Preweaning Purified Fucoidan Drench: Effects on Growth, Immune Response, and Intestinal Morphology in Weaned Piglets.

Weaning stress imposes considerable physiological challenges on piglets, often manifesting in intestinal disturbances, such as inflammation and compromised barrier function, ultimately affecting growth and health outcomes. While conventional interventions, including antimicrobials, have effectively mitigated these sequelae, concerns surrounding antimicrobial resistance necessitate the exploration of alternatives. Fucoidan, derived from brown seaweed, offers promise due to its antioxidant and anti-inflammatory effects. Previous research has been limited to the in-feed supplementation of partially purified fucoidan extracted from brown seaweed. The focus of the present study is assessing the effect of a preweaning drench with highly purified (85%) fucoidan on piglet growth, immune response, and intestinal morphology post-weaning. Forty-eight male piglets at 17 ± 3 days of age (5.67 ± 0.16 kg) were assigned to a saline (control), fucoidan, or antimicrobial group, receiving treatment as a single 18 mL oral drench three days before weaning. Monitoring for seven days post-weaning included body weight measurements, blood sample collection for the inflammatory protein assay, and small intestine morphological analysis. The findings revealed that the preweaning fucoidan drench did not elicit adverse effects on piglets. However, neither fucoidan nor antimicrobial drenches significantly enhanced growth parameters, immune markers, or intestinal morphology compared to that of the control-treated piglets (p > 0.05). The lack of response may be attributed to the high health status of the experimental cohort and the limitation of a single dosage. Future research should consider a more challenging production setting to evaluate the viability and optimal application of fucoidan as an antimicrobial alternative in the pig industry.

Effectiveness of Tai Chi as a non-invasive intervention for mild cognitive impairment in the elderly: A comprehensive review and meta-analysis.

The aging population warrants the increase of mild cognitive impairment (MCI) prevalence, a condition that could progress to dementia. Efforts have been made to improve the MCI and prevent its progression, including the introduction of Tai Chi, a Chinese traditional exercise. The aim of this systematic review and meta-analysis was to evaluate the efficacy of Tai Chi in attenuating MCI among the elderly population. Records investigating the effect of Tai Chi exercise intervention on cognitive function among elderly patients were searched systematically from PubMed, ScienceDirect, Google Scholar, and Europe PMC as of April 13, 2023. The risk of bias (RoB 2.0) quality assessment was employed in the quality appraisal of the studies included. Review Manager 5.4.1 was used for data extraction and meta-analysis, where the standard mean difference (SMD) and 95% confidence interval (95%CI) were computed. Eight randomized control trials with a total of 1379 participants were included in this meta-analysis. Six trials assessed Montreal Cognitive Assessment scores, where its pooled analysis suggested that Tai Chi was as effective as conventional exercise (SMD=0.15, 95%CI: -0.11 to 0.40, p=0.26). However, pooled analysis of the Mini-Mental Status Examination suggested that Tai Chi intervention more effectively improved cognitive function and reduced the rate of cognitive impairment in elderly patients (SMD=0.36, 95%CI: 0.18 to 0.54, p<0.01) as compared to the control group. This systematic review and meta-analysis suggest that, in some extent, Tai Chi is efficacious in improving cognitive function and slowing down the rate of cognitive impairment among elderly patients.

Mild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease.

BACKGROUND: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD. METHODS: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups. RESULTS: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI. CONCLUSIONS: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Background: Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Methods: Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. Results: We first identified specific non-coding variants in CTSB that drive the association with PD and are linked to changes in brain CTSB expression levels. Using iPSC-derived dopaminergic neurons we then find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. Moreover, in cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. Similarly, in midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition or knockout potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. Conclusions: The results of our genetic and functional studies indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Symptom Analysis of Early Parkinson's Disease and its Correlation with High Sensitivity C-reactive Protein.

Parkinson's disease is a debilitating neurodegenerative disease for which there is no cure. It is characterized by bradykinesia, resting tremor, rigidity and postural instability, due to impairment of function of the basal ganglia which is involved in the coordination of body movement. Neuro-inflammation is pathogenesis of development in early Parkinson's disease. High-sensitivity C-reactive protein level is a useful non-specific biochemical marker of inflammation. Objective of this study was to analyze the symptoms of Parkinson disease and it's correlation with high sensitive CRP. Seventy-six Parkinson's disease patients were enrolled in this Cross-sectional observational study that was attended in the Department of Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from September 2014 to March 2016. Analysis of the symptoms of Parkinson disease and it's correlation with high sensitive CRP were done among these patients. This study was performed on 76 Parkinson disease patients with presented early with symptoms. a positive and highly significant correlation were seen in between duration of tremor and High sensitivity CRP (r=0.430, p<0.001) and between duration of bradykinesia and High sensitivity CRP (r=0.426, p<0.001) which indicate increase duration causes increase level of high-sensitivity C-reactive protein value. The neuro-inflammation plays a significant role in the pathogenesis of symptoms development in early Parkinson's disease.

