Age-related Neurological Disorders Research Articles

Deep learning-based brain transcriptomic signatures associated with the neuropathological and clinical severity of Alzheimer's disease.

Brain tissue gene expression from donors with and without Alzheimer’s disease has been used to help inform the molecular changes associated with the development and potential treatment of this disorder. Here, we use a deep learning method to analyse RNA-seq data from 1114 brain donors from the Accelerating Medicines Project for Alzheimer’s Disease consortium to characterize post-mortem brain transcriptome signatures associated with amyloid-β plaque, tau neurofibrillary tangles and clinical severity in multiple Alzheimer’s disease dementia populations. Starting from the cross-sectional data in the Religious Orders Study and Memory and Aging Project cohort (n = 634), a deep learning framework was built to obtain a trajectory that mirrors Alzheimer’s disease progression. A severity index was defined to quantitatively measure the progression based on the trajectory. Network analysis was then carried out to identify key gene (index gene) modules present in the model underlying the progression. Within this data set, severity indexes were found to be very closely correlated with all Alzheimer’s disease neuropathology biomarkers (R ∼ 0.5, P < 1e−11) and global cognitive function (R = −0.68, P < 2.2e−16). We then applied the model to additional transcriptomic data sets from different brain regions (MAYO, n = 266; Mount Sinai Brain Bank, n = 214), and observed that the model remained significantly predictive (P < 1e−3) of neuropathology and clinical severity. The index genes that significantly contributed to the model were integrated with Alzheimer’s disease co-expression regulatory networks, resolving four discrete gene modules that are implicated in vascular and metabolic dysfunction in different cell types, respectively. Our work demonstrates the generalizability of this signature to frontal and temporal cortex measurements and additional brain donors with Alzheimer’s disease, other age-related neurological disorders and controls, and revealed that the transcriptomic network modules contribute to neuropathological and clinical disease severity. This study illustrates the promise of using deep learning methods to analyse heterogeneous omics data and discover potentially targetable molecular networks that can inform the development, treatment and prevention of neurodegenerative diseases like Alzheimer’s disease.

The effect of pelvic movements of a gait training system for stroke patients: a single blind, randomized, parallel study

BackgroundAging societies lead to higher demand for gait rehabilitation as age-related neurological disorders such as stroke and spinal cord injury increase. Since conventional methods for gait rehabilitation are physically and economically burdensome, robotic gait training systems have been studied and commercialized, many of which provided movements confined in the sagittal plane. For better outcomes of gait rehabilitation with more natural gait patterns, however, it is desirable to provide pelvic movements in the transverse plane. In this study, a robotic gait training system capable of pelvic motions in the transverse plane was used to evaluate the effect of the pelvic motions on stroke patients.MethodHealbot T, which is a robotic gait training system and capable of providing pelvic movements in the transverse plane as well as flexion/extension of the hip and knee joints and adduction/abduction of the hip joints, is introduced and used to evaluate the effect of the pelvic movement on gait training of stroke patients. Gait trainings in Healbot T with and without pelvic movements are carried out with stroke patients having hemiparesis.ExperimentTwenty-four stroke patients with hemiparesis were randomly assigned into two groups and 23 of them successfully completed the experiment except one subject who had dropped out due to personal reasons. Pelvis-on group was provided with pelvic motions whereas no pelvic movement was allowed for pelvis-off group during 10 sessions of gait trainings in Healbot T. Electromyography (EMG) signals and interaction forces as well as the joint angles of the robot were measured. Gait parameters such as stride length, cadence, and walking speed were measured while walking on the ground without assistance of Healbot T after gait training on 1st, 5th, and 10th day.ResultStride length significantly increased in both groups. Furthermore, cadence and walking speed of the pelvis-on group were increased by 10.6% and 11.8%. Although interaction forces of both groups except the thighs showed no differences, EMG signals from gluteus medius of the pelvis-on group increased by 88.6% during stance phase. In addition, EMG signals of biceps femoris, gastrocnemius medial, and gastrocnemius lateral of the pelvis-on group increased whereas EMG signals of the pelvis-off group except gastrocnemius lateral showed no difference after gait trainings.ConclusionGait training using a robotic gait training system with pelvic movements was conducted to investigate the effects of lateral and rotational pelvic movements in gait training of stroke patients. The pelvic movements affected to increase voluntary muscle activation during the stance phase as well as cadence and walking speed.Clinical trial registrationKCT0003762, 2018-1254, Registered 28 October 2018, https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=14310<ype=&rtype=

Association between lower serum vitamin D (25-hydroxy-cholecalciferol) concentrations and cognitive impairment in older adults: data from a populational-based cohort study in a middle-income country.

