Neurodegenerative disorders and gut-brain interactions

Hou Y., Li X., Liu C., Zhang M., Zhang X., Ge S., Zhao L.

Gut microbial metabolites, SCFAs, were related with the occurrence and development of Parkinson's disease (PD). But the effects of different short-chain fatty acids (SCFAs) on PD and involving mechanisms are still undefined. In this study we evaluate the effects of three dominant SCFAs (acetate, propionate and butyrate) on motor damage, dopaminergic neuronal degeneration and underlying neuroinflammation related mechanisms in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. High (2.0 g/kg) or low doses (0.2 g/kg) of sodium acetate (NaA), sodium propionate (NaP) or sodium butyrate (NaB) were gavaged into PD mice for 6 weeks. High doses of NaA reduced the turning time of PD mice. NaB significantly reduced the turning and total time in pole test, and increased the average velocity in open field test when compared with PD mice, indicating the most effective alleviation of PD-induced motor disorder. Low and high doses of NaB significantly increased the content of tyrosine hydroxylase (TH) by 12.3% and 20.2%, while reduced α-synuclein activation by 159.4% and 132.7% in the substantia nigra pars compacta (SNpc), compared with PD groups. Butyrate reached into the midbrain SNpc and suppressed microglia over-activation. It inhibited the levels of pro-inflammatory factors (IL-6, IL-1β and TNF-α) (P

Colombo A.V., Sadler R.K., Llovera G., Singh V., Roth S., Heindl S., Sebastian Monasor L., Verhoeven A., Peters F., Parhizkar S., Kamp F., Gomez de Aguero M., MacPherson A.J., Winkler E., Herms J., et. al.

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer’s disease (AD) progression. However, the mechanisms of microbiome–brain interaction in AD were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.

Kulkarni S., Kurapati S., Bogunovic M.

The gastrointestinal (GI) tract performs a set of vital physiological functions related to food and water consumption. To help regulate these complex physiological processes, the GI tract is innervated by extensive neural networks. The GI tract also serves as the largest immune organ aimed to protect hosts from harmful microbes and toxins ingested with food. It emerges that the enteric nervous and immune systems are highly integrated to optimize digestion while reinforcing immune protection. In this review, we will discuss key cellular players involved in the neuro-immune interactions within the GI mucosa with the focus on the recently uncovered neural pathways that regulate mucosal immunity in a context relevant to GI health and disease.

Sohrabi M., Pecoraro H.L., Combs C.K.

Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and AppNL-G-F mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and AppNL-G-F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated AppNL-G-F mice compared to vehicle treated AppNL-G-F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system.

Sackeim H.A., Dibué M., Bunker M.T., Rush A.J.

The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population.A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described.Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life.Most comparisons of VNS+TAU and TAU were derived from observational, open label studies.The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.

Borsom E.M., Lee K., Cope E.K.

The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota–brain axis. The gut microbiota–brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota–brain axis is a novel target for Alzheimer’s disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota–brain axis and neuroinflammation in the onset and development of Alzheimer’s disease, limitations of current research, and potential for gut microbiota–brain axis targeted therapies.

Stan T.L., Soylu-Kucharz R., Burleigh S., Prykhodko O., Cao L., Franke N., Sjögren M., Haikal C., Hållenius F., Björkqvist M.

Huntington’s disease (HD) is a progressive, multifaceted neurodegenerative disease associated with weight loss and gut problems. Under healthy conditions, tight junction (TJ) proteins maintain the intestinal barrier integrity preventing bacterial translocation from the intestinal lumen to the systemic circulation. Reduction of TJs expression in Parkinson’s disease patients has been linked with increased intestinal permeability—leaky gut syndrome. The intestine contains microbiota, most dominant phyla being Bacteroidetes and Firmicutes; in pathogenic or disease conditions the balance between these bacteria might be disrupted. The present study investigated whether there is evidence for an increased intestinal permeability and dysbiosis in the R6/2 mouse model of HD. Our data demonstrate that decreased body weight and body length in R6/2 mice is accompanied by a significant decrease in colon length and increased gut permeability compared to wild type littermates, without any significant changes in the protein levels of the tight junction proteins (occludin, zonula occludens). Moreover, we found an altered gut microbiota in R6/2 mice with increased relative abundance of Bacteroidetes and decreased of Firmicutes. Our results indicate an increased intestinal permeability and dysbiosis in R6/2 mice and further studies investigating the clinical relevance of these findings are warranted.