Guinea fowl eggshell structural analysis at different scales reveals how organic matrix induces microstructural shifts that enhance its mechanical properties.

Guinea fowl eggshells have an unusual structural arrangement that is different from that of most birds, consisting of two distinct layers with different microstructures. This bilayered organization, and distinct microstructural characteristics, provides it with exceptional mechanical properties. The inner layer, constituting about one third of the eggshell thickness, contains columnar calcite crystal units arranged vertically as in most bird shells. However, the thicker outer layer has a more complex microstructural arrangement formed by a switch to smaller calcite domains with diffuse/interlocking boundaries, partly resembling the interfaces seen in mollusk shell nacre. The switching process that leads to this remarkable second-layer microstructure is unknown. Our results indicate that the microstructural switching is triggered by changes in the inter- and intracrystalline organic matrix. During production of the outer microcrystalline layer in the later stages of eggshell formation, the interactions of organic matter with mineral induce an accumulation of defects that increase crystal mosaicity, instill anisotropic lattice distortions in the calcite structure, interrupt epitaxial growth, reduce crystallite size, and induce nucleation events which increase crystal misorientation. These structural changes, together with the transition between the layers and each layer having different microstructures, enhance the overall mechanical strength of the Guinea fowl eggshell. Additionally, our findings provide new insights into how biogenic calcite growth may be regulated to impart unique functional properties. STATEMENT OF SIGNIFICANCE: Avian eggshells are mineralized to protect the embryo and to provide calcium for embryonic chick skeletal development. Their thickness, structure and mechanical properties have evolved to resist external forces throughout brooding, yet ultimately allow them to crack open during chick hatching. One particular eggshell, that of the Guinea fowl, has structural features very different from other galliform birds - it is bilayered, with an inner columnar mineral structure (like in most birds), but it also has an outer layer with a complex microstructure which contributes to its superior mechanical properties. This work provides novel and new fundamental information about the processes and mechanisms that control and change crystal growth during the switch to microcrystalline domains when the second outer layer forms.

GBA1-and LRRK2-directed Treatments: The Way Forward.

There is an urgent need to identify drug targets for disease modification in Parkinson's Disease (PD). In this mini-review we highlight the reasons genetically-defined drug targets show great promise. Specifically, clinical trials targeting the glucocerebrosidase-1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes are underway. Two key knowledge gaps are 1. How should we modify the GBA1 and LRRK2 pathways? and 2. Which patient populations are most likely to benefit? The exact mechanisms by which mutations in these genes cause PD are not fully understood. Most drugs targeting the GBA1 pathway in clinical trials aim at increasing glucocerebrosidase enzymatic (GCase) activity and targeting the LRRK2 pathway, at reducing its kinase activity. Carriers of mutations in these genes are natural candidates for such interventions; however, there are some biomarker data, specifically for GBA1, to support studying such interventions in non-carriers, i.e., sporadic PD. In summary, we anticipate significant progress in our path towards precision medicine in PD in the coming years.

PINK1 is a target of T cell responses in Parkinson's disease.

Parkinson's disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Distinctive CD56dim NK subset profiles and increased NKG2D expression in blood NK cells of Parkinson's disease patients.

Mounting data suggest an important role for the immune system in Parkinson's disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

Effect of Feeding a Calcium Chloride Supplement on Sow Stillbirth Rate.

The present study was undertaken to determine the effect of daily calcium chloride (CaCl2) supplementation from day of entry into the farrowing house until day of farrowing (6.4 ± 0.3 d) on stillbirth rates. Landrace × Large White sows (parities 4 to 6; n = 53) were offered 40 g/d CaCl2 (n = 28) or served as controls (n = 25). The morning before their estimated farrowing date, a blood sample was obtained from 25 sows for calcium measurement and a urine sample from 22 sows for pH measurement. The feeding of CaCl2 decreased urinary pH compared to the control group (p < 0.001), indicative of an induced metabolic acidosis, but there was no effect of feeding CaCl2 on serum calcium concentrations or the incidence of stillbirths. Nonetheless, regardless of treatment, sows with higher serum calcium concentrations (>2.5 vs. <2.5 mmol) or lower urine pH (<7.0 vs. >7.0) had fewer stillborn piglets (p < 0.001 for both). While showing that low serum calcium levels will increase stillbirth rates, our data indicate that the administration of 40 g/d CaCl2 for 6 d prior to farrowing was not sufficient to increase serum calcium or decrease stillbirth incidence.

A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Factors affecting birth weight and stillbirth in sows housed in a tropical environment.

