Progressive Cognitive Deficits Research Articles

Psychotic behavior in normal pressure hydrocephalus

Normal pressure hydrocephalus (NPH) usually presents with progressive gait impairment, urinary incontinence, and cognitive deficits. Many studies have shown that NPH can mimic other disorders like Parkinson disease with tremors and rigidity. In this report, we present our experience with three patients who had psychotic behavior and were treated with psychiatric medications but were subsequently investigated and found to have NPH. After lumboperitoneal shunting, all the three became normal and were even able to stop the psychiatric medications completely. The message is that NPH can mimic a psychiatric disorder and awareness about this well treatable condition is important especially among the psychiatrists and geriatricians.

Brain glycogen build-up measured by magnetic resonance spectroscopy in classic infantile Pompe disease.

Classic infantile Pompe disease is caused by abnormal lysosomal glycogen accumulation in multiple tissues, including the brain due to a deficit in acid α-glucosidase. Although treatment with recombinant human acid α-glucosidase has dramatically improved survival, recombinant human acid α-glucosidase does not reach the brain, and surviving classic infantile Pompe patients develop progressive cognitive deficits and white matter lesions. We investigated the feasibility of measuring non-invasively glycogen build-up and other metabolic alterations in the brain of classic infantile Pompe patients. Four classic infantile patients (8-16 years old) and 4 age-matched healthy controls were scanned on a 7 T MRI scanner. We used T2-weighted MRI to assess the presence of white matter lesions as well as 1H magnetic resonance spectroscopy and magnetic resonance spectroscopy imaging to obtain the neurochemical profile and its spatial distribution, respectively. All patients had widespread white matter lesions on T2-weighted images. Magnetic resonance spectroscopy data from a single volume of interest positioned in the periventricular white matter showed a clear shift in the neurochemical profile, particularly a significant increase in glycogen (result of acid α-glucosidase deficiency) and decrease in N-acetyl-aspartate (marker of neuronal damage) in patients. Magnetic resonance spectroscopy imaging results were in line and showed a widespread accumulation of glycogen and a significant lower level of N-acetyl-aspartate in patients. Our results illustrate the unique potential of 1H magnetic resonance spectroscopy (imaging) to provide a non-invasive readout of the disease pathology in the brain. Further study will assess its potential to monitor disease progression and the correlation with cognitive decline.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3β (GSK-3β), a potential target of AD treatment. PurposeTo investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3β pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. MethodThe oxidative stress of PC12 cells was induced by H2O2 (600 μM) and the effects of TFGF-18 (2 and 8 μM) or ISO (12.5 and 50 μM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. ResultsTFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3β (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3β pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. ConclusionsTFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3β/Nrf2 pathway.

Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism.

Zinc transporter 3 (ZnT3) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT3 knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT3 deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT3 deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT3 knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT3 knockout mice. We hypothesize that the ZnT3 deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.

"Relationships, Very Quickly, Turn to Nothing": Loneliness, Social Isolation, and Adaptation to Changing Social Lives Among Persons Living With Dementia and Care Partners.

Persons with dementia and their care partners have known risks for loneliness and social isolation throughout the disease trajectory, yet little is described about social lives in a population heterogeneous for disease stage, syndrome type, and setting. We conducted a secondary analysis of qualitative interviews from multiple studies to triangulate responses from a cohort of persons with dementia (n = 24), and active (n = 33) or bereaved (n = 15) care partners diverse in setting, dementia type and stage, and life experience. Interviews explored challenges related to social lives and were analyzed thematically. Persons with dementia were on average 80 years old (range: 67-94), 38% female, and 78% diagnosed with Alzheimer's dementia; care partners were on average 67 years old (range: 40-87) and 69% female. We identified 3 primary themes. First, dyads lost external social networks due to complex factors, including discomfort of surrounding social networks, caregiving responsibilities, and progressive cognitive deficits. Second, care partners described disruptions of meaningful dyadic relationships due to progressive cognitive and functional deficits, leading to loneliness and anticipatory grief. Third, adaptive strategies centered on care partners facilitating shared social activities and programs addressing caregiver burden. An overarching theme of disease-course accumulation of barriers to social interactions and constant adaptations was present in all themes. Isolation and loneliness are a shared experience and source of distress for persons with dementia and care partners. Results can inform interventions tailored to individual needs and disease stages of dyads that enhance social connectedness.

