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Background

Alzheimer's disease co‐pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives.

Objective

To investigate if plasma phospho‐tau217 and phospho‐tau181 can detect Alzheimer's pathology in Lewy body disease with dementia.

Methods

In this cross‐sectional study we investigated plasma phospho‐tau217 and phospho‐tau181 in 35 patients with Lewy body disease with dementia. Patients underwent tau‐PET imaging (¹⁸F‐RO948).

Results

Plasma phospho‐tau217 correlated with plasma phospho‐tau181, CSF phospho‐tau217 (r_s = 0.68, P < 0.001), and negatively with CSF β‐amyloid_42/40 (r_s = −0.52, P = 0.001). Plasma phospho‐tau217 and phospho‐tau181 correlated with tau‐PET signal in the temporal cortex (r_s > 0.56, P < 0.001) and predicted abnormal tau‐PET status and β‐amyloid status (area under the curve > 0.78 and > 0.81, respectively).

Conclusion

Plasma phospho‐tau might be a useful marker for Alzheimer's co‐pathology in Lewy body disease with dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Background

Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.

Methods

We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age‐matched controls. We measured microglial activation as ¹¹C‐(R)‐PK11195 binding potentials, and dopamine terminal integrity with ¹⁸F‐dopa influx constants.

Results

The ¹¹C‐(R)‐PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = −4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased ¹¹C‐(R)‐PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral ¹¹C‐(R)‐PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal ¹⁸F‐dopa uptake was similar to healthy controls.

Conclusions

In vivo ¹¹C‐(R)‐PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

]]> https://www.novareader.co/book/isbn/10.1002/mds.28281

Background

Manual region‐of‐interest analysis of putaminal and middle cerebellar peduncle diffusivity distinguishes patients with multiple system atrophy (MSA) and Parkinson's disease (PD) with high diagnostic accuracy. However, a recent meta‐analysis found substantial between‐study heterogeneity of diagnostic accuracy due to the lack of harmonized imaging protocols and standardized analyses pipelines.

Objective

Evaluation of diagnostic accuracy of observer‐independent analysis of microstructural integrity as measured by diffusion‐tensor imaging in patients with MSA and PD.

Methods

A total of 29 patients with MSA and 19 patients with PD (matched for age, gender, and disease duration) with 3 years of follow‐up were investigated with diffusion‐tensor imaging and T1‐weighted magnetic resonance imaging. Automated localization of relevant brain regions was obtained, and mean diffusivity and fractional anisotropy values were averaged within the regions of interest. The classification was performed using a C5.0 hierachical decision tree algorithm.

Results

Mean diffusivity of the middle cerebellar peduncle and cerebellar gray and white matter compartment as well as the putamen were significantly increased in patients with MSA and showed superior effect sizes compared to the volumetric analysis of these regions. A classifier model identified mean diffusivity of the middle cerebellar peduncle and putamen as the most predictive parameters. Cross‐validation of the classification model yields a Cohen's κ and overall diagnostic accuracy of 0.823 and 0.914, respectively.

Conclusion

Analysis of microstructural integrity within the middle cerebellar peduncle and putamen yielded a superior effect size compared to the volumetric measures, resulting in excellent diagnostic accuracy to discriminate patients with MSA from PD in the early to moderate disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

]]> https://www.novareader.co/book/isbn/10.1002/mds.28260

Background

Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha‐synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [¹⁸F]fluorodeoxyglucose‐positron emission tomography (PET)–based PD‐related brain pattern can be used to monitor disease progression.

Objective

We longitudinally investigated PD‐related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters.

Methods

Subjects underwent two [¹⁸F]fluorodeoxyglucose‐PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame.

Results

At baseline, 8 of 20 (40%) subjects significantly expressed the PD‐related brain pattern (with z scores above the receiver operating characteristic–determined threshold). At follow‐up, six additional subjects exhibited significant PD‐related brain pattern expression (70% in total). PD‐related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD‐related brain pattern expression, phenoconverted to clinical PD.

Conclusions

Suprathreshold PD‐related brain pattern expression and greater score rate of change may signify greater shorter‐term risk for phenoconversion. Our results support the use of serial PD‐related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

]]> https://www.novareader.co/book/isbn/10.1002/mds.28314

Background

The Mediterranean diet has been proposed to protect against neurodegeneration.

Objectives

The aim of this study was to assess the association of adherence to Mediterranean dietary pattern (MDP) at middle age with risk for Parkinson's disease (PD) later in life.

Method

In a population‐based cohort of >47,000 Swedish women, information on diet was collected through a food frequency questionnaire during 1991–1992, from which adherence to MDP was calculated. We also collected detailed information on potential confounders. Clinical diagnosis of PD was ascertained from the Swedish National Patient Register through 2012.

