Age-related Neurodegenerative Pathologies Research Articles

Analysis of Behavior and Brain Neuronal Density in B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Mice Modeling Parkinson’s Disease

Parkinson’s disease (PD) is a progressive age-related neurodegenerative pathology of the central nervous system, characterized by a selective loss of dopaminergic neurons of the nigrostriatal pathway and by the presence of specific inclusions (Lewy bodies) in dopamine neurons. To study the mechanisms of this pathology and to search for possible ways to correct it, genetic models of PD in mice have been created. Transgenic mice of the B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J strain (referred as B6.Cg-Tg further in the text) represent a model of PD, have the A53T mutation in the human alpha-synuclein gene. The aim of this work was to study the locomotor activity and the level of anxiety, as well as the density of neurons in the brain of male B6.Cg-Tg mice at the age of six months. Wild type C57BL/6J mice of the same sex and age were used as controls. The results of the current study demonstrate that B6.Cg-Tg mice are characterized by the high locomotor activity and the low anxiety. Besides, a selective decrease in the density of neurons in the subventricular zone, the substantia nigra, as well as the CA1, CA3, CA4 zones and the granular layer of the dentate gyrus of the hippocampus was observed in these mice. Thus, mice of the B6.Cg-Tg strain at the age of six months only partially correspond to the main pathophysiological signs of PD. Decrease in the density of neurons in the substantia nigra, as well as in the CA1 and CA3 zones of the hippocampus of B6.Cg-Tg mice resemble similar changes in PD. However, these mice demonstrated neither bradykinesia nor high level of anxiety.

Postmortem Cerebellar Volume Is Not Reduced in Essential Tremor: A Comparison with Multiple System Atrophy and Controls.

Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. Cases with ET (n = 29), MSA (n = 7), and non-demented control cases without any movement disorder (n = 22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer's disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA.

Thermodynamic Signatures of Blood Plasma Proteome in Neurodegenerative Pathologies

Discovery of diagnostic biomarkers for age-related neurodegenerative pathologies (NDDs) is essential for accurate diagnosis, following disease progression and drug development. Blood plasma and blood cells are important peripheral sources for NDDs' biomarkers that, although present in lower concentrations than in cerebrospinal fluid, would allow noninvasive diagnostics. To identify new biomarkers for Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), in this work we have evaluated the modifications in the thermodynamic behavior of blood plasma proteome exploring differential scanning calorimetry. The plasma thermodynamics reflected the complexity and heterogeneity of the two pathologies. The unfolding temperature of the most abundant plasma protein albumin and the weighted average center of the calorimetric profile appeared as the two thermodynamic signatures that reflected modifications of the plasma proteome, i.e., strong thermal stabilization of albumin and plasma proteins' interaction network, related to both pathologies. Based on those two signatures, both PD and ALS patients were stratified in two sets, except several cases with thermodynamic parameters that strongly differed from those of the calorimetric sets. Along with modifications of the plasma thermodynamic behavior, we found altered globulin levels in all PD and ALS patients' plasma (higher level of α- and β-globulin fractions and lower level of γ-globulin fraction than the respective reference values) employing capillary electrophoresis. The presented results reveal the potential of calorimetry to indirectly identify NDDs' biomarkers in blood plasma.

Parkinson's Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment.

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

Acute inhibition of OGA sex-dependently alters the networks associated with bioenergetics, autophagy, and neurodegeneration

The accumulation of neurotoxic proteins characteristic of age-related neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases is associated with the perturbation of metabolism, bioenergetics, and mitochondrial quality control. One approach to exploit these interactions therapeutically is to target the pathways that regulate metabolism. In this respect, the nutrient-sensing hexosamine biosynthesis pathway is of particular interest since it introduces a protein post-translational modification known as O-GlcNAcylation, which modifies different proteins in control versus neurodegenerative disease postmortem brains. A potent inhibitor of the O-GlcNAcase enzyme that removes the modification from proteins, Thiamet G (TG), has been proposed to have potential benefits in Alzheimer’s disease. We tested whether key factors in the O-GlcNAcylation are correlated with mitochondrial electron transport and proteins related to the autophagy/lysosomal pathways in the cortex of male and female mice with and without exposure to TG (10 mg/kg i.p.). Mitochondrial complex activities were measured in the protein homogenates, and a panel of metabolic, autophagy/lysosomal proteins and O-GlcNAcylation enzymes were assessed by either enzyme activity assay or by western blot analysis. We found that the networks associated with O-GlcNAcylation enzymes and activities with mitochondrial parameters, autophagy-related proteins as well as neurodegenerative disease-related proteins exhibited sex and TG dependent differences. Taken together, these studies provide a framework of interconnectivity for multiple O-GlcNAc-dependent pathways in mouse brain of relevance to aging and sex/age-dependent neurodegenerative pathogenesis and response to potential therapies.