The microbiota-gut-brain axisin Huntington's disease: pathogenic mechanisms and therapeutic targets.

Huntington's disease (HD) is a currently incurable neurogenerative disorder and is typically characterized by progressive movement disorder (including chorea), cognitive deficits (culminating in dementia), psychiatric abnormalities (the most common of which is depression), and peripheral symptoms (including gastrointestinal dysfunction). There are currently no approved disease-modifying therapies available for HD, with death usually occurring approximately 10-25 years after onset, but some therapies hold promising potential. HD subjects are often burdened by chronic diarrhea, constipation, esophageal and gastric inflammation, and a susceptibility to diabetes. Our understanding of the microbiota-gut-brain axis in HD is in its infancy and growing evidence from preclinical and clinical studies suggests a role of gut microbial population imbalance (gut dysbiosis) in HD pathophysiology. The gut and the brain can communicate through the enteric nervous system, immune system, vagus nerve, and microbiota-derived-metabolites including short-chain fatty acids, bile acids, and branched-chain amino acids. This review summarizes supporting evidence demonstrating the alterations in bacterial and fungal composition that may be associated with HD. We focus on mechanisms through which gut dysbiosis may compromise brain and gut health, thus triggering neuroinflammatory responses, and further highlight outcomes of attempts to modulate the gut microbiota as promising therapeutic strategies for HD. Ultimately, we discuss the dearth of data and the need for more longitudinal and translational studies in this nascent field. We suggest future directions to improve our understanding of the association between gut microbes and the pathogenesis of HD, and other 'brain and body disorders'.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43

TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as “TDP-43 proteinopathies”. Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

Abstract TP298: Cellular Senescence and Microglial Dysfunction are Linked to Progressive Cognitive Deficits in the Chronic Phase of Ischemic Stroke

Improvements in acute stroke treatment, including endovascular thrombectomy and critical care management, have increased survival rates after stroke. However, many survivors have significant neurological deficits, as stroke remains one of the leading causes of long-term disability. Despite this, the chronic progression and long-term sequelae of ischemic stroke pathology remains woefully understudied. This study examined long-term progressive deficits in young adult male C57Bl/6 mice at 3 and 6 months after a 60-minute transient middle cerebral artery occlusion (MCAO) or sham surgery to identify secondary injury processes, and neuropathology of chronic stroke human brains. Depressive-like behavior persisted for 6 months post-stroke (PS) (p= <0.0001). Cognitive function progressively worsened from 3 to 6 months as seen by a continual reduction in the discrimination index in the novel object recognition task (p=.0063). Deficits in memory retention in mice 6-months PS were observed using the fear-conditioning test (p=.0084). Brain atrophy was evident by MicroCT imaging. Histopathological assessment revealed increased microglial activation in the hippocampus and frontal cortex in both mouse and human brains chronically after stroke. Interestingly, we also observed microglia activation proximal to apoptotic neurons in the brains of stroke mice, as shown by TUNEL assay. TUNEL co-labeling with a neuronal marker showed the same neuronal apoptosis in human samples from patients with chronic stroke, in both the hippocampus and thalamus. Disease-associated microglial (DAM) phenotypes were marked by both increased proliferative status and senescent-like phenotypes, including elevated production of cytokines and other proinflammatory molecules. Our findings demonstrate that experimental stroke accelerates inflammaging in the brain, which induces premature senescence within the chronic infarct microenvironment. Cellular senescence and chronic neurodegenerative signatures likely contribute to progressive cognitive impairment following stroke. The chronic and evolving neurological consequences of stroke may offer viable targets for delayed treatment strategies to reduce risk of vascular dementia and neurodegenerative disease.

