Journal of Alzheimer's disease & Parkinsonism最新文献

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.

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.

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.

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 in vivo biomarkers.

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.

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.

Objective: Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD.

Methods: Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized.

Results: Rare variants were found in known AD risk genes including AKAP9, CD33, CR1, EPHA1, INPP5D, NME8, PSEN1, SORL1, TREM2 and UNC5C. Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include CD163L1 and CLECL1, two genes that have both been implicated in immunity, CTNNA1, which encodes a catenin in the cerebral cortex and MIEF1, a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include PLEKHG5, a gene that causes Charcot-Marie-Tooth disease and THBS2, which promotes synaptogenesis.

Conclusion: Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia among aged people whose population is rapidly increasing. AD not only seriously affects the patient's physical health and quality of life, but also adds a heavy burden to the patient's family and society. It is urgent to understand AD pathogenesis and develop the means of prevention and treatment. AD is a chronic devastating neurodegenerative disease without effective treatment. Current approaches for management focus on helping patients relieve or delay the symptoms of cognitive dysfunction. The calcium ion (Ca²⁺) is an important second messenger in the function and structure of nerve cell circuits in the brain such as neuronal growth, exocytosis, as well as in synaptic and cognitive function. Increasing numbers of studies suggested that disruption of intracellular Ca²⁺ homeostasis, especially the abnormal and excessive Ca²⁺ release from the endoplasmic reticulum (ER) via the ryanodine receptor (RYR), plays important roles in orchestrating the dynamic of the neuropathology of AD and associated memory loss, cognitive dysfunction. Dantrolene, a known antagonist of the RYR and a clinically available drug to treat malignant hyperthermia, can ameliorate the abnormal Ca²+ release from the RYR in AD and the subsequent pathogenesis, such as increased β-secretase and γ-secretase activities, production of Amyloid-β 42 (Aβ 42) and its oligomer, impaired autophagy, synapse dysfunction, and memory loss. However, more studies are needed to confirm the efficacy and safety repurposing dantrolene as a therapeutic drug in AD.