To investigate the association between serum vitamin D (25-hydroxy-cholecalciferol) (25(OH)D) concentrations and cognitive impairment in older adults living in Southern Brazil. Cross-sectional analysis using data from the second follow-up wave of the populational-based EpiFloripa Aging Cohort Study was collected in 2013-2014. Cognitive impairment was evaluated using the Mini-Mental State Examination (MMSE). Blood samples were collected to measure serum vitamin D concentrations using a chemiluminescent microparticle immunoassay. Vitamin D concentrations were distributed in quartiles (Q1: 4·0-20·7 ng/ml; Q2: 20·8-26·6 ng/ml; Q3: 26·7-32·0 ng/ml and Q4: 32·1-60·1 ng/ml), and its association with cognitive impairment was tested by crude and adjusted logistic regression (sociodemographic, behavioural and health aspects) using Q4 as a reference group. 200 men and 371 women aged 60 years or older participated in this study. The prevalence of probable cognitive impairment was 21·7 %. Those without cognitive impairment had a higher mean of vitamin D serum concentrations (26·8 v. 24·6, P = 0·014). In the crude analysis, only individuals in Q2 of vitamin D presented an increased risk for probable cognitive impairment compared with Q4 (highest quartile) (OR 2·65, 95 % CI 1·46, 4·81), remaining significant in the adjusted analysis (OR 6·04, 95 % CI 2·78, 13·13). While Q1 (lowest quartile) was not associated in the crude analysis, but when adjusted, an increased risk of cognitive impairment was observed. The lowest quartile of vitamin D was directly associated with probable cognitive impairment in older adults in Southern Brazil. More studies are needed to investigate whether maintaining adequate serum levels may represent a significant factor in preventing age-related neurological disorders as well as to verify the need for new cutoff points for this age group.

Mirror Movements in Acquired Neurological Disorders: A Mini-Review.

Mirror movements (MMs) are specifically defined as involuntary movements occurring on one side of homologous muscles when performing unilateral movements with the contralateral limb. MMs have been considered a kind of soft neurological signs, and the persistence or reappearance of MMs in adults is usually pathologic. In addition to some congenital syndrome, MMs have been also described in age-related neurological diseases including pyramidal system diseases (e.g., stroke, amyotrophic lateral sclerosis) and extrapyramidal disorders (e.g., Parkinson's disease, essential tremor). With the advances in instrumentation and detection means, subtle or subclinical MMs have been deeply studied. Furthermore, the underlying mechanism is also being further elucidated. In this mini-review, we firstly discuss the MM examination means, and then review the literature regarding MMs in individuals with acquired neurological disorders, in order to further understand the pathogenesis of MMs.

MicroRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD).

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer’s disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.

Lactobacillus plantarum GKM3 Promotes Longevity, Memory Retention, and Reduces Brain Oxidation Stress in SAMP8 Mice.

(1) Background: An age-related cognitive decline is commonly affecting the life of elderly with symptoms involved in progressive impairments to memory and learning. It has been proposed that probiotics could modulate age-related neurological disorders via the gut–brain axis. (2) Methods: To investigate the anti-aging effect of probiotic Lactobacillus plantarum GKM3, both survival tests and cognitive experiments were conducted in the SAMP8 mice model. The six-month-old SAMP8 (n = 20 in each gender) were fed with probiotic GKM3 at a dosage of 5.1 × 109 and 1.0 × 109 cfu/ kg B.W./day until their natural death. Then, the life span was investigated. Three-month-old SAMP8 (n = 10 in each gender) were administered GKM3 for 14 weeks. Then, the behavior tests and oxidation parameters were recorded. (3) Results: GKM3 groups showed significantly increased latency in the passive avoidance test and time of successful avoidance in the active avoidance test. The TBARS and 8-OHdG from mice brains also showed a significant reduction in the groups treated with GKM3. In addition, lower accumulation of the amyloid-β protein was found in SAMP8 mice brains with the supplement of GKM3. (4) Conclusions: These results indicated that L. plantarum GKM3 delayed the process of aging, alleviated age-related cognitive impairment, and reduced oxidative stress.

Hydrolyzed Chicken Meat Extract Attenuates Neuroinflammation and Cognitive Impairment in Middle-Aged Mouse by Regulating M1/M2 Microglial Polarization.