Unverricht-Lundborg Disease: Tackling the Challenges of a Complex Clinical Picture


 Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy type 1, is characterized by stimulus-induced myoclonus and seizures without major progressive cognitive deficit, usually presenting during late childhood and early adolescence. It is an autosomal recessive disease, and, so far, only pathogenic variants in the gene encoding cystatin B (CSTB) have been described. We report the case of a 9-year-old boy who presented with generalized tonic-clonic seizures and developed paroxysmal myoclonic events over several years. The patient was started on antiseizure medication, but disease progression resulted in several changes to the therapeutic scheme, with highly variable clinical responses. The genetic study detected the pathogenic variant c.67-1G>C p.(?) in heterozygosity in the CSTB gene, after having identified the typical dodecameric expansion in the other allele, confirming the diagnosis of ULD.

The effect of Huntington's disease on cognitive and physical motivation.

Apathy is one of the most common neuropsychiatric features of Huntington's disease. A hallmark of apathy is diminished goal-directed behaviour, which is characterized by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit and/or is secondary to the progressive cognitive and physical deficits that accompany more advanced disease. We addressed this question by testing 17 individuals with manifest Huntington's disease and 22 age-matched controls on an effort-based decision-making paradigm. Participants were first trained on separate cognitively and physically effortful tasks and provided explicit feedback about their performance. Next, they chose on separate trials how much effort they were willing to exert in each domain in return for varying reward. At the conclusion of the experiment, participants were asked to rate their subjective perception of task load. In the cognitive task, the Huntington's disease group were more averse to cognitive effort than controls. Although the Huntington's disease group were more impaired than controls on the task itself, their greater aversion to cognitive effort persisted even after controlling for task performance. This suggests that the lower levels of cognitive motivation in the Huntington's disease group relative to controls was most likely driven by a primary motivational deficit. In contrast, both groups expressed a similar preference for physical effort. Importantly, the similar levels of physical motivation across both groups occurred even though participants with Huntington's disease performed objectively worse than controls on the physical effort task, and were aware of their performance through explicit feedback on each trial. This indicates that the seemingly preserved level of physical motivation in Huntington's disease was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the Huntington's disease group provided higher ratings of subjective task demand than controls for the cognitive (but not physical) effort task and when assessing the mental (but not the physical) load of each task. Together, these results revealed a dissociation in cognitive and physical motivation deficits between Huntington's disease and controls, which were accompanied by differences in how effort was subjectively perceived by the two groups. This highlights that motivation is the final manifestation of a complex set of mechanisms involved in effort processing, which are separable across different domains of behaviour. These findings have important clinical implications for the day-to-day management of apathy in Huntington's disease.

Novel Pathogenic Mechanism of Late-onset Alzheimer's Disease by Deficiency of NMDA Receptor Subunit GluN3A