Amelioration of Alzheimer\u2019s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

Oxidative stress-mediated alterations in histone post-translational modifications

Epigenetic regulation of gene expression provides a finely tuned response capacity for cells when undergoing environmental changes. However, in the context of human physiology or disease, any cellular imbalance that modulates homeostasis has the potential to trigger molecular changes that result either in physiological adaptation to a new situation or pathological conditions. These effects are partly due to alterations in the functionality of epigenetic regulators, which cause long-term and often heritable changes in cell lineages. As such, free radicals resulting from unbalanced/extended oxidative stress have been proved to act as modulators of epigenetic agents, resulting in alterations of the epigenetic landscape. In the present review we will focus on the particular effect that oxidative stress and free radicals produce in histone post-translational modifications that contribute to altering the histone code and, consequently, gene expression. The pathological consequences of the changes in this epigenetic layer of regulation of gene expression are thoroughly evidenced by data gathered in many physiological adaptive processes and in human diseases that range from age-related neurodegenerative pathologies to cancer, and that include respiratory syndromes, infertility, and systemic inflammatory conditions like sepsis.

Space-Dependent Glia-Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition.

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

Elevated p38MAPK activity promotes neural stem cell aging.

Age-progressive neural stem cell (NSC) dysfunction leads to impaired neurogenesis, cognitive decline and the onset of age-related neurodegenerative pathologies. p38MAPK signalling pathway limits stem cell activity during aging in several tissues. Its role in NSCs remains controversial. In this work, we show that p38MAPK activity increases in NSCs with age in the subventricular zone (SVZ) and its pharmacological inhibition is sufficient to rejuvenate their activity in vitro. These data reveal a cell-autonomous role for p38MAPK increase in decreasing NSC homeostasis with age. This information shed light in the role of p38MAPK in NSC aging.

Circle of Willis abnormalities and their clinical importance in ageing brains: A cadaveric anatomical and pathological study

The circle of Willis (CW) located at the base of the brain forms an important collateral network to maintain adequate cerebral perfusion, especially in clinical situations requiring compensatory changes in blood flow. Morphopathological changes in the CW may relate to the severity of the symptoms of certain neurodegenerative and cerebrovascular disorders. The purpose of this study was to investigate the CW abnormalities and their clinical importance in ageing brains. The CW was examined macroscopically in 73 formalin-fixed samples to determine the degree of stenosis of each CW component, atherosclerosis of the CW, hypoplasia (threshold diameter < 1 mm), anatomical variations and aneurysms. Age-related neurodegenerative and cerebrovascular pathologies were screened using immunohistopathological techniques on specific neuroanatomical regions based on standard guidelines. The majority of the elderly brains −93 % (68/73) presented at least a single hypoplastic CW component at death. Anatomical variations were mostly identified in communicating arteries, followed by proximal posterior and anterior cerebral arteries. Arterial bifurcations were found to be the predominant sites for cerebral aneurysms. More than 90 % of the elderly brains presented CW atherosclerosis at death. CW abnormalities did not show any strong associations with neurodegenerative pathologies except for an “at risk” significant association observed between Braak’s neurofibrillary tangle (NFT) stages 1-VI and CW atherosclerosis grades ≥ mild (p = 0.05). However, a significant association was observed between microscopic infarcts in deep white matter and hypoplasia in communicating arteries with Fisher’s exact test (p < 0.05). Overall, CW abnormalities were predominant in the ageing brains, however their relationships to the occurrence and severity of the symptoms of neurodegenerative pathologies were found to be low.