Results

We observed an inverse association between adherence to MDP and PD, multivariable hazard ratio of 0.54 (95% confidence interval: 0.30–0.98), comparing high with low adherence. The association was noted primarily from age 65 years onward. One unit increase in the adherence score was associated with a 29% lower risk for PD at age ≥ 65 years (95% confidence interval: 0.57–0.89).

Conclusion

Higher adherence to a Mediterranean diet at middle age was associated with lower risk for PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2021.1874740 Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells’ permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2021.1874740 Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells’ permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.

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Background

Multiple system atrophy (MSA) and Parkinson's disease (PD) patients develop respiratory and cardiovascular disturbances including obstructive sleep apnea, orthostatic hypotension, and nocturnal stridor. We hypothesized that, associated with these respiratory and cardiovascular disturbances, hypoxic events may occur in MSA and PD brains that may play a role in disease progression. The objective of this study was to evaluate the presence of hypoxia in nonneurological controls and PD and MSA patients.

Methods

Molecular levels of hypoxia markers were measured in postmortem brain tissue from controls and PD and MSA cases.

Results

MSA brain showed signs of chronic hypoxia characterized by the significant accumulation of the hypoxic marker HIF2α as compared to PD patients and controls. We detected no differences between MSA subtypes. Signs of hypoxia were also observed in PD patients with a clinical presentation similar to the MSA cases.

Conclusions

The results obtained from this study suggest a new alternative pathway associated with α‐synucleinopathies that may contribute to the pathogenesis of these disorders. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1869505 Current metagenomic species-based colorectal cancer (CRC) microbial biomarkers may confuse diagnosis because the genetic content of different microbial strains, even those belonging to the same species, may differ from 5% to 30%. Here, a total of 7549 non-redundant single nucleotide variants (SNVs) were annotated in 25 species from 3 CRC cohorts (n = 249). Then, 22 microbial SNV markers that contributed to distinguishing subjects with CRC from healthy subjects were identified by the random forest algorithm to construct a novel CRC predictive model. Excitingly, the predictive model showed high accuracy both in the training (AUC = 75.35%) and validation cohorts (AUC = 73.08%-88.02%). We further explored the specificity of these SNV markers in a broader background by performing a meta-analysis across 4 metabolic disease cohorts. Among these SNV markers, 3 SNVs that were enriched in CRC patients and located in the genomes of Eubacterium rectale and Faecalibacterium prausnitzii were CRC specific (AUC = 72.51%-94.07%).

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1869505 Current metagenomic species-based colorectal cancer (CRC) microbial biomarkers may confuse diagnosis because the genetic content of different microbial strains, even those belonging to the same species, may differ from 5% to 30%. Here, a total of 7549 non-redundant single nucleotide variants (SNVs) were annotated in 25 species from 3 CRC cohorts (n = 249). Then, 22 microbial SNV markers that contributed to distinguishing subjects with CRC from healthy subjects were identified by the random forest algorithm to construct a novel CRC predictive model. Excitingly, the predictive model showed high accuracy both in the training (AUC = 75.35%) and validation cohorts (AUC = 73.08%-88.02%). We further explored the specificity of these SNV markers in a broader background by performing a meta-analysis across 4 metabolic disease cohorts. Among these SNV markers, 3 SNVs that were enriched in CRC patients and located in the genomes of Eubacterium rectale and Faecalibacterium prausnitzii were CRC specific (AUC = 72.51%-94.07%).