Late-onset Alzheimer’s disease (AD) and related dementia (ADRD) are serious neurodegenerative disorders among aging populations. The progress of AD/ADRD cultivates over years to decades in humans and several months in animal models. Ca<sup>2+</sup> homeostasis is a core function of neurons where the N-methyl-D-aspartate (NMDA) receptor plays a major role in excitatory neuronal activities. The Ca<sup>2+</sup> hypothesis of AD proposes that even slight but sustained Ca<sup>2+</sup> dyshomeostasis in the brain is a critical pathophysiology or pathogenesis of AD. However, instigating factors like the trigger and time/duration of the Ca<sup>2+</sup> dysregulation in AD progression have been largely obscure, while β-amyloid (Aβ) peptides are often indicated as the trigger. Hyperactivities of excitatory neurons and NMDARs have been implicated in AD as a main mediating mechanism caused by AD pathologies such as Aβ deposition. NMDAR overactivation is restrained by the unique regulatory GluN3 subunits (GluN3A and GluN3B; previously known as NR3A and NR3B). Expression of GluN3A in the receptor complex reduces NMDAR currents and Ca<sup>2+</sup> influx, while deletion of GluN3A causes larger NMDA currents and elevated intracellular Ca<sup>2+</sup>. Significant GluN3A levels are detected in both rodent and human adult/aging brains. We hypothesized that the “gatekeeper” role of GluN3A is constantly required for Ca<sup>2+</sup> homeostasis and normal aging; its deficiency can lead to slowly evolved “degenerative excitotoxicity”. Our in vitro, ex vivo, and in vivo studies using GluN3A knockout (KO) mice of young and older ages revealed neuronal hyperactivity, moderate but sustained elevation of cytosolic Ca<sup>2+</sup>, chronic inflammation, neuronal loss/apoptosis, synaptic impairments and progressive cognitive deficits. The AD hallmarks of Aβ and tau pathology were identified after, but not before, cognition decline. In the “gain of function” experiment, expression of GluN3A in the GluN3A KO brain prevented AD progression. Specific regional knockdown of GluN3A in the cortex and hippocampus of wild-type mice at the adult age (3 months old) resulted in similar AD/ADRD phenotypic alterations in the following 3-6 months. The NMDAR antagonist memantine (MEM) is approved by FDA as a symptomatic treatment for moderate-severe AD patients. According to the chronic neurohyperactivity in AD progression and the modified Ca<sup>2+</sup> hypothesis that Ca<sup>2+</sup> dysregulation is an early and “life-long” pathogenesis, the maintenance of NMDAR normal activity by MEM or other safe NMDAR antagonists could be a disease-modifying early treatment in preclinical/prodromal stages. This prediction is endorsed by clinical trials using MEM and other NMDAR antagonists in mild cognitive impairment (MCI) and early AD patients, showing beneficial effects of maintaining cognitive functions. Consistently, we showed that, in GluN3A KO mice and 5xFAD mice, early and chronic MEM treatment (started at 3-month of age and lasted for 3-6 months) prevented or attenuated AD phenotypes. Meanwhile, the chronic MEM therapy in mice showed preconditioning effect of neuroprotection against ischemic stroke that strikes over 50% AD patients. Large clinical trials of long-term and more systematic examinations on AD/ADRD progression and the comorbidity of stroke are warranted for this innovative therapy. Our results support the modification of Ca<sup>2+</sup> hypothesis of AD with the novel amyloid-independent mechanism. Specifically, the deficiency of GluN3A alone causes lifelong Ca<sup>2+</sup>-related progression of AD pathophysiology and amyloid pathology. The long-term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for late-onset AD/ ADRD.

Distribution of APP in endo‐lysosomal system induced by Aβ is modulated by Gβγ signaling

AbstractBackgroundAlzheimer´s disease is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. We recently found that Aβ assemblies, oligomers and fibrils, increase APP and BACE1 interaction in recycling endosomes and accumulation of intracellular Aβ42 in human neurons derived from iPSCs by a mechanism dependent of APP/Go/Gβγ signaling (Antonino et al 2022, https://doi.org/10.3389/fcell.2022.852738). Now, we are interested on deepen in the APP trafficking in the endo‐lysosomal pathway in order to understand the mechanism underlying such effect.MethodN2a and human neurons derived from iPSc cultures were transfected with fluorescently tagged proteins (APP‐YFP, BACE‐CH, Rab11‐RFP, LAMP1‐CH, Rab7‐CH, APP‐VN, BACE‐VC). Cultures were treated with vehicle or the Gβγ inhibitor gallein and 30 minutes later with vehicle or 1 µM of Aβ oligomeric or fibrillar. After 24 h of treatment quantitative colocalization analysis and bimolecular fluorescence complementation assays were performed.ResultWe found that Aβ induced an enrichment of APP in recycling endosomes at the expense of a decrement of its levels in lysosomes. This change in APP intracellular distribution is drive by Gβγ signaling. Moreover, we found that the changes on APP distribution correlate with an increase in its interaction with BACE1 and with an increase in the number of recycling endosomes, both events modulated by Gβγ signaling (Figure 1,2).ConclusionTogether, these results suggest that Aβ pathological assemblies induce a re‐direction of APP from its physiological route to lysosomes, to recycling endosomes which favors its encounter with BACE1 and its amyloidogenic processing. These finding elucidate the intracellular process which sustain the feed‐forward mechanisms implicated in the amyloidogenesis induced by pathological assemblies of Aβ.

Minimal hepatic encephalopathy: clinical, neurophysiological, neuroimaging markers

Hepatic encephalopathy in the initial stages is a diagnostically challenging clinical phenomenon, based on the accumulation of ammonia. Symptoms of encephalopathy are extremely varied: from a slight cognitive decrease and minimal affective disorders to disorders of consciousness and coma in the terminal stages. However, the severity of liver pathology and neurophysiological and neuroimaging data do not always correlate with the severity of encephalopathy. The greatest difficulties in diagnosis arise at the initial stage of the disease, and a timely recognized and established diagnosis can not only slow down the progression of cognitive deficits and characterological changes, but also significantly improve the patient’s prognosis.

