Abstract
Background
The genetic, clinical and anatomical presentation of Alzheimer's disease (AD) is extremely heterogenous. Although increasing evidences show that alterations in the gut microbiota ...(GMB) composition are involved in AD, their contribution to AD pathology remain unclear. The aim of this study is to evaluate whether disease‐specific alterations of the microbiome are present in patients with AD pathology and can identify individuals with peculiar clinical features.
Method
Sixty‐two cognitive impaired subjects underwent Florbetapir amyloid PET and stool collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum (SUVRs) in the frontal, parietal, temporal, anterior cingulate, posterior cingulate and precuneus regions of interest. Amyloid positivity was defined as global PET florbetapir SUVR>1.11. Bacterial composition of fecal samples was inferred using 16S metagenomic sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology,
https://qiime2.org/
). We first compared amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific profiles. We then applied Principal Component Analysis (PCA) on those taxa found differentially abundant in Amy+ and Amy‐.
Result
Despite a similar GMB structure (Unweighted and weighted Unifrac, p>0,05) of Amy+ (n=29) and Amy‐ (n=33), taxonomic comparison showed that Amy+ were mainly characterized by rare genera. PCA identified a small subgroup of 6 Amy+ with lower amyloid SUVR uptake in the temporal cortex (p=0,009) and lower cognitive deficits, as showed by better performance at MMSE, ADAScog, logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (p<0.044) compared to the other Amy+ patients. Amyloid SUVR uptake in the temporal cortex was negatively associated with logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (moderate: rho£0.44, p£0.047) and MMSE (weak: rho=0.36, p=0.076) as well as negatively associated with FAQ (moderate: rho=0.47, p=0.010) in the whole Amy+ group.
Conclusion
Despite the small sample size, this study suggests that distinctive bacterial signatures might be associated with specific clinical AD phenotypes.
Abstract
Background
Increasing evidence shows that the gut microbiota (GMB) may be involved in the pathogenesis of several brain disorders. Metagenomic data support an association between certain ...bacterial genera and Alzheimer’s Disease (AD), but the functional dynamics of the gut microbiota remains elusive. This study aimed at evaluating whether inflammatory mediators and bacterial products represent a potential pathogenic link between specific gut bacteria and amyloid pathology in AD.
Method
Seventy‐two older persons with cognitive performance from normal to dementia with brain amyloid status were recruited and stool and blood samples were collected. Bacterial composition of fecal samples was inferred using 16S sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). Blood lipopolysaccharide (LPS), short chain fatty acids (SCFAs) acetate, propionate, valerate and butyrate by gas chromatography with flame ionization detector (GC‐FID) and circulating adhesion molecules by flow cytometry bead‐based immunoassay panel. We compared HC, amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific variables and endothelial biomarkers.
Result
Metagenomic differences were mainly related to the HC rather than Amy+ or Amy‐. Despite a similar GMB, Amy+ and Amy‐ reported differences in the levels of several blood GMB‐related products: Amy+ had increased valerate (p<.001 vs both HC and Amy‐) and LPS (p=.011 vs Amy‐; p=.031 vs HC) levels while Amy‐ decreased acetate (p<.001 vs Amy+; p=.003 vs HC) and increased butyrate (p<.001 vs Amy+; p=.002 vs HC) levels. Endothelial dysfunction, as indicated by the upregulation of adhesion molecules (NCAM, PECAM‐1, ICAM‐2, PSGL‐1), was observed in Amy+ only (p<.030 vs Amy‐; p<.010 vs HC). High levels of these adhesion molecules were associated with elevated levels of acetate and valerate and low levels of butyrate (0.26<|rho|<0.51, p<.024).
Conclusion
The mechanisms linking GMB dysbiosis and cognitive impairment in the presence or absence of brain amyloid deposition are different. Reduction of butyrate together with increased acetate, valerate and LPS levels may compromise the tissue‐blood barrier integrity, facilitating the AD pathological cascade. Microbiota functional dynamics, more than its composition, may be a potential biomarker of AD and provide new leads for treatments aimed at preventing or delaying neurodegeneration.
Background
Increasing evidence shows that the gut microbiota (GMB) may be involved in the pathogenesis of several brain disorders. Metagenomic data support an association between certain bacterial ...genera and Alzheimer’s Disease (AD), but the functional dynamics of the gut microbiota remains elusive. This study aimed at evaluating whether inflammatory mediators and bacterial products represent a potential pathogenic link between specific gut bacteria and amyloid pathology in AD.
Method
Seventy‐two older persons with cognitive performance from normal to dementia with brain amyloid status were recruited and stool and blood samples were collected. Bacterial composition of fecal samples was inferred using 16S sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). Blood lipopolysaccharide (LPS), short chain fatty acids (SCFAs) acetate, propionate, valerate and butyrate by gas chromatography with flame ionization detector (GC‐FID) and circulating adhesion molecules by flow cytometry bead‐based immunoassay panel. We compared HC, amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific variables and endothelial biomarkers.