Aging is the most common cause of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The pathological hallmarks of age-dependent neuropathology consist of chronic neuroinflammation, oxidative stress, gliosis, learning disability, and cognitive decline. A novel hydrolyzed bioactive peptide mixture extracted from chicken meat, that is, hydrolyzed chicken extract (HCE) has been previously demonstrated to exert neuroprotective effects in rodents and humans. However, the mechanism of HCE on age-related neurological disorders remains unclear. Herein, we aimed to clarify the impact and mechanism of isolated bioactive components (BCs) from HCE on age-dependent neuroinflammation and cognitive impairment in middle-aged mice. We found that both BC and HCE supplementation ameliorated age-induced memory loss, alleviated hippocampal neuroinflammation and oxidative stress, followed by promoting hippocampal neurogenesis in mice. BC and HCE treatment also ameliorated age-dependent morphological anomalies and alleviated microgliosis and astrogliosis. In parallel, BC and HCE treatment showed a significant decrease in the NF-κB p65 and p38 MAPK signaling, which were associated with the enhancement of antioxidative enzymes activities. Furthermore, BC treatment attenuated the neuroinflammatory phenotypes by the decrease in M1-polarized microglia and the increase in M2-polarized microglia in vivo and in vitro. In addition, we found that cyclo(Phe-Phe), one of the cyclopeptides purified from BC, showed notable anti-inflammatory effects in BV2 cells. Taken together, BC might be used as a dietary supplement for alleviating age-dependent neuropathology in middle-aged individuals.

How Do We Motorically Resonate in Aging? A Compensatory Role of Prefrontal Cortex.

Aging is the major risk factor for chronic age-related neurological diseases such as neurodegenerative disorders and neurovascular injuries. Exploiting the multimodal nature of the Mirror Neuron System (MNS), rehabilitative interventions have been proposed based on motor-resonance mechanisms in recent years. Despite the considerable evidence of the MNS’ functionality in young adults, further investigation of the action-observation matching system is required in aging, where well-known structural and functional brain changes occur. Twenty-one healthy young adults (mean age 26.66y) and 19 healthy elderly participants (mean age 71.47y) underwent a single MRI evaluation including a T1-3D high-resolution and functional MRI (fMRI) with mirror task. Morphological and functional BOLD data were derived from MRI images to highlight cortical activations associated with the task; to detect differences between the two groups (Young, Elderly) in the two MRI indexes (BOLD and thickness z-scores) using mixed factorial ANOVA (Group∗Index analyses); and to investigate the presence of different cortical lateralization of the BOLD signal in the two groups. In the entire sample, the activation of a bilateral MNS fronto-parietal network was highlighted. The mixed ANOVA (pFDR-corr < 0.05) revealed significant interactions between BOLD signal and cortical thickness in left dorsal premotor cortex, right ventral premotor and prefrontal cortices. A different cortical lateralization of the BOLD signal in frontal lobe activity between groups was also found. Data herein reported suggest that age-related cortical thinning of the MNS is coupled with increased interhemispheric symmetry along with premotor and prefrontal cortex recruitment. These physiological changes of MNS resemble the aging of the motor and cognitive neural systems, suggesting specific but also common aging and compensatory mechanisms.

Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo.

Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.

Left-prefrontal alpha-dynamics predict executive working-memory functioning in elderly people

ABSTRACT Recent findings suggest that electroencephalography (EEG) oscillations in the theta and alpha frequency-bands reflect synchronized interregional neuronal activity and are considered to reflect cognitive-control, and executive working memory mechanisms in humans. Above the age of 50 years, hypothesized pronounced alterations in alpha and theta-band power at resting or across different WM-functioning brain states may well be due to pre-dementia cognitive impairments, or increasing severity of age-related neurological disorders. Executive working memory (EWM) functioning was assessed in older-adult participants (54 to 83 years old) by obtaining their WM-related EEG oscillations and WM performance scores. WM performance and WM brain-state EEG were recorded during online-WM periods as well as during specific online WM events within EWM periods, and during resting offline-WM periods that preceded online-WM periods. Left-prefrontal alpha-power was enhanced during offline-WM periods versus online-WM periods and was significantly related to WM accuracy. Left-prefrontal alpha power and left prefrontal-parietal theta power anterior-posterior difference-gradient during online WM activity were related to reaction times (RT’s). Importantly, during active-storage events, WM-offset offline-periods, and preparatory pre-retrieval events, excessive left-prefrontal alpha activity was related to poor EWM performance. The potential for developing targeted noninvasive cognition-enhancing interventions and developing clinical-monitoring EEG-based biomarkers of pathological cognitive-decline in elderly people is discussed.

Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders.

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

MiR-34a-5p regulates PINK1-mediated mitophagy via multiple modes

AimsPTEN induced putative kinase 1 (PINK1)-mediated mitophagy process is tightly associated with various age-dependent diseases in mammals. The roles of miRNAs (miRNAs) in the PINK1-mediated mitophagy process are not fully understood. Here we discovered that miR-34a-5p suppresses PINK1 expression directly though two post-transcriptional non-classical binding modes, resulting in inhibition of PINK1-mediated mitophagy process. Main methodsFor in vivo experiments, brains were dissected from 8 weeks old and 40 weeks old C57BL/6 male mice to measure miR-34a-5p expression and PINK1 expression. For in vitro experiments, overexpression of miR-34a-5p mimics in HEK293 cells was performed to investigate the effect of miR-34a-5p on PINK1 expression and its regulatory mechanism, parkin recruitment and mitophagy process. Key findingsThe level of miR-34a-5p was upregulated and the level of PINK1 mRNA was downregulated in brains of aged mice. Both the 3′-untranslated region (3’UTR) and the Coding DNA sequence (CDS) of PINK1 mRNA were bound to the non-seed region of miR-34a-5p, rather than the seed region, resulting in a decrease in PINK1 expression. Endogenous miR-34a-5p knockout increased PINK1 expression. Further results indicated that miR-34a-5p inhibits mitophagy process by reduction of PINK1. miR-34a-5p hinders phosphorylated Ser65-ubiquitin (pS65-Ub) accumulation, prevents the mitochondrial recruitment of Parkin, attenuates ubiquitination and delays the clearance of damaged mitochondria. SignificanceWe firstly found that miR-34a-5p suppresses PINK1 directly and further regulates mitophagy through non-canonical modes. This finding hints at a crucial role of miR-34a-5p implicated in accelerating the pathogenesis of age-related neurological diseases.

Alendronate reduces the cognitive and neurological disturbances induced by combined doses of d-galactose and aluminum chloride in mice.

Neurological disturbances including cholinergic dysfunction, oxidative stress, neuroinflammation, and cognitive impairments are the well-reported consequences of old age-related disorders like Alzheimer's disease (AD) or dementia. Bisphosphonates were shown to ameliorate dementia in osteoporotic patients, neuroinflammation, and cholinesterase activity in rodents. Thus, the present study has been designed to examine the role of alendronate against cognitive and neurological disturbances in mice induced by a combined oral dose of d-galactose and aluminum chloride (AlCl3 ) for 6weeks. d-galactose acts as a senescence agent, whereas AlCl3 is a neurotoxin and in combination generates neuropathologies and cognitive depletion resembling aging and AD. It was found that memory was markedly impaired in d-galactose + AlCl3 -treated mice as assessed in different behavioral paradigms. Additionally, d-galactose + AlCl3 led to neurotoxicity assessed on the basis of neuroinflammation, oxidative stress, glial cell activation, neuronal damage, and augmented GSK-3β level in mice hippocampus. Consequently, alendronate administration orally for 15 days in d-galactose + AlCl3 -exposed mice prominently reversed all these behavioral and neuropathological changes. These findings show that alendronate can be a potential therapeutic molecule with multiple targets for the management of age-related neurological disorders such as AD.

Delivery Platforms for CRISPR/Cas9 Genome Editing of Glial Cells in the Central Nervous System.

Glial cells (astrocytes, oligodendrocytes, and microglia) are emerging as key players in several physiological and pathological processes of the central nervous system (CNS). Astrocytes and oligodendrocytes are not only supportive cells that release trophic factors or regulate energy metabolism, but they also actively modulate critical neuronal processes and functions in the tripartite synapse. Microglia are defined as CNS-resident cells that provide immune surveillance; however, they also actively contribute to shaping the neuronal microenvironment by scavenging cell debris or regulating synaptogenesis and pruning. Given the many interconnected processes coordinated by glial cells, it is not surprising that both acute and chronic CNS insults not only cause neuronal damage but also trigger complex multifaceted responses, including neuroinflammation, which can critically contribute to the disease progression and worsening of symptoms in several neurodegenerative diseases. Overall, this makes glial cells excellent candidates for targeted therapies to treat CNS disorders. In recent years, the application of gene editing technologies has redefined therapeutic strategies to treat genetic and age-related neurological diseases. In this review, we discuss the advantages and limitations of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based gene editing in the treatment of neurodegenerative disorders, focusing on the development of viral- and nanoparticle-based delivery methods for in vivo glial cell targeting.

