Journal of Neural Transmission最新文献

Advanced Parkinson's disease (APD) represents a late stage of Parkinson's disease and is characterized by complex motor and non-motor symptoms that are less responsive to oral dopaminergic therapies. While APD has a relevant impact on patients' quality of life and requires intensified treatment, consistent diagnostic criteria have only recently been proposed. The precise pathophysiology underlying the symptoms of APD remains poorly understood, making early prognostication and intervention difficult. Neuroimaging has emerged as a promising tool for elucidating the mechanisms driving APD, identifying biomarkers for disease staging, and predicting therapeutic response. Techniques such as molecular imaging and magnetic resonance imaging provide insight into molecular and structural changes associated with the progression of PD, including protein aggregation, neuroinflammation, and regional neurodegeneration. While positron emission tomography imaging of alpha-synuclein and other pathologies offers avenues for staging and differential diagnosis, advanced magnetic resonance imaging approaches have the potential for capturing subtle microstructural changes i.e. through neuromelanin-sensitive or diffusion-weighted imaging. However, the majority of imaging studies has focused on early Parkinson's disease, leaving their applicability to APD uncertain. Future research should prioritize the validation of neuroimaging findings in well-defined APD cohorts and extend their use to predict clinical milestones such as motor fluctuations, dyskinesia, and cognitive decline. These efforts are essential to advance personalized therapeutic strategies and bridge the gap between research and clinical management of APD.

Protein misfolding and aggregation is a major pathological hallmark in a variety of human conditions, including cancer, diabetes, and neurodegeneration. However, we still do not fully understand the role of protein accumulation in disease. Interestingly, recent breakthroughs in artificial intelligence (AI) are having a tremendous impact on our ability to predict three-dimensional protein structures and understand the molecular rules governing protein folding/misfolding. This progress will enable us to understand how intrinsic and extrinsic factors trigger protein misfolding, thereby changing protein function. These changes, in some cases, are related to normal biological responses and, in other cases, associated with pathological alterations, such as those found in many neurodegenerative disorders. Here, we provide a brief historical perspective of how findings in the field of prion diseases and prion biology have enabled tremendous advances that are now forming the basis for our understanding of disease processes and discuss how this knowledge is now emerging as central for our ability to classify, diagnose, and treat devastating neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

Patients with advanced Parkinson's disease (PD) face a variety of nutritional challenges, including dysphagia, malnutrition, impaired absorption, gastrointestinal issues, and adverse drug interactions, in addition to body weight fluctuations. These challenges are especially significant for those utilising device-aided therapies (DATs), requiring personalised management strategies. Integrating dietitians into the multidisciplinary team (MDT) is vital for optimising nutrition, enhancing medication efficacy, and managing symptoms. This paper outlines strategies for supporting advanced PD patients using DATs, highlighting the critical role of dietitian assessments. Although there is no one-size-fits-all solution, dietary interventions are essential for improving motor function, preventing complications, and promoting overall health.

Rats treated intracerebroventricularly with streptozotocin (STZ-icv) develop pathologic features, which resemble those in Alzheimer's disease and have been proposed as a non-transgenic model for sporadic type of the disease (sAD). We aimed to characterize cholinergic transmission in the rat brain as a function of STZ-icv dose and time after the treatment. Acetylcholinesterase (AChE) activity and expression of muscarinic (M1, M4) and nicotinic (α7) receptors, cholin acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were measured in hippocampus (HPC) and parietotemporal cortex (CTX) of STZ-icv and age-matched control rats one week, and one, three, six and nine months after the icv administration of STZ (0.3, 1 and 3 mg/kg), respectively. Cholinergic and astroglial changes were found most pronounced with a highest STZ dose in time-dependent manner. The cortex and hippocampus exhibited specific alterations in cholinergic transmission following STZ-icv administration, with either similar or distinct patterns depending on the parameter observed: increased AChE activity in HPC and invariable in CTX; increased M4 and ChAT levels in both regions; substantial cortical M1 level increment and moderate hippocampal M1 decrement; and decreased α7 levels in both regions, with subsequent increase observed only in HPC. Alterations in cerebral cholinergic neurotransmission in STZ-icv rat model were mostly following a threephasic time pattern: acute response (Phase I), complete/partial compensation (Phase II), and reappearance/progression of changes (Phase III). Staging structure of cholinergic changes in STZ-icv rat model might be speculated to partly correlate with cholinergic pathology in clinical AD stages.