New insights into the therapeutic approaches for the treatment of tauopathies.

Tauopathies are a group of neurological disorders, including Alzheimer's disease and frontotemporal dementia, which involve progressive neurodegeneration, cognitive deficits, and aberrant tau protein accumulation. The development of tauopathies cannot currently be stopped or slowed down by treatment measures. Given the significant contribution of tau burden in primary tauopathies and the strong association between pathogenic tau accumulation and cognitive deficits, there has been a lot of interest in creating therapies that can alleviate tau pathology and render neuroprotective effects. Recently, small molecules, immunotherapies, and gene therapy have been used to reduce the pathological tau burden and prevent neurodegeneration in animal models of tauopathies. However, the major pitfall of the current therapeutic approach is the difficulty of drugs and gene-targeting modalities to cross the blood-brain barrier and their unintended side effects. In this review, the current therapeutic strategies used for tauopathies including the use of oligonucleotide-based gene therapy approaches that have shown a promising result for the treatment of tauopathies and Alzheimer's disease in preclinical animal models, have been discussed.

P08.05.A A LONGITUDINAL CASE STUDY OF PATIENTS' EXPERIENCES IN THE INITIAL PHASE OF A BRAIN CANCER PATHWAY - AIMING TO IMPROVE PATIENT CARE

Abstract BACKGROUND A brain cancer diagnosis is life-transforming and involves accelerated diagnostics and treatment and care involving multiple settings and healthcare professionals. Patients are confronted with an uncurable cancer disease but also face progressive neurological and cognitive deficits over time, adding to the uncertain and stressful situation. Knowledge of patients' experiences during their hospital stay in the initial diagnostic phase is sparse. This study aimed to explore patients' experiences at the hospital during the diagnostic workup, the brain surgery, and the post-operative period until discharge and to describe what matters to patients when diagnosed with a malignant brain tumour. MATERIAL AND METHODS We used a descriptive longitudinal single-case study design to produce in-depth, context-dependent knowledge and capture real-life situations in patients' day-to-day care experiences from admission to discharge across three different departments throughout the initial diagnostic phase. To explore patients' views directly in the actual situations unfolding in practice, we followed one patient at a time and did 180 hours of field observation and 16 semi-structured interviews. We analyzed field notes and interviews by applying systematic text condensation. RESULTS An overarching theme, "A fast transition", was identified, describing the patients' experiences in the two central themes; "From feeling fine to an unknown journey" and "Patient involvement determined by system factors". Within the two themes, six subthemes emerged from the data: Overwhelming uncertainty and fear, Putting life on hold, An unfamiliar dependency and Being unprepared and side-lined, The significance of close relatives, and Managing care needs and demands. CONCLUSION The results add to understanding patients' experiences during the initial diagnostic phase. While part of the findings are a fact of life for patients diagnosed with a brain tumour, others point to specific areas for improvement. Small changes in care delivery can enhance patient involvement by proactively informing patients about their care plan, ensuring the presence of relatives during information giving and identifying patients' care needs and preferences. Establishing a patient and public involvement group in 2023 will provide more knowledge gaps for future research.

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease.

The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and wild type (WT) littermates underwent in vivo 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

Screening for Novel Inhibitors of Amyloid Beta Aggregation and Toxicity as Potential Drugs for Alzheimer's Disease.