Sex-specific patterns of age-related cerebral atrophy in a nonhuman primate Microcebus murinus

Steadily aging populations result in a growing need for research regarding age-related brain alterations and neurodegenerative pathologies. By allowing a good translation of results to humans, nonhuman primates, such as the gray mouse lemur Microcebus murinus, have gained attention in this field. Our aim was to examine correlations between atrophy-induced brain alterations and age, with special focus on sex differences in mouse lemurs. For cerebral volumetric measurements, in vivo magnetic resonance imaging was performed on 59 animals (28♀♀/31♂♂) aged between 1.0 to 11.9 years. Volumes of different brain regions, cortical thicknesses, and ventricular expansions were evaluated. Analyses revealed significant brain atrophies with increasing age, particularly around the caudate nucleus, the thalamus, and frontal, parietal, and temporo-occipital regions. Especially old females showed a strong decline in cingulate cortex thickness and had higher values of ventricular expansion, whereas cortical thickness of the splenium and occipital regions decreased mainly in males. Our study, thus, provides first evidence for sex-specific, age-related brain alterations in a nonhuman primate, suggesting that mouse lemurs can help elucidating the mechanism underlying sex disparities in cerebral aging, for which there is mixed evidence in humans.

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups. WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

Age-related neurodegenerative diseases.

Converging evidence indicates the dysregulation of unique cytosolic compartments called stress granules (SGs) might facilitate the accumulation of toxic protein aggregates that underlie many age-related neurodegenerative pathologies (ANPs). SG dynamics are particularly susceptible to the cellular conditions that are commonly induced by aging, including the elevation in reactive oxygen species and increased concentration of aggregate-prone proteins. In turn, the persistent formation of these compartments is hypothesized to serve as a seed for subsequent protein aggregation. Notably, the protein quality control (PQC) machinery responsible for inhibiting persistent SGs (e.g., Hsc70-BAG3) can become compromised with age, suggesting that the modulation of such PQC mechanisms could reliably inhibit pathological processes of ANPs. As exemplified in the context of accelerated aging syndromes (i.e., Hutchinson-Gilford progeria), PQC enhancement is emerging as a potential therapeutic strategy, indicating similar techniques might be applied to ANPs. Collectively, these recent findings advance our understanding of how the processes that might facilitate protein aggregation are particularly susceptible to aging conditions, and present investigators with an opportunity to develop novel targets for ANPs.

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier.

During the last decade, several articles have reported a relationship between advanced age and changes in the integrity of the blood-brain barrier (BBB). These changes were manifested not only in the morphology and structure of the cerebral microvessels but also in the expression and function of the transporter proteins in the luminal and basolateral surfaces of the capillary endothelial cells. Age-associated downregulation of the efflux pumps ATP-binding cassette transporters (ABC transporters) resulted in increased permeability and greater brain exposure to different xenobiotics and their possible toxicity. In age-related neurodegenerative pathologies like Alzheimer’s disease (AD), the amyloid-β (Aβ) clearance decreased due to P-glycoprotein (P-gp) dysfunction, leading to higher brain exposure. In stroke, however, an enhanced P-gp function was reported in the cerebral capillaries, making it even more difficult to perform effective neuroprotective therapy in the infarcted brain area. This mini-review article focuses on the efflux functions of the transporters and receptors of the BBB in age-related brain pathologies and also in healthy aging.

Probing H2O2-mediated Structural Dynamics of the Human 26S Proteasome Using Quantitative Cross-linking Mass Spectrometry (QXL-MS)