Fisetin Rescues the Mice Brains Against D-Galactose-Induced Oxidative Stress, Neuroinflammation and Memory Impairment.

Herein, we have evaluated the protective potentials of Fisetin against d-galactose-induced oxidative stress, neuroinflammation, and memory impairment in mice. d-galactose (D-gal) causes neurological impairment by inducing reactive oxygen species (ROS), neuroinflammation, and synaptic dysfunction, whereas fisetin (Fis) is a natural flavonoid having potential antioxidant effects, and has been used against different models of neurodegenerative diseases. Here, the normal mice were injected with D-gal (100 mg/kg/day for 60 days) and fisetin (20 mg/kg/day for 30 days). To elucidate the protective effects of fisetin against d-galactose induced oxidative stress-mediated neuroinflammation, we conducted western blotting, biochemical, behavioral, and immunofluorescence analyses. According to our findings, D-gal induced oxidative stress, neuroinflammation, synaptic dysfunctions, and cognitive impairment. Conversely, Fisetin prevented the D-gal-mediated ROS accumulation, by regulating the endogenous anti-oxidant mechanisms, such as Sirt1/Nrf2 signaling, suppressed the activated p-JNK/NF-kB pathway, and its downstream targets, such as inflammatory cytokines. Hence, our results together with the previous reports suggest that Fisetin may be beneficial in age-related neurological disorders.

Moderate Mocha Coffee Consumption Is Associated with Higher Cognitive and Mood Status in a Non-Demented Elderly Population with Subcortical Ischemic Vascular Disease.

To date, interest in the role of coffee intake in the occurrence and course of age-related neurological and neuropsychiatric disorders has provided an inconclusive effect. Moreover, no study has evaluated mocha coffee consumption in subjects with mild vascular cognitive impairment and late-onset depression. We assessed the association between different quantities of mocha coffee intake over the last year and cognitive and mood performance in a homogeneous sample of 300 non-demented elderly Italian subjects with subcortical ischemic vascular disease. Mini Mental State Examination (MMSE), Stroop Colour-Word Interference Test (Stroop T), 17-items Hamilton Depression Rating Scalfe (HDRS), Activities of Daily Living (ADL), and Instrumental ADL were the outcome measures. MMSE, HDRS, and Stroop T were independently and significantly associated with coffee consumption, i.e., better scores with increasing intake. At the post-hoc analyses, it was found that the group with a moderate intake (two cups/day) had similar values compared to the heavy drinkers (≥three cups/day), with the exception of MMSE. Daily mocha coffee intake was associated with higher cognitive and mood status, with a significant dose-response association even with moderate consumption. This might have translational implications for the identification of modifiable factors for vascular dementia and geriatric depression.

Effects of innate immune receptor stimulation on extracellular \u03b1-synuclein uptake and degradation by brain resident cells

Synucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of α-syn aggregates varies from study to study, and how different α-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of α-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of α-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated α-syn fibril uptake in neurons and glia while delaying the degradation of α-syn in neurons and astrocytes. Internalized α-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular α-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic α-syn transmission, but activation of microglial TLR2 enhances microglial extracellular α-syn clearance.

Effect of Capsaicinoids on Neurophysiological, Biochemical, and Mechanical Parameters of Swallowing Function

Oropharyngeal dysphagia is prevalent in age-related neurological disorders presenting with impaired efficacy and safety of swallowing due to a loss of muscle force and sensory deficits. Stimulating the oropharynx with capsaicin that mediates Substance P release is an emerging pharmacological treatment option which needs further scientific evidence. Our aim was to comprehensively evaluate the effect of capsaicin on biochemical, neurophysiological, and biomechanical parameters of swallowing function. In a randomized study on healthy individuals, the impact of orally administered capsaicinoids at different dosages and application durations in comparison to non-carbonated water was evaluated. Time course and magnitude of salivary Substance P increase were monitored. Magnetoencephalography was used to detect cortical swallowing network alterations. Modifications in swallowing biomechanics were measured applying high-resolution pharyngeal manometry. Capsaicinoids at 10 μmol/L improved swallowing efficacy as seen by a significant increase of pharyngeal contractile integral and upper esophageal sphincter activation and relaxation times in manometry. Significant improvement of precision in a challenging swallow task accompanied by a reduction in swallowing-related submental electromyographic power was observed with capsaicinoids preconditioning at 10 μmol/L over 5 min, but not with continuous stimulation. The cortical activation pattern remained unchanged after any intervention. A significant increase of salivary Substance P was not detected with 10 μmol/L but with 50 μmol/L and lasted for 15 min after application. Capsaicinoids mediate dose-dependent Substance P release and positively alter swallowing biomechanics in healthy subjects. The results provide supportive evidence for the value of natural capsaicinoids to improve swallowing function.