Result
Metagenomic differences were mainly related to the HC rather than Amy+ or Amy‐. Despite a similar GMB, Amy+ and Amy‐ reported differences in the levels of several blood GMB‐related products: Amy+ had increased valerate (p<.001 vs both HC and Amy‐) and LPS (p=.011 vs Amy‐; p=.031 vs HC) levels while Amy‐ decreased acetate (p<.001 vs Amy+; p=.003 vs HC) and increased butyrate (p<.001 vs Amy+; p=.002 vs HC) levels. Endothelial dysfunction, as indicated by the upregulation of adhesion molecules (NCAM, PECAM‐1, ICAM‐2, PSGL‐1), was observed in Amy+ only (p<.030 vs Amy‐; p<.010 vs HC). High levels of these adhesion molecules were associated with elevated levels of acetate and valerate and low levels of butyrate (0.26<|rho|<0.51, p<.024).
Conclusion
The mechanisms linking GMB dysbiosis and cognitive impairment in the presence or absence of brain amyloid deposition are different. Reduction of butyrate together with increased acetate, valerate and LPS levels may compromise the tissue‐blood barrier integrity, facilitating the AD pathological cascade. Microbiota functional dynamics, more than its composition, may be a potential biomarker of AD and provide new leads for treatments aimed at preventing or delaying neurodegeneration.
Background
The genetic, clinical and anatomical presentation of Alzheimer's disease (AD) is extremely heterogenous. Although increasing evidences show that alterations in the gut microbiota (GMB) ...composition are involved in AD, their contribution to AD pathology remain unclear. The aim of this study is to evaluate whether disease‐specific alterations of the microbiome are present in patients with AD pathology and can identify individuals with peculiar clinical features.
Method
Sixty‐two cognitive impaired subjects underwent Florbetapir amyloid PET and stool collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum (SUVRs) in the frontal, parietal, temporal, anterior cingulate, posterior cingulate and precuneus regions of interest. Amyloid positivity was defined as global PET florbetapir SUVR>1.11. Bacterial composition of fecal samples was inferred using 16S metagenomic sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). We first compared amyloid negative (Amy‐) and positive (Amy+) patients with respect to GMB‐specific profiles. We then applied Principal Component Analysis (PCA) on those taxa found differentially abundant in Amy+ and Amy‐.
Result
Despite a similar GMB structure (Unweighted and weighted Unifrac, p>0,05) of Amy+ (n=29) and Amy‐ (n=33), taxonomic comparison showed that Amy+ were mainly characterized by rare genera. PCA identified a small subgroup of 6 Amy+ with lower amyloid SUVR uptake in the temporal cortex (p=0,009) and lower cognitive deficits, as showed by better performance at MMSE, ADAScog, logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (p<0.044) compared to the other Amy+ patients. Amyloid SUVR uptake in the temporal cortex was negatively associated with logical memory, Rey auditory verbal learning test, Raven’s progressive matrices test and Functional Activities Questionnaire (moderate: rho£0.44, p£0.047) and MMSE (weak: rho=0.36, p=0.076) as well as negatively associated with FAQ (moderate: rho=0.47, p=0.010) in the whole Amy+ group.
Conclusion
Despite the small sample size, this study suggests that distinctive bacterial signatures might be associated with specific clinical AD phenotypes.
Background
Microbiota‐derived short chain fatty acids (SCFA) and liposaccharide (LPS) could modulate astrocyte and neuronal activity. Glial fibrillary acidic protein (GFAP) and neurofilament light ...(NfL) are markers of astroglial activation and neuronal damage, can be measured in blood samples and have been associated with Alzheimer’s disease (AD) pathology. The aim of the present study was to assess the association of SCFAs and LPS with GFAP and NfL in 13 amyloid‐β‐negative cognitively unimpaired individuals (CU), 38 patients with cognitive impairment and no brain amyloidosis (CI‐NAD) and 34 patients with cognitive impairment and amyloid‐β positivity (CI‐AD).
Method
Blood levels of 4 SCFAs (acetate, propionate, valerate and butyrate) were measured by GC‐FID gaschromatography, LPS by ELISA, and GFAP and NfL by single‐molecule array technology.
Result
Plasma valerate, LPS and GFAP concentrations were increased in CI‐AD compared with CI‐NAD and CU (p<0.034), acetate was increased in CI‐AD as well as decreased in CI‐NAD as compared with CU (p<0.018) and NfL was increased in both CI groups (p<0.023). In the pooled group of CI‐AD and CU, there were significant associations between plasma LPS and valerate with higher GFAP and NfL (p<0.032). Conversely, in the pooled group of CI‐NAD and CU, there were associations between plasma acetate with lower level of GFAP and NfL (p<0.026).
Conclusion
Valerate and LPS were associated with astrogliosis and neuronal damage only in patients with AD. These results suggest that microbiota‐derived molecules might be mediators along the gut‐brain axis and contribute to AD pathology by modulating microglial and neuronal activity.
Background
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of beta‐amyloid (Aβ42) and phosphorylated tau (P‐tau) deposits in the brain, neurodegeneration in ...specific brain regions, and inflammation. This study aimed at investigating the association of periferal inflammatory signaling with brain structural alterations in MCI patients with or without AD pathology.