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1866974 Parkinson’s disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms’ including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1866974 Parkinson’s disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms’ including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1862027 Secretory immunoglobulin A (IgA) interacts with intestinal microbiota and promotes mucosal homeostasis. IgA-bacteria interactions are altered during inflammatory diseases, but how these interactions are shaped by bacterial, host, and environmental factors remains unclear. In this study, we utilized IgA-SEQ to profile IgA-bound fecal bacteria in 48 recurrent Clostridioides difficile patients before and after successful fecal microbiota transplantation (FMT) to gain further insight. Prior to FMT, Escherichia coli was the most highly IgA-targeted taxon; following restoration of the microbiota by FMT, highly IgA-targeted taxa included multiple Firmicutes species. Post-FMT IgA-targeting was unaffected by the route of FMT delivery (colonoscopy versus capsule), suggesting that both methods lead to the establishment of healthy immune–bacterial interactions in the gut. Interestingly, IgA-targeting in FMT recipients closely resembled the IgA-targeting patterns of the donors, and fecal donor identity was significantly associated with IgA-targeting of the recipient microbiota. These data support the concept that intrinsic bacterial properties drive IgA recognition across genetically distinct human hosts. Together, this study suggests that IgA-bacterial interactions are reestablished in human FMT recipients to resemble that of the healthy fecal donor.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1862027 Secretory immunoglobulin A (IgA) interacts with intestinal microbiota and promotes mucosal homeostasis. IgA-bacteria interactions are altered during inflammatory diseases, but how these interactions are shaped by bacterial, host, and environmental factors remains unclear. In this study, we utilized IgA-SEQ to profile IgA-bound fecal bacteria in 48 recurrent Clostridioides difficile patients before and after successful fecal microbiota transplantation (FMT) to gain further insight. Prior to FMT, Escherichia coli was the most highly IgA-targeted taxon; following restoration of the microbiota by FMT, highly IgA-targeted taxa included multiple Firmicutes species. Post-FMT IgA-targeting was unaffected by the route of FMT delivery (colonoscopy versus capsule), suggesting that both methods lead to the establishment of healthy immune–bacterial interactions in the gut. Interestingly, IgA-targeting in FMT recipients closely resembled the IgA-targeting patterns of the donors, and fecal donor identity was significantly associated with IgA-targeting of the recipient microbiota. These data support the concept that intrinsic bacterial properties drive IgA recognition across genetically distinct human hosts. Together, this study suggests that IgA-bacterial interactions are reestablished in human FMT recipients to resemble that of the healthy fecal donor.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1857514 Campylobacter jejuni is among the leading causes of bacterial foodborne illness. Poultry is the major reservoir and source of human campylobacteriosis. Currently, there is no effective and practical method to decrease C. jejuni colonization in chickens or to reduce human infections. Additionally, antibiotic-resistant infections pose a serious public health concern; therefore, antibiotic-alternative approaches are needed to reduce transmission of C. jejuni including resistant bacteria from chickens to humans. Here, we evaluated the effect of E. coli Nissle 1917 (EcN) on innate responses of polarized HT-29 cells and consequently on C. jejuni 81176 infections in HT-29 cells. Pre-treatment of HT-29 cells with EcN for 4 h had a significant effect on the invasion of different C. jejuni strains (2 h post-infection) (P < .05) and no intracellular C. jejuni (24 h post-infection) were recovered. To further understand how EcN mediates its impact on C. jejuni’s survival inside the cells, we used Human Antibacterial RT² Profiler^TM PCR arrays to profile gene expression in HT-29 cells after treatment with EcN with or without C. jejuni 81–176 infection. Our results suggest that pre-treatment of the HT-29 cells with EcN induced the anti-inflammatory cytokines and activated the anti-apoptotic Akt signaling which likely to protect the cells against the proinflammatory and apoptosis responses induced by C. jejuni. EcN also positively affected the expression of genes involved in cellular maintenance, growth, development, and proliferation. Further, EcN modulated the expression of genes involved in protective innate immunity, such as TLRs, ERK1/2, p38 MAPK, Ap1, JNK, IL1B, IL17A, and NF-κB signaling.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1857514 Campylobacter jejuni is among the leading causes of bacterial foodborne illness. Poultry is the major reservoir and source of human campylobacteriosis. Currently, there is no effective and practical method to decrease C. jejuni colonization in chickens or to reduce human infections. Additionally, antibiotic-resistant infections pose a serious public health concern; therefore, antibiotic-alternative approaches are needed to reduce transmission of C. jejuni including resistant bacteria from chickens to humans. Here, we evaluated the effect of E. coli Nissle 1917 (EcN) on innate responses of polarized HT-29 cells and consequently on C. jejuni 81176 infections in HT-29 cells. Pre-treatment of HT-29 cells with EcN for 4 h had a significant effect on the invasion of different C. jejuni strains (2 h post-infection) (P < .05) and no intracellular C. jejuni (24 h post-infection) were recovered. To further understand how EcN mediates its impact on C. jejuni’s survival inside the cells, we used Human Antibacterial RT² Profiler^TM PCR arrays to profile gene expression in HT-29 cells after treatment with EcN with or without C. jejuni 81–176 infection. Our results suggest that pre-treatment of the HT-29 cells with EcN induced the anti-inflammatory cytokines and activated the anti-apoptotic Akt signaling which likely to protect the cells against the proinflammatory and apoptosis responses induced by C. jejuni. EcN also positively affected the expression of genes involved in cellular maintenance, growth, development, and proliferation. Further, EcN modulated the expression of genes involved in protective innate immunity, such as TLRs, ERK1/2, p38 MAPK, Ap1, JNK, IL1B, IL17A, and NF-κB signaling.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1862613 Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations.

]]> https://www.novareader.co/book/isbn/10.1080/19490976.2020.1862613 Infection with Helicobacter pylori is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized H. pylori proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed H. pylori virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. In vitro, depletion of Hp0305 and Hp1564 significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of H. pylori to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that Hp1564 is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel H. pylori pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment H. pylori-mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused H. pylori eradication strategies to prevent development of gastric malignancies in high-risk populations.

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