AD is the most common neurodegenerative disorder characterized by progressive memory impairment and cognitive deficits. The pathology of AD is still unclear; however, several studies have shown that the aggregation of the Aβ peptide in the CNS is an exclusively pathological process involved in AD. Currently, there is no proven medication to cure or prevent the disease progression. Nevertheless, various therapeutic approaches for AD show only relief of symptoms and mostly work on cognitive recovery. However, one of the promising approaches for therapeutic intervention is to use inhibitors for blocking the Aβ peptide aggregation process. Recently, herbal phenolic compounds have been shown to have a therapeutic property for treatment of AD due to their multifaceted action. In this study, we investigated the effectiveness of SA, Gn Rb1, and DMyr on inhibiting the aggregation and toxicity of Aβ40 and Aβ42 using different biochemical and cell-based assays. Our results showed that SA and DMyr inhibit Aβ40 and Aβ42 fibrillation, seeded aggregation, and toxicity. Gn Rb1 did not have any effect on the aggregation or toxicity induced by Aβ40 and Aβ42. Moreover, SA and DMyr were able to disaggregate the preformed fibrils. Overall, these compounds may be used alone or synergistically and could be considered as a lead for designing new compounds that could be used as effective treatment of AD and related disorders.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990–1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or lipopolysaccharide (LPS, 30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

The Neurotoxic Effect of β-Amyloid Is Accompanied by Changes in the Mitochondrial Dynamics and Autophagy in Neurons and Brain Endothelial Cells in the Experimental Model of Alzheimer's Disease.

A comparative assessment of the expression of the mitochondrial fission marker Drp1 and the autophagy marker LC3 in neurons and endothelial cells in the hippocampus and entorhinal cortex during progression of cognitive deficit was performed in animals with intrahippocampal administration of β-amyloid. In both brain regions, the expression of Drp1 and LC3 in neuronal and endothelial cells was enhanced. The peak of cognitive impairment corresponded to the maximum expression of Drp1 and LC3 in hippocampal neurons and was preceded by an increase in the number of Drp1+ and LC3+ endothelial cells in this brain region. These data attests to a possible role of aberrant mitochondrial dynamics and autophagy of endothelial cells in the impairment of brain plasticity in the Alzheimer's type neurodegeneration.

ELUCIDATING THE COMBINED EFFECTS OF AMYLOID AND TAU IN A NOVEL BIGENIC RAT MODEL WITH HUMAN ALZHEIMER’S DISEASE‐LIKE PATHOLOGY

AbstractBackgroundBoth amyloid beta (Aβ) and tau pathologies co‐exist in Alzheimer’s disease. While studies have shown that Aβ and tau interaction results in elevated AD pathology, it is not clearly understood how they might affect one another during early pathology stages leading to Aβ plaque formation. This study aimed at determining how and to which extent a combination of gradually developing amyloid and tau pathologies exacerbate each other in the context of Alzheimer’s disease‐like pathology in a novel transgenic rat model.MethodsHeterozygous McGill‐R‐Thy1‐APP and R955‐hTau single transgenic rats were crossed, producing a novel bigenic rat model with both human amyloid and tau pathologies, named McGill‐R‐APPxhTau955. Bigenic rats express human APP with the Swedish and Indiana mutations (KM670/671NL, V717F) as well as the longest isoform of human tau (2N4R) with the P301S mutation causative of frontotemporal dementia. Transgenic rats (n = 10‐12) were raised to cohorts at 12, 20 and 24 months of age and were subject to a battery of behavioural testing for cognition. Examination of amyloid and tau pathology, as well as inflammatory and neurodegenerative processes, was performed primarily using immunohistochemistry (IHC) and Western blot (WB). Levels of amyloid, tau and p‐tau were measured in CSF, brain and blood serum by electrochemiluminescence immunoassays. Bigenic animals were compared to single transgenics and wild‐type littermate controls.ResultsAPPxR955‐hTau bigenic rats produced a gradual accumulation of human amyloid and tau, resulting in progressive cognitive deficits and Alzheimer‐like pathology. We discovered that tau accumulation produced a compensatory effect on cognition and long‐term potentiation at 20 months, rescuing amyloid‐induced cognitive effects. However, at 24 months of age, bigenic rats displayed worsened cognition compared to single transgenics in spatial learning and memory. Reflective of these findings, bigenic rats developed an increased phosphorylaton of tau at 24 months and increased Aβ plaque pathology. Status of biomarker levels, neuroinflammation and neurodegeneration are actively under investigation and are expected to trend similarly.ConclusionsThe McGill‐R‐APPxhTau novel bigenic rat, developing slow progressing amyloid and tau pathologies, is an attractive model for the further investigation of mechanisms by which both proteins effect one another, the observation of biomarker changes and elucidation of early disease stages.