Method
Study population: 89 consecutive enrolled amnestic MCI patients. AD pathology definition: based on baseline CSF Aβ42/P‐tau level as well as APOE genotype (positivity defined as Aβ42/P‐tau ratio<7.8 for APOE4 non‐carriers, <15.2 for carriers). MRI processing: volumes of the hippocampus and its subfields were extracted with Freesurfer (version 7). Cytokine expression: pro‐ (IL6, IL8, IL1beta, TNF‐alpha, NLRP3) and anti‐ (IL10) inflammatory molecules were measured by Real Time PCR Assay. Subjects provided written informed consent, validated by the local ethics commitee
Result
As expected, MCI patients with AD pathology had lower volume in the presubiculum (p=.007), subiculum (p=.030) and CA1 (p=.028) than negative patients. Moreover, positive patients showed lower expression of IL‐10 (p=.033) as well as higher expression of NLRP3 (p=.050) and IL‐8 (p=.037). Correlation analyses in all MCI patients revealed a negative association between IL10 levels and ADAScog13 (r=‐0.27, p=0.01) and P‐tau (r=‐0.22, p=0.04), and a positive association with CSF Aβ42 (r=0.22, p=0.037), hippocampal volume (r=0.23, p=0.03), temporal lobe (r=0.38, p=0.0004) and precuneus thicknesses (r=0.37 p=0.0006), consistent with a protective effect of IL10 in AD pathology. More analysis are ongoing on the effect of cytokines on different rates of atrophy of brain subfields.
Conclusion
Higher expression of anti‐inflammatory factors are associated to a lower hippocampal neurodegeneration and better clinical and pathophysiological outcome in prodromal AD patients. These preliminary results suggest that non‐invasive peripheral inflammatory biomarkers could represent possible biomarkers to support the early diagnosis of AD.
Background
The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers’ physical and mental health. According to the recent literature, there is a ...need for studies testing the implementation of affordable and accessible interventions for improving caregivers’ well-being.
Aims
This study aimed to explore the feasibility and effectiveness of an 8 week eHealth psychoeducation intervention held during the COVID-19 pandemic in Italy in reducing the psychological burden and neuroendocrine markers of stress in caregivers of PwD.
Methods
Forty-one informal caregivers of PwD completed the eHealth psychoeducation intervention. Self-reported (i.e., caregiver burden, anxiety symptoms, depressive symptoms, and caregiver self-efficacy) and cortisol measurements were collected before and after the intervention.
Results
Following the intervention, the caregivers’ self-efficacy regarding the ability to respond to disruptive behaviours improved (
t
= − 2.817,
p
= 0.007), anxiety and burden levels decreased (state anxiety:
t
= 3.170,
p
= 0.003; trait anxiety:
t
= 2.327,
p
= 0.025; caregiver burden:
t
= 2.290,
p
= 0.027), while depressive symptoms and cortisol levels did not change significantly. Correlation analyses showed that the increase in self-efficacy was positively associated with the improvement of caregiver burden from pre- to post-intervention (
r
= 0.386,
p
= 0.014). The intervention had a low rate of dropout (
n
= 1, due to the patient’s death) and high levels of appreciation.
Discussion
The positive evidence and participation rate support the feasibility and effectiveness of the proposed eHealth psychoeducational intervention to meet the need for knowledge of disease management and possibly reduce detrimental effects on caregivers’ psychological well-being.
Conclusion
Further placebo-controlled trials are needed to test the generalizability and specificity of our results.
Are posterior resting-state electroencephalographic (rsEEG) alpha rhythms sensitive to the Alzheimer’s disease mild cognitive impairment (ADMCI) progression at a 6-month follow-up? Clinical, ...cerebrospinal, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy old seniors (equivalent groups for demographic features) were available from an international archive (www.pdwaves.eu). The ADMCI patients were arbitrarily divided into two groups: REACTIVE and UNREACTIVE, based on the reduction (reactivity) in the posterior rsEEG alpha eLORETA source activities from the eyes-closed to eyes-open condition at ≥ −10% and −10%, respectively. 75% of the ADMCI patients were REACTIVE. Compared to the UNREACTIVE group, the REACTIVE group showed (1) less abnormal posterior rsEEG source activity during the eyes-closed condition and (2) a decrease in that activity at the 6-month follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. Such a biomarker might reflect abnormalities in cortical arousal in quiet wakefulness to be used for clinical studies in ADMCI patients using 6-month follow-ups.
•Low EEG alpha rhythms in Alzheimer’s disease mild cognitive impairment patients.•EEG alpha rhythms decreased (reacted) to eye-opening in 70% of them.•EEG alpha rhythms decreased in those “reactive” patients at 6-month follow-up.
Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be ...reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness.
•In Parkinson's disease patients, resting-state delta and alpha electroencephalographic source activities were abnormal.•Those abnormalities were differently related to cognitive, motor, and perceptual deficits.•Those source activities may reflect the effect of Parkinson's disease on cognitive, motor, and perceptual systems.
PDF