Horsager J., Andersen K.B., Knudsen K., Skjærbæk C., Fedorova T.D., Okkels N., Schaeffer E., Bonkat S.K., Geday J., Otto M., Sommerauer M., Danielsen E.H., Bech E., Kraft J., Munk O.L., et. al.

Abstract Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson’s disease into this case-control PET study. Patients with Parkinson’s disease were divided into 24 RBD-negative (PDRBD−) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD− and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P &lt; 10−13, ANOVA). When compared to the PDRBD− patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P &lt; 10−5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD− (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P &lt; 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD− data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson’s disease.

Zeng Q., Shen J., Chen K., Zhou J., Liao Q., Lu K., Yuan J., Bi F.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied with severe paralysis or even death, while the pathogenesis of ALS is still unclear and no effective therapy exists. The accumulating evidence has indicated the association between gut microbiota and various neurological diseases. Thus, to explore the potential role of gut microbiome in ALS, 20 patients diagnosed with probable or definite ALS and 20 healthy controls were enrolled and their fecal excrements were collected. The analysis of fecal community diversity with 16S rDNA sequencing showed an obvious change in microbial structure of ALS patients, where Bacteroidetes at the phylum level and several microbes at the genus level were up-regulated, while Firmicutes at the phylum level and Megamonas at the genus level were down-regulated compared to healthy controls. Additionally, decreased gene function associated with metabolic pathways was observed in ALS patients. The metagenomics further demonstrated the discrepancies in microflora at the species level and relevant metabolites thereof were also revealed when combined with metabolomics. In conclusion, the altered composition of the gut microbiota and metabolic products in ALS patients provided deeper insights into the pathogenesis of ALS, and these biomarkers might be established as potential therapeutic targets which deserve further exploration.

Wasser C.I., Mercieca E., Kong G., Hannan A.J., McKeown S.J., Glikmann-Johnston Y., Stout J.C.

Abstract Huntington’s disease is characterized by a triad of motor, cognitive and psychiatric impairments, as well as unintended weight loss. Although much of the research has focused on cognitive, motor and psychiatric symptoms, the extent of peripheral pathology and the relationship between these factors, and the core symptoms of Huntington’s disease, are relatively unknown. Gut microbiota are key modulators of communication between the brain and gut, and alterations in microbiota composition (dysbiosis) can negatively affect cognition, behaviour and affective function, and may be implicated in disease progression. Furthermore, gut dysbiosis was recently reported in Huntington’s disease transgenic mice. Our main objective was to characterize the gut microbiome in people with Huntington’s disease and determine whether the composition of gut microbiota are significantly related to clinical indicators of disease progression. We compared 42 Huntington’s disease gene expansion carriers, including 19 people who were diagnosed with Huntington’s disease (Total Functional Capacity &gt; 6) and 23 in the premanifest stage, with 36 age- and gender-matched healthy controls. Participants were characterized clinically using a battery of cognitive tests and using results from 16S V3 to V4 rRNA sequencing of faecal samples to characterize the gut microbiome. For gut microbiome measures, we found significant differences in the microbial communities (beta diversity) based on unweighted UniFrac distance (P = 0.001), as well as significantly lower alpha diversity (species richness and evenness) between our combined Huntington’s disease gene expansion carrier group and healthy controls (P = 0.001). We also found major shifts in the microbial community structure at Phylum and Family levels, and identified functional pathways and enzymes affected in our Huntington’s disease gene expansion carrier group. Within the Huntington’s disease gene expansion carrier group, we also discovered associations among gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in Huntington’s disease gene expansion carriers. These results highlight the importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington’s disease, and whether it may be a potential target for future therapeutic intervention.

Muller P.A., Schneeberger M., Matheis F., Wang P., Kerner Z., Ilanges A., Pellegrino K., del Mármol J., Castro T.B., Furuichi M., Perkins M., Han W., Rao A., Pickard A.J., Cross J.R., et. al.

Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content1, regulating both physiological intestinal functions such as nutrient absorption and motility2,3, and brain-wired feeding behaviour2. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology4. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut–brain circuit. A combination of gnotobiotic mouse models, transcriptomics, circuit tracing and chemogenetic manipulations identifies neuronal circuits that integrate microbial signals in the gut with regulation of the sympathetic nervous system.

Sun Y., Sommerville N.R., Liu J.Y., Ngan M.P., Poon D., Ponomarev E.D., Lu Z., Kung J.S., Rudd J.A.

Key points Alzheimer's disease (AD) patients and transgenic mice have beta-amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion-like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β-amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. Abstract Alzheimer's disease (AD) is the most common age-related cause of dementia, characterised by extracellular beta-amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra-GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD-related pathology such as dementia. We micro-injected Aβ1–42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555-labelled Aβ1–42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555-labelled Aβ1–42 in the body of the stomach and proximal colon had partly re-distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y-maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD-like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD.

Yarandi S.S., Kulkarni S., Saha M., Sylvia K.E., Sears C.L., Pasricha P.J.

Background & Aims The enteric nervous system (ENS) exists in close proximity to luminal bacteria. Intestinal microbes regulate ENS development, but little is known about their effects on adult enteric neurons. We investigated whether intestinal bacteria or their products affect the adult ENS via toll-like receptors (TLRs) in mice. Methods We performed studies with conventional C57/BL6, germ-free C57/BL6, Nestin-creERT2:tdTomato, Nestin-GFP, and ChAT-cre:tdTomato. Mice were given drinking water with ampicillin or without (controls). Germ-free mice were given drinking water with TLR2 agonist or without (controls). Some mice were given a blocking antibody against TLR2 or a TLR4 inhibitor. We performed whole gut transit, bead latency, and geometric center studies. Feces were collected and analyzed by 16S ribosomal RNA gene sequencing. Longitudinal muscle myenteric plexus (LMMP) tissues were collected, analyzed by immunohistochemistry, and levels of nitric oxide were measured. Cells were isolated from colonic LMMP of Nestin-creERT2:tdTomato mice and incubated with agonists of TLR2 (receptor for gram-positive bacteria), TLR4 (receptor for gram-negative bacteria), or distilled water (control) and analyzed by flow cytometry. Results Stool from mice given ampicillin had altered composition of gut microbiota with reduced abundance of gram-positive bacteria and increased abundance of gram-negative bacteria, compared with mice given only water. Mice given ampicillin had reduced colon motility compared with mice given only water, and their colonic LMMP had reduced numbers of nitrergic neurons, reduced neuronal nitric oxide synthase production, and reduced colonic neurogenesis. Numbers of colonic myenteric neurons increased after mice were switched from ampicillin to plain water, with increased markers of neurogenesis. Nestin-positive enteric neural precursor cells expressed TLR2 and TLR4. In cells isolated from the colonic LMMP, incubation with the TLR2 agonist increased the percentage of neurons originating from enteric neural precursor cells to approximately 10%, compared with approximately 0.01% in cells incubated with the TLR4 agonist or distilled water. Mice given an antibody against TLR2 had prolonged whole gut transit times; their colonic LMMP had reduced total neurons and a smaller proportion of nitrergic neurons per ganglion, and reduced markers of neurogenesis compared with mice given saline. Colonic LMMP of mice given the TLR4 inhibitor did not have reduced markers of neurogenesis. Colonic LMMP of germ-free mice given TLR2 agonist had increased neuronal numbers compared with control germ-free mice. Conclusions In the adult mouse colon, TLR2 promotes colonic neurogenesis, regulated by intestinal bacteria. Our findings indicate that colonic microbiota help maintain the adult ENS via a specific signaling pathway. Pharmacologic and probiotic approaches directed towards specific TLR2 signaling processes might be developed for treatment of colonic motility disorders related to use of antibiotics or other factors.

Buhmann C., Kassubek J., Jost W.H.

Pain is a very frequent symptom with influence on the quality of life in Parkinson’s disease (PD), but is still underdiagnosed and commonly treated only unsystematically. Pain etiology and pain character are often complex and multi-causal, and data regarding treatment recommendations are limited. Pain can be primarily related to PD but frequently it is associated with secondary diseases, such as arthrosis of the spine or joints. However, even basically PD-unrelated pain often is amplified by motor- or non-motor PD symptoms, such as akinesia or depression. Beyond an optimization of anti-parkinsonian treatment, additional pain treatment strategies are usually needed to properly address pain in PD. A careful pain history and diagnostic work-up is essential to rate the underlying pain pathophysiology and to develop a targeted therapeutic concept. This review gives an overview on how pain is treated in PD patients and how patients assess the effectiveness of these therapies; here, the manuscript focuses on pathophysiology-driven suggestions for a multimodal pain management in clinical practice.

Qiao C., Sun M., Jia X., Li Y., Zhang B., Zhao L., Shi Y., Zhou Z., Zhu Y., Cui C., Shen Y.

The abnormal production of short chain fatty acid (SCFAs) caused by gut microbial dysbiosis plays an important role in the pathogenesis and progression of Parkinson’s disease (PD). This study sought to evaluate how butyrate, one of SCFAs, affect the pathology in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated mouse model of PD. Sodium butyrate (NaB; 165 mg/kg/day i.g., 7 days) was administrated from the day after the last MPTP injection. Interestingly, NaB significantly aggravated MPTP-induced motor dysfunction (P < 0.01), decreased dopamine (P < 0.05) and 5-HT (P < 0.05) levels, exacerbated declines of dopaminergic neurons (34%, P < 0.05) and downregulated expression of tyrosine hydroxylase (TH, 47%, P < 0.05), potentiated glia-mediated neuroinflammation by increasing the number of microglia (17%, P < 0.05) and activating astrocytes (28%, P < 0.01). In vitro study also confirmed that NaB could significantly exacerbate pro-inflammatory cytokines expression (IL-1β, 4.11-fold, P < 0.01; IL-18, 3.42-fold, P < 0.01 and iNOS, 2.52-fold, P < 0.05) and NO production (1.55-fold, P < 0.001) in LPS-stimulated BV2 cells. In addition, NaB upregulated the expression of pro-inflammatory cytokines (IL-6, 3.52-fold, P < 0.05; IL-18, 1.72-fold, P < 0.001) and NLRP3 (3.11-fold, P < 0.001) in the colon of PD mice. However, NaB had no effect on NFκB, MyD88 and TNF-α expression in PD mice. Our results indicate that NaB exacerbates MPTP-induced PD by aggravating neuroinflammation and colonic inflammation independently of the NFκB/MyD88/TNF-α signaling pathway.

Uyanik H., Sengur A., Salvi M., Tan R., Tan J.H., Acharya U.R.

ABSTRACTMental and neurological disorders significantly impact global health. This systematic review examines the use of artificial intelligence (AI) techniques to automatically detect these conditions using electroencephalography (EEG) signals. Guided by Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA), we reviewed 74 carefully selected studies published between 2013 and August 2024 that used machine learning (ML), deep learning (DL), or both of these two methods to detect neurological and mental health disorders automatically using EEG signals. The most common and most prevalent neurological and mental health disorder types were sourced from major databases, including Scopus, Web of Science, Science Direct, PubMed, and IEEE Xplore. Epilepsy, depression, and Alzheimer's disease are the most studied conditions that meet our evaluation criteria, 32, 12, and 10 studies were identified on these topics, respectively. Conversely, the number of studies meeting our criteria regarding stress, schizophrenia, Parkinson's disease, and autism spectrum disorders was relatively more average: 6, 4, 3, and 3, respectively. The diseases that least met our evaluation conditions were one study each of seizure, stroke, anxiety diseases, and one study examining Alzheimer's disease and epilepsy together. Support Vector Machines (SVM) were most widely used in ML methods, while Convolutional Neural Networks (CNNs) dominated DL approaches. DL methods generally outperformed traditional ML, as they yielded higher performance using huge EEG data. We observed that the complex decision process during feature extraction from EEG signals in ML‐based models significantly impacted results, while DL‐based models handled this more efficiently. AI‐based EEG analysis shows promise for automated detection of neurological and mental health conditions. Future research should focus on multi‐disease studies, standardizing datasets, improving model interpretability, and developing clinical decision support systems to assist in the diagnosis and treatment of these disorders.

Morgos D., Eftimie L., Nicolae H., Nica R.I., Stefani C., Miricescu D., Hristu R., Stanciu G.A., Tulin A., Filipoiu F.

Background/Objectives: This study explores the micro-structure of celiac ganglia using two-photon microscopy (TPM) to highlight histological features in neurodegenerative conditions. Neurodegenerative diseases like Parkinson’s disease (PD) are linked to dysautonomia, impacting autonomic regulation and leading to significant gastrointestinal and autonomic symptoms. Our research compares imaging results from TPM and SHG microscopy, visualizing neuronal integrity, collagen distribution, and the architectural organization of celiac ganglia. SHG specifically allows detailed imaging of collagen fibers and neuronal structures, revealing alterations in collagen density and organization that correlate with dysautonomia. Methods: The cross-sectional study was conducted at “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania, involving 70 participants diagnosed with PD (Hoehn and Yahr stages 2–4), including 35 with dysautonomia and 35 without. We utilized samples from PD patients with and without dysautonomia, applying immunohistochemical markers for sympathetic neurons. Results: Our findings reveal significant pathological changes in neuronal structure and collagen architecture. Immunohistochemical markers (neuropeptide Y, neurofilament heavy chain (NF-H), and tyrosine hydroxylase) were employed to characterize sympathetic neurons, while TPM and SHG provided high-resolution imaging of neuronal integrity and extracellular matrix composition. Conclusions: These imaging techniques present a promising tool for early diagnosis and assessment of neurodegeneration and dysautonomia in PD patients. Moreover, these techniques may represent a critical bridge between histopathological findings and clinical manifestations, underscoring their role in enhancing our understanding of neurodegeneration and autonomic dysfunction in Parkinson’s disease.

Ghanem A.S., Móré M., Nagy A.C.

Neurodegenerative diseases (NDDs) represent a considerable global health burden with no definitive treatments. Emerging evidence suggests that periodontitis may contribute to NDD through shared inflammatory, microbial, and genetic pathways. A retrospective cohort design was applied to analyze hospital records from 2012–2022 and to determine whether periodontitis independently increases NDD risk when accounting for major cardiovascular, cerebrovascular, metabolic, and inflammatory confounders. Likelihood ratio-based Cox regression tests and Weibull survival models were applied to assess the association between periodontitis and NDD risk. Model selection was guided by Akaike and Bayesian information criteria, while Harrell’s C-index and receiver operating characteristic curves evaluated predictive performance. Periodontitis demonstrated an independent association with neurodegenerative disease risk (HR 1.43, 95% CI 1.02–1.99). Cerebral infarction conferred the highest hazard (HR 4.81, 95% CI 2.90–7.96), while pneumonia (HR 1.96, 95% CI 1.05–3.64) and gastroesophageal reflux disease (HR 2.82, 95% CI 1.77–4.51) also showed significant increases in risk. Older individuals with periodontitis are at heightened risk of neurodegenerative disease, an effect further intensified by cerebrovascular, cardiometabolic, and gastroesophageal conditions. Pneumonia also emerged as an independent pathophysiological factor that may accelerate disease onset or progression. Attention to oral and systemic factors through coordinated clinical management may mitigate the onset and severity of neurodegeneration.

Ko E., Zhou T., Ko J., Jung S.

Ziółkowska E.A., Jansen M.J., Williams L.L., Wang S.H., Eultgen E.M., Takahashi K., Le S.Q., Nelvagal H.R., Sharma J., Sardiello M., DeBosch B.J., Dickson P.I., Anderson J.B., Sax S.E., Wright C.M., et. al.

Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival.

Shouman S., Hesham N., Salem T.Z.

Abstract Neurodegenerative diseases (NDDs) cause a progressive loss of neurons. Since NDDs are multifactorial, the precise etiology varies on the basis of the type of disease and patient history. Cohort studies and case studies have demonstrated a potential link between viral infections and the onset or progression of NDDs. Recent findings concerning the mechanisms by which neuropathic infections occur have provided more insights into the importance of such connections. In this review, we aim to elaborate on the occurrence of the neuropathic effects of viruses from epidemiological, clinical, and biological perspectives while highlighting potential treatments and challenges. One of the key players in viral neuropathogenesis is neuroinflammation caused by the immune response to the virus; this can occur due to both neurotropic and nonneurotropic viruses. The COVID-19 pandemic has raised concerns about whether vaccines are essential for preventing viruses or whether vaccines may play a part in exacerbating or accelerating NDDs. By classifying viruses and the common NDDs associated with them and further delving into their cellular pathways, this review provides insights to advance the development of potential treatments and diagnostic methods. Graphical Abstract

Niu T., Wang P., Zhou X., Liu T., Liu Q., Li R., Yang H., Dong H., Liu Y.

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and rare neurodegenerative disease. Therefore, evaluating the risk factors affecting the survival of patients with ALS is crucial. Constipation, a common but overlooked symptom of ALS, can be effectively managed. It is currently unknown whether constipation contributes to the progression and survival of ALS. Objectives: This study aimed to investigate the association between constipation and ALS development and survival using a novel overlap-weighted (OW) method to enhance the robustness and reliability of results. Design: This prospective matching nested case-control (NCC) study was conducted within an ongoing ALS cohort at the Second Hospital of Hebei Medical University. Baseline data were collected from patients meeting the inclusion and exclusion criteria, with constipation as the exposure factor. A 9-month follow-up was conducted, with death as the endpoint event. Methods: We primarily used the OW method in NCC studies to examine the association between constipation and ALS development and survival. Weighted Cox proportional hazards model was used to assess risk factors associated with overall survival. Survival differences between the two groups were analyzed using Kaplan-Meier’s plots and log-rank tests. Finally, the bioinformatic analysis explored common pathways between ALS and constipation. Results: Among the 190 patients included, the prevalence of constipation was 50%. Patients with ALS constipation exhibited faster disease progression ( p < 0.001), with a positive correlation between constipation severity and progression rate ( r = 0.356, p < 0.001). The constipation group had poorer survival before and after OW (log-rank test, p < 0.0001). In the Cox proportional hazards model of 114 patients, constipation was a risk factor for ALS both before (hazard ratio (HR) = 5.840, 95% confidence interval (CI) = 1.504–22.675, p = 0.011) and after (HR = 5.271, 95% CI = 1.241–22.379, p = 0.024) OW. Conclusion: Constipation in individuals with ALS is associated with faster disease progression and reduced survival rates, potentially through the peroxisome proliferator-activated receptor pathway.

Abbaszadeh F., Fakhri S., Varnamkhasti B.S., Moradi S.Z., Khirehgesh M.R., Echeverría J.

Hsu F., Weng T., Pu T., Chang P., Lin T., Jao S., Chen C., Hu J., Chien W.

Infectious intestinal diseases (IIDs) pose a significant health and economic burden worldwide. Recent observations at the Tri-Service General Hospital, Taiwan, suggest a potential association between IIDs and neurodegenerative diseases, prompting an investigation into this relationship. This study explored interactions between IIDs and neurodegenerative diseases. We conducted a population-based retrospective cohort analysis using data from the National Health Insurance Research Database (NHIRD) of Taiwan. Patients diagnosed with IIDs between 2000 and 2015 were identified along with a matched control group. Covariates, including demographics, comorbidities, and healthcare utilization were considered. The hazard ratios (HRs) of neurodegenerative diseases were assessed using a Cox proportional regression analysis. This study included 297,438 patients: 99,146 and 198,292 patients in the IID and control groups, respectively. Patients with IIDs showed a significantly higher overall risk of neurodegenerative diseases (adjusted hazard ratio [aHR] = 1.144, P < 0.001). Subgroup analyses revealed an elevated risk of Parkinson's disease, multiple sclerosis, and other neurodegeneration-associated disorders in the study group. Additionally, a positive correlation was observed between the frequency of medical visits for IIDs and neurodegenerative disease risk. This study provides evidence for a significant association between IIDs and the neurodegenerative disease risk. Early detection and management of IIDs may have implications for long-term neurological health outcomes. Further research is required to elucidate underlying mechanisms and develop targeted interventions and preventive strategies.

Alexiev A., Stretch E., Kasschau K.D., Wilson L.B., Truong L., Tanguay R.L., Sharpton T.J.

Developmental exposure to benzo[a]pyrene (BaP), a ubiquitous environmental pollutant, has been linked to various toxic effects, including multigenerational behavioral impairment. While the specific mechanisms driving BaP neurotoxicity are not fully understood, recent work highlights two important determinants of developmental BaP neurotoxicity: (1) the aryl hydrocarbon receptor (AHR), which induces host metabolism of BaP, and (2) the gut microbiome, which may interact with BaP to affect its metabolism, or be perturbed by BaP to disrupt the gut–brain axis. We utilized the zebrafish model to explore the role of AHR, the gut microbiome, and their interaction, on BaP-induced neurotoxicity. We tested (1) how developmental BaP exposure and AHR2 perturbation in zebrafish link to adult behavior, (2) how these variables associate with the structure and function of the adult zebrafish gut metagenome, and (3) whether these associations are multigenerational. Our findings reveal a reticulated axis of association between BaP exposure, developmental AHR2 expression, the zebrafish gut metagenome, and behavior. Results indicate that AHR2 is a key modulator of how BaP elicits neurotoxicity and microbiome dysbiosis. Additionally, this axis of association manifests generationally. These findings demonstrate the importance of studying pollutant–microbiome interactions and elucidate the role of specific host genes in neurotoxicity and dysbiosis.

Kakraba S., Wenzheng H., Srivastav S., Shaffer J.

BACKGROUND Recent studies have demonstrated that AI can surpass medical practitioners in diagnostic accuracy, underscoring the increasing importance of AI-assisted diagnosis in healthcare. This research introduces SMART-Pred (Shiny Multi-Algorithm R Tool for Predictive Modeling), an innovative AI-based application for Alzheimer's disease (AD) prediction utilizing handwriting analysis OBJECTIVE Our objective is to develop and evaluate a non-invasive, cost-effective, and efficient AI tool for early AD detection, addressing the need for accessible and accurate screening methods. METHODS Our methodology employs a comprehensive approach to AI-driven Alzheimer's disease (AD) prediction. We begin with Principal Component Analysis for dimensionality reduction, ensuring efficient processing of complex handwriting data. This is followed by the training and evaluation of ten diverse, highly optimized AI models, including logistic regression, Naïve Bayes, random forest, AdaBoost, Support Vector Machine, and neural networks. This multi-model approach allows for a robust comparison of different machine learning techniques in AD prediction. To rigorously assess model performance, we utilize a range of metrics including accuracy, sensitivity, specificity, F1-score, and ROC-AUC. These comprehensive metrics provide a holistic view of each model's predictive capabilities. For validation, we leveraged the DARWIN dataset, which comprises handwriting samples from 174 participants (89 AD patients and 85 healthy controls). This balanced dataset ensures a fair evaluation of our models' ability to distinguish between AD patients and healthy individuals based on handwriting characteristics. RESULTS The random forest model demonstrated strong performance, achieving an accuracy of 88.68% on the test set during comprehensive model analysis. Meanwhile, the AdaBoost algorithm exhibited even higher accuracy, reaching 92.00% after leveraging AI models to identify the most significant variables for predicting Alzheimer's disease. These results surpass current clinical diagnostic tools, which typically achieve around 81.00% accuracy. SMART-Pred's performance aligns with recent AI advancements in AD prediction, such as the Cambridge scientists' AI tool achieving 82.00% accuracy in identifying AD progression within three years using cognitive tests and MRI scans. Furthermore, our comprehensive analysis utilizing SMART-Pred revealed a consistent pattern across all ten AI models employed. The variables "air_time" and "paper_time" consistently stood out as critical predictors for Alzheimer's disease (AD). These two factors were repeatedly identified as the most influential variables in assessing the probability of AD onset, underscoring their potential importance in early detection and risk assessment of the disease. CONCLUSIONS Even though some limitations exist with SMART-Pred, it offers several advantages, including being non-invasive, cost-effective, efficient, and customizable for complex datasets and disease diagnostics. The study demonstrates the transformative potential of AI in healthcare, particularly in AD prediction, and may contribute to improved patient outcomes through early detection and intervention. Clinical validation is necessary to confirm whether the key variables identified in this study are sufficient for accurately predicting Alzheimer's disease in real-world medical settings. This step is crucial to ensure the practical applicability and reliability of these findings in clinical practice.

Hong S.M., Qian X., Deshpande V., Kulkarni S.

AbstractGastrointestinal (GI) motility is regulated in a large part by the cells of the enteric nervous system (ENS), suggesting that ENS dysfunctions either associate with, or drive GI dysmotility in patients. However, except for select diseases such as Hirschsprung’s Disease or Achalasia that show a significant loss of all neurons or a subset of neurons, our understanding of human ENS histopathology is extremely limited. Recent endoscopic advances allow biopsying patient’s full thickness gut tissues, which makes capturing ENS tissues simpler than biopsying other neuronal tissues, such as the brain. Yet, our understanding of ENS aberrations observed in GI dysmotility patients lags behind our understanding of central nervous system aberrations observed in patients with neurological disease. Paucity of optimized methods for histopathological assessment of ENS in pathological specimens represent an important bottleneck in ascertaining how the ENS is altered in diverse GI dysmotility conditions. While recent studies have interrogated ENS structure in surgically resected whole mount human gut, most pathological specimens are banked as formalin fixed paraffin embedded (FFPE) tissue blocks – suggesting that methods to interrogate ENS in FFPE tissue blocks would provide the biggest impetus for ENS histopathology in a clinical setting. In this report, we present optimized methods for immunohistochemical interrogation of the human ENS tissue on the basis of >25 important protein markers that include proteins expressed by all neurons, subset of neurons, hormones, and neurotransmitter receptors. This report provides a resource which will help pathologists and investigators assess ENS aberrations in patients with various GI dysmotility conditions.

McGorum B., Pirie R.S., Bano L., Davey T., Harris J., Montecucco C.

Cao H., Tian Q., Chu L., Wu L., Gao H., Gao Q.

Emerging evidence suggests that Parkinson's disease (PD) is strongly associated with altered gut microbiota.

Lotfi A., Abroodi Z., Khazaei M.