Neurodegenerative Disease and the Experience of Homelessness.

Introduction: Today, half of the American homeless population is older than 50 years of age. This shift in age distribution among people experiencing homelessness has challenged our long-held views of the causes of homelessness. Age-related neurological diseases, especially neurodegenerative diseases of the brain (NDDB), may play a role eliciting homelessness in a significant proportion of vulnerable older adults. This article aims to explore relationships between homelessness and NDDB in a cohort of research participants enrolled in observational studies on NDDB at an academic center.Methods: We reviewed charts of the Memory and Aging Center (MAC) of the University of California, San Francisco's database searching for research participants with NDDB that had direct relationship to homelessness. We reviewed all research visits conducted between 2004 and 2018 (N = 5,300). Research participants who had any relationship to homelessness were included in this analysis. NDDB was diagnosed via comprehensive neurological, functional, neuropsychological, and biomarker assessments. Non-parametric tests were used for analysis. Thirteen participants were found to have a direct relationship with homelessness. Seven were female and the median of education was 16 (IR: 12.0–19.5) years. Participants were divided into two groups: Those who experienced homelessness while symptomatic from a NDDB but before formal diagnosis (n = 5, Group 1); and participants with formally diagnosed NDDB who exhibited a new propensity toward homelessness (n = 8, Group 2). Compared to Group 2, participants in Group 1 were younger (p = 0.021) and showed similar results in the neuropsychological evaluation. In both groups, the most prevalent diagnosis was frontotemporal dementia. In Group 1, the majority of participants became homeless in the setting of a fragile socioeconomic situation and informants believed that NDDB contributed or caused their homeless state. In Group 2, a new propensity toward homelessness became manifest in different ways and it stood out that all of these participants were well-supported by family and friends during their illness.Conclusions and Relevance: This case series highlights the role that NDDB may have in precipitating homelessness among vulnerable older adults, particularly in the setting of challenging socioeconomic circumstances and unsupportive living environments. Social ramifications of these findings, particularly pertaining to challenges around rehousing these individuals is discussed.

Neurofilament Light (NF-L) Chain Protein from a Highly Polymerized Structural Component of the Neuronal Cytoskeleton to a Neurodegenerative Disease Biomarker in the Periphery.

Neurofilaments (NFs) are critical scaffolding components of the axoskeleton of healthy neurons interacting directly with multiple synaptic-phosphoproteins to support and coordinate neuronal cell shape, cytoarchitecture, synaptogenesis and neurotransmission. While neuronal presynaptic proteins such as synapsin-2 (SYN II) degrade rapidly via the ubiquitin-proteasome pathway, a considerably more stable neurofilament light (NF-L) chain protein turns over much more slowly, and in several neurological diseases is accompanied by a pathological shift from an intracellular neuronal cytoplasmic location into various biofluid compartments. NF-L has been found to be significantly elevated in peripheral biofluids in multiple neurodegenerative disorders, however it is not as widely appreciated that NF-L expression within neurons undergoing inflammatory neurodegeneration exhibit a significant down-regulation in these neuron-specific intermediate-filament components. Down-regulated NF-L in neurons correlates well with the observed axonal and neuronal atrophy, neurite deterioration and synaptic disorganization in tissues affected by Alzheimer’s disease (AD) and other progressive, age-related neurological diseases. This Review paper: (i) will briefly assess the remarkably high number of neurological disorders that exhibit NF-L depolymerization, liberation from neuron-specific compartments, mobilization and enrichment into pathological biofluids; (ii) will evaluate how NF-L exhibits compartmentalization effects in age-related neurological disorders; (iii) will review how the shift of NF-L compartmentalization from within the neuronal cytoskeleton into peripheral biofluids may be a diagnostic biomarker for neuronal-decline in all cause dementia most useful in distinguishing between closely related neurological disorders; and (iv) will review emerging evidence that deficits in plasma membrane barrier integrity, pathological transport and/or vesicle-mediated trafficking dysfunction of NF-L may contribute to neuronal decline, with specific reference to AD wherever possible.