In this study, we further characterized a non-transgenic model of tauopathy by examining tau protein changes using ELISA and Western blot upon inoculation of human tau oligomers (TO) and human tau synthetic pre-formed fibrils (TF) into the medial entorhinal cortex of Wistar rats. Our analyses showed that inoculation with TO did not significantly alter the ratio of phosphorylated tau at AT8 epitopes (pSer202/pThr205) to total tau protein in the hippocampus and entorhinal cortex, but only resulted in a decrease of phosphorylation at AT100 epitopes (pThr212/pSer214). As we previously observed an increase in AT8 immunostaining in both regions, this suggests method-dependent conformational alterations. In contrast, eleven months after inoculation, TF caused significant AT8 and PHF-1 (pSer396/pSer404) epitope-specific changes in tau phosphorylation in the hippocampus, but not in the entorhinal cortex, reflecting a more advanced stage of Alzheimer's disease (AD)-like changes compared to TO. Importantly, amyloid plaques appeared as early as four months post-inoculation with TO, preceding significant phosphorylation changes of tau, thus indicating that amyloid probably facilitates early tau seeding and spreading. This was corroborated by the observed dynamic changes in Aβ_1-42 levels in cerebrospinal fluid, with initial decreases followed by increases, similar to patterns seen in transgenic mouse models of AD and in AD patients. Altogether, these findings lead us to conclude that changes in tau protein induce amyloid changes and vice versa, which is actually what defines AD as a unique neurodegenerative disease.

Alzheimer's disease (AD) is the main cause of dementia and accounts for 60% of dementia syndromes in people older than 75 years. The correct classification of AD and non-AD cases is mandatory to study disease mechanisms or new treatment possibilities. A typical clinical picture of AD consists of a progressive cognitive decline, with primary memory impairment. Structural, functional, and molecular brain imaging, along with CSF biomarkers of amyloid pathology, neurodegeneration, and the presence of a vulnerability-associated APOE genotype, support the diagnosis of AD. Use of biomarkers have led to the identification of individuals with mild cognitive impairment who are amyloid-negative addressing a conceptually separate clinical entity named suspected non-Alzheimer disease pathophysiology (SNAP). Clinical presentation and progression of SNAP can mimic AD which makes the final diagnosis and possible treatment uncertain in up to 30% of cases in clinical centers that are not using biomarkers. These non-AD pathologies are common with advancing age both in cognitively impaired and clinically normal elderly people and include Argyrophilic Grain Disease (ARG), Tangle Predominant Dementia and TDP-43 proteinopathy. The terms Primary age-related tauopathy (PART) and Limbic-dominant TDP-43 age-related encephalopathy (LATE) have been proposed as the most common and useful biological and emerging clinical construct to describe this phenomenon in > 80 years old individuals. Current evidence underlines the limitations of existing diagnostic tools, which remain inadequate for fully capturing the complexities of these conditions. Addressing these diagnostic ambiguities is crucial for assigning accurate diagnoses, reducing frequent misdiagnoses of AD, and implementing appropriate therapeutic strategies for elderly patients with mild cognitive impairment and dementia.