Cytotoxic protein aggregation-induced impairment of cell function and homeostasis are hallmarks of age-related neurodegenerative pathologies. As proteasomal degradation represents the major clearance pathway for oxidatively damaged proteins, a detailed understanding of the molecular events underlying its stress response is critical for developing strategies to maintain cell viability and function. Although the 26S proteasome has been shown to disassemble during oxidative stress, its conformational dynamics remains unclear. To this end, we have developed a new quantitative cross-linking mass spectrometry (QXL-MS) workflow to explore the structural dynamics of proteasome complexes in response to oxidative stress. This strategy comprises SILAC-based metabolic labeling, HB tag-based affinity purification, a 2-step cross-linking reaction consisting of mild in vivo formaldehyde and on-bead DSSO cross-linking, and multi-stage tandem mass spectrometry (MSn) to identify and quantify cross-links. This integrated workflow has been successfully applied to explore the molecular events underlying oxidative stress-dependent proteasomal regulation by comparative analyses of proteasome complex topologies from treated and untreated cells. Our results show that H2O2 treatment weakens the 19S-20S interaction within the 26S proteasome, along with reorganizations within the 19S and 20S subcomplexes. Altogether, this work sheds light on the mechanistic response of the 26S to acute oxidative stress, suggesting an intermediate proteasomal state(s) before H2O2-mediated dissociation of the 26S. The QXL-MS strategy presented here can be applied to study conformational changes of other protein complexes under different physiological conditions.

Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients.

Alzheimer's disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients.

Mechanisms of Hydrogen Sulfide against the Progression of Severe Alzheimer’s Disease in Transgenic Mice at Different Ages

Backgroud: Alzheimer disease is an age-related severe neurodegenerative pathology. The level of the third endogenous gas, hydrogen sulfide (H₂S), is decreased in the brain of Alzheimer’s disease (AD) patients compared with the brain of the age-matched normal individuals; also, plasma H₂S levels are negatively correlated with the severity of AD. Recently, we have demonstrated that systemic H₂S injections are neuroprotective in an early phase of preclinical AD. Objectives: This study focuses on the possible neuroprotection of a chronic treatment with an H₂S donor and sulfurous water (rich of H₂S) in a severe transgenic 3×Tg-AD mice model. Method: 3×Tg-AD mice at 2 different ages (6 and 12 months) were daily treated intraperitoneally with an H₂S donor and sulfurous water (rich of H₂S) for 3 months consecutively. We investigated the cognitive ability, brain morphological alterations, amyloid/tau cascade, excitotoxic, inflammatory and apoptotic responses. Results: Three months of treatments with H₂S significantly protected against impairment in learning and memory in a severe 3×Tg-AD mice model, at both ages studied, and reduced the size of Amyloid β plaques with preservation of the morphological picture. This neuroprotection appeared mainly in the cortex and hippocampus, associated with reduction in activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in the phosphorylation of tau protein but also in the inflammatory and excitotoxic response. Conclusion: Our findings indicate that appropriate treatments with various sources of H₂S, might represent an innovative approach to counteract early and severe AD progression in humans.

Perspective of application of nonlinear stimulation therapy in the treatment of traumatic brain injuries and maintenance of cognitive functions in the elderly

Cognitive decline characterizes normal physiological aging and is aggravated by the development of age-related neurodegenerative pathology and traumatic brain damage (TBI). Te review analyzes widely discussed in the scientifc literature non-drug methods of rehabilitation of patients with TBI and elderly people suffering from cognitive decline, including the paradigm of enrichment of the environment, cognitive and physical training and various types of stimulation therapy and their shortcomings. Special attention is paid to the advantages of fractal stimulation of the brain by complex-structured optical signals and sensory stimuli of another modality. It is assumed that the use of new approaches to neurorehabilitation, which increase the potential of neuroplasticity will also allow strengthening the therapeutic and learning impacts of any other methods of training and treating the brain.

The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders.

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.

An automated compound screening for anti-aging effects on the function of C. elegans sensory neurons

Discovery of molecular targets or compounds that alter neuronal function can lead to therapeutic advances that ameliorate age-related neurodegenerative pathologies. Currently, there is a lack of in vivo screening technologies for the discovery of compounds that affect the age-dependent neuronal physiology. Here, we present a high-throughput, microfluidic-based assay for automated manipulation and on-chip monitoring and analysis of stimulus-evoked calcium responses of intact C. elegans at various life stages. First, we successfully applied our technology to quantify the effects of aging and age-related genetic and chemical factors in the calcium transients of the ASH sensory neuron. We then performed a large-scale screen of a library of 107 FDA-approved compounds to identify hits that prevented the age-dependent functional deterioration of ASH. The robust performance of our assay makes it a valuable tool for future high-throughput applications based on in vivo functional imaging.