This study analysed data from a commercial swine herd in Thailand equipped with a free-farrowing housing system, comprising 17,196 piglets from 1318 litters, to explore the impact of sow and litter characteristics on the piglet birth weight and the incidence of stillbirth. The piglets were classified into four groups based on the total number of piglets born per litter (TB): ≤9 (n = 1434), 10-12 (n = 3232), 13-15 (n = 6537) and ≥16 (n = 5993). Sows were classified into four groups based on parity number: 1, 2-4, 5-7 and ≥8. The piglets were categorized into quartiles based on their birth order ranking: Q1 (n = 4786), Q2 (n = 4143), Q3 (n = 3808) and Q4 (n = 4456). Piglet birth weight was individually measured before colostrum ingestion. On average, TB, the number of live-born piglets and the incidence of stillbirth were 13.1 ± 3.7, 11.5 ± 3.8 and 6.3%, respectively. Among these litters, 26.6% had TB numbers ≥16. The average piglet birth weight was 1.37 ± 0.36 kg, with 18.3% of piglets weighing ≤1.0 kg at birth. Piglet birth weight was influenced by birth order ranking, as Q4 piglets were found to be heavier than piglets born in Q1-Q3 (p < .001). Moreover, the percentage of piglets with a birth weight of ≤1.0 kg increased from 5.9% in litters with TB of ≤9-25.3% in litters with TB of ≥16 (p < .001). Additionally, primiparous sows had lower piglet birth weights compared to sows with parity numbers 2-4, 5-7 and ≥8 (p < .001). Piglets born in the fourth quartile (Q4) had a higher risk of stillbirth compared to those born in the first (Q1), second (Q2) and third (Q3) quartiles (12.5% vs. 2.2%, 4.1% and 6.6%, respectively, p < .001). The incidence of stillbirth in litters with TB ≥16 was also higher than that in litters with TB ≤9 and 10-12 (p < .05). Furthermore, sows with parity numbers ≥8 had a higher incidence of stillbirth (9.7%) compared to primiparous sows (4.0%, p < .001), sows with 2-4 parity (5.2%, p < .001) and sows with 5-7 parity (7.6%, p = .003). In summary, a high incidence of stillbirth was found in piglets born in the last quartile of litters, in litters with >16 piglets and for sows with parity numbers ≥8. Piglets born in the last quartile of litters were heavier than those born in the first to third quartiles.

The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Associations between Surface and Rectal Temperature Profiles of Low-Birth-Weight Piglets.

The use of infrared cameras to record surface temperature has shown some promise in older pigs, but neonatal piglets are metabolically less mature and experience rapid temperature changes during their first 24 h. The present experiment aimed to compare rectal temperature to surface temperature at the base of the ear, measured using an infrared camera, for piglets of different birth weights. During farrowing, 48 multiparous sows were monitored, and rectal and surface temperatures were recorded for their lower-birth-weight (≤1.2 kg) piglets within 3 min of birth and at 0.25, 0.50, 0.75, 1, 1.25, 1.50, 2, 3, 4, and 24 h. Piglet birth weights were assigned to one of three categories (BWC): BWC1 (≤0.80 kg), BWC2 (0.81 to 1.10 kg), or BWC3 (1.11 to 1.20 kg). Piglet rectal temperatures at 1.25 h after birth were assigned to one of three categories: RC1 (≤32.0 °C), RC2 (32.1 to 35.0 °C), or RC3 (≥35.1 °C). Surface temperatures showed a similar recovery pattern to rectal temperatures in the first 24 h across all piglet birth weights, although large and variable differences seen in the current study militate against surface temperature being an appropriate replacement for neonatal rectal temperature for use in production.

Myasthenia gravis patients exhibiting an eyelid myotonia-like phenomenon.

We report here a retrospective case series of 3 MG patients suffering from difficulty opening eyes that appeared together with a diagnosis of MG. All are male patients with late-onset MG who are seropositive for anti-acetylcholine receptor antibodies. The phenomenon was characterized by difficulty opening the eyes after forced closure or reflex eye closure, improving with the ice pack test and with repeated forced eye closure but worsening with pyridostigmine treatment. We provide a detailed clinical, serological, imaging and electrophysiological examination of these patients. Electromyography evaluation did not show spontaneous muscle activity or myotonia at rest in the orbital part of the orbicularis oculi muscle. However, there was sustained muscle activity lasting several seconds in the pre-tarsal and pre-septal parts of this muscle. Videos of those reported symptoms were produced and provided. We discuss the possible neurological pathophysiology of this disorder and suggest to name this rare ocular disorder "myotonia-like disorder of the pre-tarsal and pre-septal parts of the orbicularis oculi". This study expands our knowledge of this rare clinical feature of MG and highlights the need for increased awareness of it and further investigation of this ocular manifestation.

Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.