Neurodegenerative diseases raise public health concerns. Recent evidence indicates that Alzheimer's disease (AD) sufferers will triple by 2050. The rising incidence of dementia diagnoses raises concerns about the socio-economical and emotional impact of this uncurable illness, which reduces quality of life through cognitive decline. Although genetic and environmental factors may contribute to its aetiology, neuropathological mechanisms underlying these disorders are still under investigation. One is brain insulin resistance (BIR), which has been associated with clinical cognitive dysfunction and linked to mitochondrial dysfunction, neurogenesis deficits, and cell death. Not limited to neurodegeneration, these phenotypes have been associated with other neuropsychiatric disorders. Streptozotocin (STZ), a diabetes-causing drug that targets pancreatic β-cells, may imitate BIR in suitable models. From patients' neuroimaging to in vitro approaches, scientists have been striving to understand the pathophysiology of such disorders at the behavioural, molecular, and cellular levels. Although animal models are useful for studying insulin resistance's systemic effects, in vitro phenotypic research represents an alternative to study molecular and cellular aspects. STZ and hypoglycaemia-like scenarios have been successful for studying neurodegenerative disorders in primary cell culture (e.g., neuroblastoma cells) and patient-specific neural cell lines derived from pluripotent stem cells (iPSCs). Intriguingly, STZ treatment or hypoglycaemia-like conditions in a dish were able to induce AD pathological characteristics such Aβ plaque deposition and Tau protein hyperphosphorylation. Such approaches have shown potential in understanding molecular and cellular implications of metabolic changes in neuropsychiatric disorders, according to this review. Furthermore, these models may help identify novel treatment targets.

Alzheimer's disease (AD) and epilepsy exhibit a complex bidirectional relationship. Curiously, diabetes as a comorbidity increases the risk of epilepsy among AD patients. Recently, we reported that the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy, displays a partial AD-like phenotype, including brain insulin resistance. We also assessed seizure susceptibility in an AD model created through intracerebroventricular injections of streptozotocin (icv-STZ), which induces AD features via brain insulin resistance. Our goal was to explore how disrupted brain insulin signaling influences AD-like features and seizure susceptibility in the WAR strain. Adult male WARs received a single intracerebroventricular injection of streptozotocin (icv-STZ) (1.5 mg/kg) or vehicle (saline). Two weeks post-injection, spatial memory was assessed using the Barnes Maze (BM) test. Three weeks later, the rats underwent an audiogenic kindling (AuK) protocol (20 acoustic stimuli, 2 per day) to evaluate seizure frequency and severity. Seizures were analyzed using the Categorized Severity Index and Racine's scale and Western blot analysis was performed on hippocampal tissue. Our findings revealed that icv-STZ significantly worsened memory performance, increased seizure frequency, and reduced seizure onset relative to vehicle. Furthermore, icv-STZ decreased Akt activation and increased Glycogen Synthase Kinase-3 (GSK3) phosphorylation, indicating disrupted insulin signaling. Notably, icv-STZ decreased tau phosphorylation without altering amyloid β precursor protein (AβPP) levels. In conclusion, a low-dose icv-STZ injection exacerbates memory deficits and seizure susceptibility in the WAR strain by disturbing downstream proteins involved in insulin signaling. This highlights the implications of brain insulin resistance in both AD and epilepsy.

During the COVID-19 pandemic, some children experienced psychological distress. Moreover, pandemic-related stressors were associated with changes in hair cortisol concentrations (HCC) in youth. Research has shown that parental distress influenced children's well-being during the pandemic, but it remains unclear whether parental distress is associated with children's HCC during the pandemic. Furthermore, as some preliminary evidence suggests that children's HCC may predict their emotional response to the pandemic, it is essential to assess whether children's HCC provides insight into their susceptibility to developing symptoms associated with stress-related psychopathologies. The present study aimed to (1) examine the association between parental pandemic-related distress and children's HCC; (2) investigate the moderating role of parental distress on the association between parent and child HCC; and (3) explore the association between children's HCC and their distress longitudinally. In June 2020, 71 parent-child (8-15 y/o) dyads provided a hair sample to assess pre-pandemic HCC (December 2019-March 2020) and pandemic HCC (March-June 2020) in Quebec, Canada. Post-traumatic stress, anxiety, depression, and stress symptoms were also assessed in dyads every three months from June 2020 to March 2021. Results showed that parental stress symptoms and HCC were positively associated with children's HCC during the pandemic. Moreover, children's pre-pandemic and pandemic HCC were independently negatively associated with children's anxiety symptoms during the pandemic. These results provide evidence of an association between parental physiological and psychological stress and their children's HCC during the pandemic and suggest that HCC may help identify youth at risk of developing anxiety symptoms during chronic stressful events.