism · 2018 · PMID 29862137 · Full text
Significant advancements have been made in unraveling and understanding the non-coding elements of the human genome. New insights into the structure and function of noncoding RNAs have emerged. Their relevance in the con...
Significant advancements have been made in unraveling and understanding the non-coding elements of the human genome. New insights into the structure and function of noncoding RNAs have emerged. Their relevance in the context of both physiological cellular homeostasis and human diseases is getting appreciated. As a result, exploration of noncoding RNAs, in particular microRNAs (miRs), as therapeutic agents or targets of therapeutic strategies is under way. This review summarizes and discusses in depth the current literature on the role of miRs in neurodegenerative diseases.
Occipital and Cingulate Hypometabolism are Significantly Under-Reported on 18-Fluorodeoxyglucose Positron Emission Tomography Scans of Patients with Lewy Body Dementia.
Hamed M, Schraml F, Wilson J … +2 more , Galvin J, Sabbagh MN
J Alzheimers Dis Parkinsonism · 2018 · PMID 29657900 · Full text
OBJECTIVE: To determine whether occipital and cingulate hypometabolism is being under-reported or missed on 18-fluorodeoxyglucose positron emission tomography (FDG-PET) CT scans in patients with Dementia with Lewy Bodies...
OBJECTIVE: To determine whether occipital and cingulate hypometabolism is being under-reported or missed on 18-fluorodeoxyglucose positron emission tomography (FDG-PET) CT scans in patients with Dementia with Lewy Bodies (DLB). BACKGROUND: Recent studies have reported higher sensitivity and specificity for occipital and cingulate hypometabolism on FDG-PET of DLB patients. METHODS: This retrospective chart review looked at regions of interest (ROI's) in FDG-PET CT scan reports in 35 consecutive patients with a clinical diagnosis of probable, possible, or definite DLB as defined by the latest DLB Consortium Report. ROI's consisting of glucose hypometabolism in frontal, parietal, temporal, occipital, and cingulate areas were tabulated and charted separately by the authors from the reports. A blinded Nuclear medicine physician read the images independently and marked ROI's separately. A Cohen's Kappa coefficient statistic was calculated to determine agreement between the reports and the blinded reads. RESULTS: On the radiology reports, 25.71% and 17.14% of patients reported occipital and cingulate hypometabolism respectively. Independent reads demonstrated significant disagreement with the proportion of occipital and cingulate hypometabolism being reported on initial reads: 91.43% and 85.71% respectively. Cohen's Kappa statistic determinations demonstrated significant agreement only with parietal hypometabolism (p<0.05). CONCLUSION: Occipital and cingulate hypometabolism is under-reported and missed frequently on clinical interpretations of FDG-PET scans of patients with DLB, but the frequency of hypometabolism is even higher than previously reported. Further studies with more statistical power and receiver operating characteristic analyses are needed to delineate the sensitivity and specificity of these biomarkers.
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