Alzheimer & Parkinson

We reviewed the connections among Alzheimer's disease (AD), sleep deprivation, and circadian rhythm disorders. Evidence is mounting that disrupted sleep and abnormal circadian rhythms are not merely symptoms of AD, but are also involved in accelerating the disease. Amyloid-beta (Aβ) accumulates, a feature of AD, and worsens with sleep deprivation because glymphatic withdrawal is required to clear toxic proteins from the brain. In addition, disturbances in circadian rhythm can contribute to the...

Mitochondrial dysfunction has been associated with neurodegenerative diseases (NDDs). This study aimed to explore the association between blood mitochondrial DNA copy number (mtDNA-CN) and development of NDDs. This study was based on two-sample Mendelian randomization (MR) analysis. The genome wide association study (GWAS) data of NDDs including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), multiple sclerosis (MS), Parkinson's disease...

Alzheimer's disease (AD) is the most prevalent type of neurological disorder characterized by cognitive decline and memory loss, marked by the accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein, causing extensive neuronal death and neuroinflammation. There is growing evidence that AD development extends beyond the neuronal compartment and has a major impact on the immunological functions of the brain. The cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA, including...

Parkinson's disease (PD) remains a major challenge in the field of neurodegenerative diseases and requires innovative therapeutic approaches. In this study, we investigated the therapeutic potential of chenodeoxycholic acid (CDCA) in PD using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. CDCA, a naturally occurring bile acid, has previously shown promise in various neurological disorders by reducing neuronal degeneration and promoting neuronal health, however its...

Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and...

Parkinson's disease (PD) is one of the rapidly growing neurodegenerative diseases, affecting more than 10 million people worldwide. Early and accurate diagnosis of PD is highly desirable for therapeutic interventions but remains a substantial challenge. We developed a soft, portable intelligent keyboard leveraging magnetoelasticity to detect subtle pressure variations in keystroke dynamics by converting continuous keystrokes into high-fidelity electrical signals, thus enabling the quantitative...

Over the past few decades, extensive basic, translational and clinical research has been devoted to deciphering the physiological and pathogenic roles of extracellular vesicles (EVs) in the nervous system. The presence of brain cell-derived EVs in the blood, carrying diverse cargoes, has enabled the development of predictive, diagnostic, prognostic, disease-monitoring and treatment-response biomarkers for various neurological disorders. In this Review, we consider how EV biomarkers can bring us...

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and...

In Alzheimer's disease, tau pathology spreads across brain regions as the disease progresses. Intracellular tau can be released and taken up by nearby neurons. We evaluated single domain anti-tau antibodies, also called VHHs, as inhibitors of tau internalization. We identified three VHH inhibitors of tau uptake: A31, H3-2, and Z70(mut1). These VHHs compete with the membrane protein LRP1, a major receptor mediating neuronal uptake of tau. A31 and Z70(mut1) bind to microtubule binding domain...

GWAS of Alzheimer's disease have been predominantly based on European ancestry cohorts with clinically diagnosed patients. Increasing the ancestral diversity of GWAS and focusing on imaging brain biomarkers for Alzheimer's disease may lead to the identification of new genetic loci. Here, we perform a GWAS on cerebral β-amyloid deposition measured by PET imaging in 3,885 East Asians and a cross-ancestry GWAS meta-analysis with data from 11,816 European participants. Our GWAS analysis replicates...

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We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized...

Mesodiencephalic dopamine neurons (mdDA) of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) play critical roles in regulating movement and motivation. Pitx3 is an essential transcription factor required for proper embryonic development and terminal differentiation of mdDA neurons. Although Pitx3 is expressed in every mdDA neuron, its ablation results only in the absence of the SNc, not the VTA. The developmental stage at which the loss of SNc first becomes apparent, as...

Freezing of gait (FOG) is a debilitating motor symptom that commonly occurs in Parkinson disease, atypical parkinsonism and other neurodegenerative conditions. Management of FOG is complex and requires a multifaceted approach that includes pharmacological, surgical and non-pharmacological interventions. In this Expert Recommendation, we provide state-of-the-art practical recommendations for the management of FOG, based on the latest insights into the pathophysiology of the condition. We propose...

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CONCLUSIONS: Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.

Drug repositioning or drug reprofiling, involves identifying novel indications for approved and previously abandoned drugs in the treatment of other diseases. The traditional drug discovery process is tedious, time-consuming, risky, and challenging. Fortunately, the inception of the drug repositioning concept has expedited the process by using compounds with established safety profiles in humans, and thereby significantly reducing costs. Alzheimer's disease (AD) is a severe neurological disorder...

Alzheimer's disease (AD) pathology includes transcriptional changes in the neurons, which are in part caused by the heterodimerization of two stress response transcription factors, CREB3L2 and ATF4. We investigated the role of proteasome inhibition and the eIF2α-kinase HRI in the formation of CREB3L2-ATF4 in neurons exposed to soluble oligomeric Aβ(42). While HRI activation increased ATF4 expression, it decreased CREB3L2 and CREB3L2-ATF4 levels. Proteasome inhibition, induced by Aβ(42), leads to...

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the...

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically...