Pathology Deficits Research Articles

The deficient CLEC5A ameliorates the behavioral and pathological deficits via the microglial Aβ clearance in Alzheimer’s disease mouse model

BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive dysfunction in older adults. One of the AD pathological factors, β-Amyloid (Aβ), triggers inflammatory responses and phagocytosis of microglia. C-type lectin domain family 5 member A (CLEC5A) induces over-reactive inflammatory responses in several virus infections. Yet, the role of CLEC5A in AD progression remains unknown. This study aimed to elucidate the contribution of CLEC5A to Aβ-induced microglial activation and behavioral deficits.MethodsThe AD mouse model was crossed with Clec5a knockout mice for subsequent behavioral and pathological tests. The memory deficit was revealed by the Morris water maze, while the nociception abnormalities were examined by the von Frey filament and hotplate test. The Aβ deposition and microglia recruitment were identified by ELISA and immunohistochemistry. The inflammatory signals were identified by ELISA and western blotting. In the Clec5a knockdown microglial cell model and Clec5a knockout primary microglia, the microglial phagocytosis was revealed using the fluorescent-labeled Aβ.ResultsThe AD mice with Clec5a knockout improved Aβ-induced memory deficit and abnormal nociception. These mice have reduced Aβ deposition and increased microglia coverage surrounding the amyloid plaque, suggesting the involvement of CLEC5A in AD progression and Aβ clearance. Moreover, the phagocytosis was also increased in the Aβ-stressed Clec5a knockdown microglial cell lines and Clec5a knockout primary microglia.ConclusionThe Clec5a knockout ameliorates AD-like deficits by modulating microglial Aβ clearance. This study implies that targeting microglial Clec5a could offer a promising approach to mitigate AD progression.

Plakophilin 2 gene therapy prevents and rescues arrhythmogenic right ventricular cardiomyopathy in a mouse model harboring patient genetics

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a fatal genetic heart disease characterized by cardiac arrhythmias, in which fibrofatty deposition leads to heart failure, with no effective treatments. Plakophilin 2 (PKP2) is the most frequently mutated gene in ARVC, and although altered RNA splicing has been implicated, there are no models to study its effect and therapeutics. Here, we generate a mouse model harboring a PKP2 mutation (IVS10-1G>C) affecting RNA splicing, recapitulating ARVC features and sudden death starting at 4 weeks. Administering AAV-PKP2 gene therapy (adeno-associated viral therapy to drive cardiac expression of PKP2) to neonatal mice restored PKP2 protein levels, completely preventing cardiac desmosomal and pathological deficits associated with ARVC, ensuring 100% survival of mice up to 6 months. Late-stage AAV-PKP2 administration rescued desmosomal protein deficits and reduced pathological deficits including improved cardiac function in adult mice, resulting in 100% survival up to 4 months. We suggest that AAV-PKP2 gene therapy holds promise for circumventing ARVC associated with PKP2 mutations, including splice site mutations.

Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration.

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.05 compared to sham-injured animals) up to 5 weeks postinjury. In the first week following single or repetitive brain injury, axonal and neuronal degeneration, and microglial activation were observed in the cortex, white matter, thalamus, and subiculum; the extent of the histopathologic damage was significantly greater in the repetitive-injured animals compared to single-injured animals. At 40 days postinjury, loss of cortical, white matter and hippocampal tissue was evident only in the repetitive-injured animals, along with evidence of microglial activation in the white matter tracts and thalamus. Axonal injury and neurodegeneration were evident in the thalamus up to 40 days postinjury in the repetitive-injured rats. These data demonstrate that while single closed head injury in the neonate rat is associated with pathologic alterations in the acute post-traumatic period, repetitive closed head injury results in sustained behavioral and pathologic deficits reminiscent of infants with abusive head trauma.

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

BackgroundMutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice.MethodsWe generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r+/− microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r+/− mice and wild-type control littermates.ResultsWe found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r+/− mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r+/− microglia. Treatment with minocycline could suppress the activation of Csf1r+/− microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r+/− mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r+/− mice.ConclusionsOur study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

Cardiac Inflammation As an Underlying Trigger for the Pathological Deficits Associated with Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that causes cardiomyocyte loss, resulting in myocardial fibro-fatty deposition leading to cardiac dysfunction and sudden cardiac death, particularly in young patients and athletes, with no available treatments. The genetics of ARVC follow an autosomal dominant pattern, although severe cases (especially in pediatric populations) have been reported as recessive. Mutations in genes encoding components of desmosomes (specialized cell-cell junction that act as mechanical anchor between cardiac muscle cells) resulting in loss of desmosomal proteins underlie approximately 40-60% genetic cases of ARVC. Studies highlight that cardiac inflammation may be a critical and early component of ARVC as patients harboring mutations in the desmosomal gene desmoplakin (DSP) present with recurrent myocardial episodes (observed as myocarditis); however, the mechanisms and whether inflammation is a driver of ARVC remain unclear. We hypothesize that desmosomal gene mutations/loss/byproducts alter the acute inflammatory response on the cardiomyocyte cell surface leading to chronic immune intolerance and triggering of ARVC disease. To test our hypothesis, we injected DSP heterozygous deficient mice (harboring 50% loss of DSP without overt signs of ARVC) with a fragment of α-myosin and pertussis toxin to stimulate the immune system to assess its impact on ARVC pathogenesis. We show that DSP heterozygous mice exposed to acute immunological challenge triggered a destructive cardiomyocyte immune response in DSP heterozygous deficient hearts, reminiscent of fulminant myocarditis. Furthermore, we show that this acute immunological challenge was sufficient to trigger classic ARVC disease features in DSP heterozygous deficient mice as exemplified by: (i) enlarged ventricular (mostly right ventricular) chambers and heart size, (ii) fibrotic remodeling, with more clearly striking effects in the right ventricle (RV), (iii) epicardial fat tissue accumulation, (iv) electrophysiological deficits, such as premature ventricular contractions and QRS prolongation as well as (v) right and left ventricular physiological deficits associated with the bi-ventricular form of ARVC, although the RV appeared to be more significantly impacted. Our studies highlight the development of a novel DSP-related model of myocarditis. Using this model, we show that immunological stress is sufficient to lead to loss of cardiomyocyte immune tolerance in DSP heterozygous deficient mice with compromised desmosomal integrity to drive ARVC pathogenesis. More broadly these studies suggest that the immune system maybe an important driver of ARVC pathogenesis in patients with underlying desmosomal gene mutations/heterozygous loss, especially in the setting of autosomal dominant genetics. Work in the laboratory of FS is supported by grants from the NIH (HL142251, HL162369) and industry (LEXEO Therapeutics Inc.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acai Berry (Euterpe sp.) Extracts Are Neuroprotective against L-Glutamate-Induced Toxicity by Limiting Mitochondrial Dysfunction and Cellular Redox Stress.

Aberrant accumulation of the neurotransmitter L-glutamate (L-Glu) has been implicated as a mechanism of neurodegeneration, and the release of L-Glu after stroke onset leads to a toxicity cascade that results in neuronal death. The acai berry (Euterpe oleracea) is a potential dietary nutraceutical. The aim of this research was to investigate the neuroprotective effects of acai berry aqueous and ethanolic extracts to reduce the neurotoxicity to neuronal cells triggered by L-Glu application. L-Glu and acai berry effects on cell viability were quantified using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and effects on cellular bioenergetics were assessed via quantitation of the levels of cellular ATP, mitochondrial membrane potential (MMP), and production of reactive oxygen species (ROS) in neuroblastoma cells. Cell viability was also evaluated in human cortical neuronal progenitor cell culture after L-Glu or/and acai berry application. In isolated cells, activated currents using patch-clamping were employed to determine whether L-Glu neurotoxicity was mediated by ionotropic L-Glu-receptors (iGluRs). L-Glu caused a significant reduction in cell viability, ATP, and MMP levels and increased ROS production. The co-application of both acai berry extracts with L-Glu provided neuroprotection against L-Glu with sustained cell viability, decreased LDH production, restored ATP and MMP levels, and reduced ROS levels. Whole-cell patch-clamp recordings showed that L-Glu toxicity is not mediated by the activation of iGluRs in neuroblastoma cells. Fractionation and analysis of acai berry extracts with liquid chromatography-mass spectrometry identified several phytochemical antioxidants that may have provided neuroprotective effects. In summary, the acai berry contains nutraceuticals with antioxidant activity that may be a beneficial dietary component to limit pathological deficits triggered by excessive L-Glu accumulations.

Early detection of neurological abnormalities using a combined phase space reconstruction and deep learning approach

The scientific literature on depression detection using electroencephalogram (EEG) signals is extensive and offers numerous innovative approaches. However, these existing state-of-the-art (SOTA) have limitations that hinder their overall efficacy. They rely significantly on datasets with limited scope and accessibility, which introduces potential biases and diminishes generalizability. In addition, they concentrate on analyzing a single dataset, potentially overlooking the inherent variability and complexity of EEG patterns associated with depression. Moreover, certain SOTA methods employ deep learning architectures with exponential time complexity, resulting in computationally intensive and time-consuming training procedures. Therefore, their practicability and applicability in real-world scenarios are compromised. To address these limitations, a novel integrated methodology that combines the advantages of phase space reconstruction and deep neural networks is proposed. It employs publicly available EEG datasets, mitigating the inherent biases of exclusive data sources. Moreover, the method incorporates reconstructed phase space analysis, a feature engineering technique that captures more accurately the complex EEG patterns associated with depression. Simultaneously, the incorporation of a deep neural network component guarantees optimal efficiency and accurate, seamless classification. Using publicly available datasets, cross-dataset validation, and a novel combination of reconstructed phase space analysis and deep neural networks, the proposed method circumvents the shortcomings of current state-of-the-art (SOTA) approaches. This innovation represents a significant advance in enhancing the accuracy of depression detection and provides the base for EEG-based depression assessment tools applicable to real-world settings. The findings of the study provide a more robust and efficient model, which increases classification precision and decreases computing burden. The study findings layout the foundation for scalable, accessible mental health solutions, identification of the pathological deficits in affected brain tissues, and demonstrate the potential of technology-driven approaches to support and guide depressed individuals and enhance mental health outcomes.

Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

Mapping entorhinal cortex circuitry in mouse models of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide that comes with significant personal and economic burdens. Unfortunately, the brain circuitry underlying AD pathophysiology is yet to be fully understood. Elucidating the circuits that change before the onset of cognitive deficits would help to identify neuronal populations that change early in disease progression. After the identification of these brain regions and cell types, they can be selectively targeted to reverse both the anatomical pathology and eventual behavioral decline.MethodHere we used a novel viral‐genetic method, rabies virus (RABV) tracing, which maps the inputs of targeted starter cell populations. We utilized this method in two mouse models of AD to measure circuit changes in the entorhinal cortex, which is one of the earliest brain regions to degenerate in Alzheimer’s. We implemented RABV mapping at three different time points, using aging as a key measure of comparison between circuit states. In using RABV tracing throughout disease progression, we were able to capture how these circuits look before any overt behavioral or histopathological deficits, as well as at a more advanced stage of the disease when both cognitive and pathological deficits are present.ResultOur preliminary results have identified key cells and circuits that are disrupted related to AD pathogenesis as targets to slow or prevent the development of the disease.ConclusionKey cells and circuits change early on in AD pathogenesis elucidated by rabies virus tracing.

Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations.

Immunization stress-related responses presenting as stroke-like symptoms could develop following COVID-19 vaccination. Therefore, this study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination in Thailand. We conducted a retrospective study of the secondary data of reported adverse events after COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Two majority types of vaccines were used at the beginning of the vaccination campaign, including CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca). Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score. The affected side was evaluated for associations with the injection site. Overall, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (68.9%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 100% of those receiving ChAdOx1 had a good outcome (modified Rankin scores ≤2, indicating slight or no disability). Immunization stress-related responses presenting as stroke-like symptoms can develop after COVID-19 vaccination. Symptoms more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs.

Personalised physiological medicine: Orthostatic hypotension

Orthostatic hypotension (OH) is a very common and debilitating condition, characterised by a significant drop in blood pressure (BP) on standing upright. Multiple neuro-cardiovascular mechanisms should stabilise BP when moving to an upright position but in OH, BP decline results from dysfunction of neuro-cardiovascular mechanisms. With the advent of non-invasive, beat-to-beat BP measurement, the detailed postural BP profile presents an opportunity to explore the underlying pathological deficits seen in OH. To date, several distinct clusters of postural BP drop have been identified, typically defined by the rate and duration of BP decline and the degree of recovery. The morphology of the BP drop may reflect the underlying cardiac output and peripheral vascular resistance. There are three principal treatment strategies for OH; conservative management, fludrocortisone or midodrine. As each of these therapies have different therapeutic mechanisms, in this review we hypothesise how they could be used in a more targeted manner to treat the underlying physiological deficit - conservative management for ‘initial drop, quick recovery’, fludrocortisone for ‘medium drop, slow recovery/venular-deficit’ and midodrine for ‘large drop, non-recovery/arteriolar-deficit’.

A Preliminary Assessment of the Nutraceutical Potential of Acai Berry (Euterpe sp.) as a Potential Natural Treatment for Alzheimer's Disease.

Alzheimer’s disease (AD) is characterised by progressive neuronal atrophy and the loss of neuronal function as a consequence of multiple pathomechanisms. Current AD treatments primarily operate at a symptomatic level to treat a cholinergic deficiency and can cause side effects. Hence, there is an unmet need for healthier lifestyles to reduce the likelihood of AD as well as improved treatments with fewer adverse reactions. Diets rich in phytochemicals may reduce neurodegenerative risk and limit disease progression. The native South American palm acai berry (Euterpe oleraceae) is a potential source of dietary phytochemicals beneficial to health. This study aimed to screen the nutraceutical potential of the acai berry, in the form of aqueous and ethanolic extracts, for the ability to inhibit acetyl- and butyryl-cholinesterase (ChE) enzymes and scavenge free radicals via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) or 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) assays. In addition, this study aimed to quantify the acai berry’s antioxidant potential via hydrogen peroxide or hydroxyl scavenging, nitric oxide scavenging, lipid peroxidation inhibition, and the ability to reduce ferric ions. Total polyphenol and flavonoid contents were also determined. Acai aqueous extract displayed a concentration-dependent inhibition of acetyl- and butyryl-cholinesterase enzymes. Both acai extracts displayed useful concentration-dependent free radical scavenging and antioxidant abilities, with the acai ethanolic extract being the most potent antioxidant and displaying the highest phenolic and flavonoid contents. In summary, extracts of the acai berry contain nutraceutical components with anti-cholinesterase and antioxidant capabilities and may therefore provide a beneficial dietary component that limits the pathological deficits evidenced in AD.

Systemic delivery of an AAV9 exon-skipping vector significantly improves or prevents features of Duchenne muscular dystrophy in the Dup2 mouse

Duchenne muscular dystrophy (DMD) is typically caused by mutations that disrupt the DMD reading frame, but nonsense mutations in the 5′ part of the gene induce utilization of an internal ribosomal entry site (IRES) in exon 5, driving expression of a highly functional N-truncated dystrophin. We have developed an AAV9 vector expressing U7 small nuclear RNAs targeting DMD exon 2 and have tested it in a mouse containing a duplication of exon 2, in which skipping of both exon 2 copies induces IRES-driven expression, and skipping of one copy leads to wild-type dystrophin expression. One-time intravascular injection either at postnatal days 0–1 or at 2 months results in efficient exon skipping and dystrophin expression, and significant protection from functional and pathologic deficits. Immunofluorescence quantification showed 33%–53% average dystrophin intensity and 55%–79% average dystrophin-positive fibers in mice treated in adulthood, with partial amelioration of DMD pathology and correction of DMD-associated alterations in gene expression. In mice treated neonatally, dystrophin immunofluorescence reached 49%–85% of normal intensity and 76%–99% dystrophin-positive fibers, with near-complete correction of dystrophic pathology, and these beneficial effects persisted for at least 6 months. Our results demonstrate the robustness, durability, and safety of exon 2 skipping using scAAV9.U7snRNA.ACCA, supporting its clinical use.

Compromised Cortical-Hippocampal Network Function From Transient Hypertension: Linking Mid-Life Hypertension to Late Life Dementia Risk.

Mid-life hypertension is a major risk factor for developing dementia later in life. While anti-hypertensive drugs restore normotension, dementia risk remains above baseline suggesting that brain damage sustained during transient hypertension is irreversible. The current study characterized a rat model of transient hypertension with an extended period of normotensive recovery: F344 rats were treated with L-NG-Nitroarginine methyl ester (L-NAME) for 1 month to induce hypertension then allowed up to 4 months of recovery. With respect to cognitive deficits, comparison between 1 month and 4 months of recovery identified initial deficits in spatial memory that resolved by 4 months post-hypertension; contrastingly, loss of cognitive flexibility did not. The specific cells and brain regions underlying these cognitive deficits were investigated. Irreversible structural damage to the brain was observed in both the prefrontal cortex and the hippocampus, with decreased blood vessel density, myelin and neuronal loss. We then measured theta-gamma phase amplitude coupling as a readout for network function, a potential link between the observed cognitive and pathological deficits. Four months after hypertension, we detected decreased theta-gamma phase amplitude coupling within each brain region and a concurrent increase in baseline connectivity between the two regions reflecting an attempt to maintain function that may account for the improvement in spatial memory. Our results demonstrate that connectivity between prefrontal cortex and hippocampus is a vulnerable network affected by transient hypertension which is not rescued over time; thus demonstrating for the first time a mechanistic link between the long-term effects of transient hypertension and dementia risk.

Fecal Microbiota Transfer Attenuates Gut Dysbiosis and Functional Deficits After Traumatic Brain Injury.

Traumatic brain injury (TBI) is an underrecognized public health threat. Survivors of TBI often suffer long-term neurocognitive deficits leading to the progressive onset of neurodegenerative disease. Recent data suggests that the gut-brain axis is complicit in this process. However, no study has specifically addressed whether fecal microbiota transfer (FMT) attenuates neurologic deficits after TBI. We hypothesized that fecal microbiota transfer would attenuate neurocognitive, anatomic, and pathologic deficits after TBI. C57Bl/6 mice were subjected to severe TBI (n = 20) or sham-injury (n = 20) via an open-head controlled cortical impact. Post-injury, this cohort of mice underwent weekly oral gavage with a slurry of healthy mouse stool or vehicle alone beginning 1 h post-TBI followed by behavioral testing and neuropathologic analysis. 16S ribosomal RNA sequencing of fecal samples was performed to characterize gut microbial community structure pre- and post-injury. Zero maze and open field testing were used to evaluate post-traumatic anxiety, exploratory behavior, and generalized activity. 3D, contrast enhanced, magnetic resonance imaging was used to determine differences in cortical volume loss and white matter connectivity. Prior to euthanasia, brains were harvested for neuropathologic analysis. Fecal microbiome analysis revealed a large variance between TBI, and sham animals treated with vehicle, while FMT treated TBI mice had restoration of gut dysbiosis back to levels of control mice. Neurocognitive testing demonstrated a rescue of normal anxiety-like and exploratory behavior in TBI mice treated with FMT. FMT treated TBI mice spent a greater percentage of time (22%, P = 0.0001) in the center regions of the Open Field as compared to vehicle treated TBI mice (13%). Vehicle-treated TBI animals also spent less time (19%) in the open areas of zero maze than FMT treated TBI mice (30%, P = 0.0001). Comparing in TBI mice treated with FMT, MRI demonstrated a marked attenuation in ventriculomegaly (P < 0.002) and a significant change in fractional anisotropy (i.e., loss of white matter connectivity) (P < 0.0001). Histologic analysis of brain sections revealed a FMT- injury dependent interaction in the microglia/macrophage-specific ionized calcium-binding protein, Iba1 (P = 0.002). These data suggest that restoring a pre-injury gut microbial community structure may be a promising therapeutic intervention after TBI.

14-3-3θ Does Not Protect against Behavioral or Pathological Deficits in Alzheimer's Disease Mouse Models.

Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with synaptic dysfunction and dendritic spine loss and the pathologic hallmarks of β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles. 14-3-3 proteins are a highly conserved family of proteins whose functions include regulation of protein folding, neuronal architecture, and synaptic function. Additionally, 14-3-3s interact with both Aβ and tau, and reduced levels of 14-3-3s have been shown in the brains of AD patients and in AD mouse models. Here, we examine the neuroprotective potential of the 14-3-3θ isoform in AD models. We demonstrate that 14-3-3θ overexpression is protective and 14-3-3θ inhibition is detrimental against oligomeric Aβ-induced neuronal death in primary cortical cultures. Overexpression of 14-3-3θ using an adeno-associated viral (AAV) vector failed to improve performance on behavioral tests, improve Aβ pathology, or affect synaptic density in the J20 AD mouse model. Similarly, crossing a second AD mouse model, the AppNL-G-F knock-in (APP KI) mouse, with 14-3-3θ transgenic mice failed to rescue behavioral deficits, reduce Aβ pathology, or impact synaptic density in the APP KI mouse model. 14-3-3θ is likely partially insolubilized in the APP models, as demonstrated by proteinase K digestion. These findings do not support increasing 14-3-3θ expression as a therapeutic approach for AD.

Nuclear-Mitochondrial Interactions.

Mitochondria, the cell’s major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.

Shift of musical hallucinations to visual hallucinations after correction of the hearing deficit in a patient with Lewy body dementia: a case report

BackgroundMusical hallucinations are a particular type of auditory hallucination in which the patient perceives instrumental music, musical sounds, or songs. Musical hallucinations are associated with acquired hearing loss, particularly within the elderly. Under conditions of reduced auditory sensory input, perception-bearing circuits are disinhibited and perceptual traces released, implying an interaction between peripheral sensory deficits and central factors related to brain dysfunction.Case presentationA 71-year-old Caucasian man with hearing loss complained of memory difficulties and resting tremor of the right upper limb in the previous 2 years. He already had difficulties in instrumental activities of daily life. Neurological examination showed Parkinsonian signs and hypoacusia. Neuropsychological examination identified deficits in executive functions and memory tests. Brain computerized tomography and nuclear magnetic resonance scans showed mild cortical and subcortical atrophy. The clinical diagnosis of possible dementia with Lewy bodies was established. Five years later, the patient began complaining of musical hallucinations. There had been no previous change in medication. An otorhinolaryngologist diagnosed age-related hearing loss and prescribed bilateral hearing aids. After using the hearing aids, the patient did not hear the songs any longer, only some tinnitus, described as a whistle. However, at the same time, the patient started experiencing visual hallucinations he never had before.DiscussionTo our knowledge, the immediate shift of hallucinations from one sensory modality to another sensory modality when perception is improved has not been previously described. This report emphasizes the interaction between brain pathology and sensory deficits for the genesis of hallucinations, and reinforces the theory that attention and control networks must couple properly to the default mode network, as well as integrate and select adequately peripheral signals to the somatosensory cortices, in order to keep a clear state of mind.ConclusionThe clinician should bear in mind and let the patient know that improving one sensory modality to ameliorate hallucinations may sometimes paradoxically lead to hallucinations in a different sensory modality.

The best interests of the child: More questions about this construct?

In this article I examine the best interests of the child construct and raise questions about the utility of the construct. I also draw attention to Winnicott’s good enough parenting proposal as an alternative conceptualisation that addresses the issue of parental child-rearing capacity.The best interests construct that emanates from the US has been the dominant international child-protection paradigm for at least two decades. Associated with this construct is a focus on individual parental pathology and child-rearing deficits. Yet, family poverty is the dominant factor, rather than parental pathology or incapacity, that precipitates many child abuse and neglect cases. The question is, has the best interests construct, one that ignores poverty and social disadvantage, outlived its usefulness? This construct has certainly affected Aboriginal families and led, as evidence shows, to the over-removal of children from these families. A range of alternative interventions and a social model of child protection is then canvassed.

Brain deficits in prediabetic adults: A systematic review.

Previous findings on the relationship between prediabetes (the precursor stage of type 2 diabetes) and brain health in humans are inconsistent. Thus, this systematic review of cross-sectional and longitudinal studies aimed to summarize what is currently known about brain deficits in prediabetic adults. Following the PRISMA reporting standards for systematic reviews, we conducted a comprehensive review of peer-reviewed journal articles published from 2009 to present, focusing on studies that assessed brain volume, structural connectivity, and cerebrovascular health in prediabetic adults and older adults (i.e., 18years or older). We systematically searched PsychINFO, Scopus, Web of Science, Ovid MEDLINE, CINAHL, and EMbase databases. Quality assessment was based on the NIH Quality Assessment Tool for Observational and Cross-sectional Studies. In total, 19 studies were included in our review. Results from these studies show that prediabetes may be associated with deficits in brain structure and pathology, however, several studies also refute these findings. Moreover, we identified clear inconsistencies in study methodologies, including diabetes measures and classification, across studies that may account for these conflicting findings.