The cost-effectiveness and versatility of plastics have made them ubiquitous, leading to widespread human exposure to plastic associated chemicals like phthalates and bisphenols. While these chemicals are linked to adverse health effects, including hormonal and neurobehavioral, their bioavailability to the brain remains poorly understood. Thus, quantifying these chemicals in brain tissue is essential to assess blood-brain barrier permeation and support animal research.To address this, a novel method was developed to quantify 14 phthalate metabolites and 7 bisphenols using a modified QuEChERS extraction with a hexane clean-up for lipid removal and quantification on LC-MS/MS. The method detection limits for phthalate metabolites ranged from 0.02 ng/g to 0.8 ng/g of brain, while bisphenol detection limits varied between 0.02 ng/g and 2 ng/g.By successfully quantifying these contaminants in brain tissue the method delivers a highly sensitive way to assess blood-brain barrier permeation, measure cerebral exposure and contribute to animal studies of exposure to plastic associated chemicals.

Abnormal activation of a developmental process driven by a bioactive peptide T14, is posited as a key mechanism in the degeneration of the primarily vulnerable nuclei during the prodromal phase of Alzheimer’s Disease (AD). We use a range of anatomical, biochemical and genetic approaches to explore changes in T14 and its target, α7nAChR, in AD and in individuals with mood disorders, a frequent prelude to the disease. Using paired samples from the same patients, levels of T14 and α7nAChR increased in the hippocampus across the AD continuum. In contrast, in early Braak stages, T14 levels in the midbrain reach a plateau and are primarily localised to glia. Moreover, in a cognitively healthy cohort, CSF derived ex vivo revealed a differential profile between T14 and tau levels in individuals with mood disorders, a well-known precursor to AD. These observations confirm a key role of T14 in the neuropathology of AD. Finally, we show a Braak-stage dependant and selective increase in an acetylcholinesterase isoform (AChE-R) already associated with AD pathology, where the profile corresponds closely to that of T14, thereby providing further clues regarding its provenance. By highlighting region and cell-specific changes in the T14 profile as AD progresses, this study further validates a key role for T14 in the progression of neurodegeneration. Finally, the mood disorder-dependent changes based on T14 in CSF might reflect dysfunction in the primarily vulnerable isodendritic core and as such be viewed as a possible, albeit non-exclusive, prelude to AD. Collectively, these results underscore the importance of T14 in AD aetiology and could aid the development of precise and effective therapeutics to target its progression.

Astrocytes play essential roles in various functions including ionic homeostasis, energy metabolism, neurotransmission, and regulation of the blood-brain barrier. Researchers have reported that hyperphosphorylated tau in astrocytes can be identified in postmortem, particularly in individuals over the age of 60 years. Astrocytic p-tau has also been reported in association with chronic traumatic encephalopathy neuropathologic change (CTE-NC). This study investigates possible association between subpial aging-related tau astrogliopathy (ARTAG) and a history of playing high school American-style football. Postmortem brain tissue samples were obtained from 176 men (median age at death = 65 years; range = 50-96) from the Lieber Institute for Brain Development. There were 128 with no known history of participating in contact or collision sports and 48 (27.3%) who participated in football. Subpial ARTAG was identified in 23 cases (13.1%). Those who participated in football had a higher percentage with subpial ARTAG than those who did not participate in football (20.8% vs 10.2%), although this difference was not statistically significant (P =.061). The 2 groups did not differ in the percentages who had subpial ARTAG in a sulcal depth (10.4% of former football players and 7.8% of controls). More research is needed to understand possible associations between subpial ARTAG, aging, and CTE-NC.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor dysfunction, dopaminergic neuronal loss in the substantia nigra and abnormal accumulation of α-synuclein Lewy bodies. Research suggests that the cerebrovascular system plays a role in fluid dynamics, waste clearance and removal of abnormal proteins. Imaging studies show that this waste clearance system, known as the glymphatic system, is disrupted in Parkinson's disease, highlighting its involvement in the disease. This immunohistochemical human brain tissue study quantified changes in the cerebrovascular system (perivascular space, string vessels, pericytes, aquaporin-4 and astrocytes) in Parkinson's disease (n = 18) cases with variable disease durations (median = 14 years, range = 19 years) compared with age- and post-mortem-matched (P > 0.05) control cases (n = 7). Analysis was carried out in brain regions variably affected by cell loss (substantia nigra) and protein deposition (substantia nigra and medial temporal cortex). The occipital cortex was included because this region is not affected by cell loss or protein deposition. Group differences were analysed, and the relationship with protein deposition (Lewy body stage, amyloid score and neurofibrillary tangle score) was assessed. Although total astrocyte density did not change (P > 0.05), Parkinson's disease cases exhibited reduced aquaporin-4 in astrocytic endfeet and enlargement of the arteriolar and venular perivascular space. Significant changes in the capillary network were also observed, with increased presence of string vessels (P < 0.001) and pericyte loss (P < 0.001), changes likely to impact blood flow and its regulation. The increased presence of string vessels was significantly correlated with disease duration (P < 0.05), especially in the occipital cortex. The occipital cortex demonstrated the greatest decreases in pericytes (P < 0.001) and aquaporin-4 mislocalization (P < 0.05), and changes in pericyte density were also significant in the substantia nigra. In contrast, these changes were not significant in the medial temporal cortex despite protein deposition in this region. Although no Lewy pathology was detected in the occipital cortex, there was a positive relationship between Lewy body stage and perivascular space size (ρ = 0.6, P < 0.05). These findings reveal progressive, region-specific alterations in the cellular components of the glymphatic system and vascular integrity in Parkinson's disease. Notably, the correlation between increased presence of string vessels and disease duration, even in a region unaffected by protein deposition, suggests that vascular changes might play an important role in disease progression. These results emphasize the need for further investigation into the interplay between regional vascular changes and Parkinson's disease progression, which might offer new insights for therapeutic strategies.

Endocannabinoids (eCBs) are lipid-derived neuromodulators that regulate numerous neurophysiological processes by modulating synaptic transmission. Synthesised on demand in response to increased postsynaptic intracellular calcium or activation of postsynaptic G-protein coupled receptors, eCBs are rapidly degraded, resulting in transient, tightly regulated signalling. Dysregulation in the endocannabinoid system (ECS), including altered peripheral and central eCB concentrations and/or cannabinoid-1 receptor (CB1R) expression, has been observed across psychiatric syndromes, including major depressive disorder, psychotic disorders, and post-traumatic stress disorder (PTSD). These associations have prompted growing interest in pharmacological strategies targeting the ECS. Though medical cannabis is increasingly prescribed for psychiatric symptoms, its clinical use remains controversial due to limited high-quality evidence, psychotropic side effects, and regulatory constraints. An alternative is to enhance the signalling of a principal eCB, anandamide (AEA), potentially offering more physiologically constrained CB1R engagement, by inhibiting fatty acid amide hydrolase (FAAH), the main enzyme degrading AEA and its congener, N-acylethanolamines (NAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This review consolidates recent clinical evidence for FAAH inhibitors, examining their influence on AEA, safety and efficacy in ameliorating symptoms across a range of psychiatric conditions, including depression, anxiety, PTSD, and cannabis use disorder (CUD). Presently, only two compounds, PF-04457845 (JZP150) and JNJ-42165279, have progressed to Phase II trials, demonstrating modest clinical benefit in CUD, with no efficacy in PTSD or osteoarthritis pain. Herein, we discuss emerging insights, safety considerations, broader mechanistic implications, and future directions for FAAH-targeted therapeutics, advocating for a precision medicine approach to realise their potential in the treatment of psychiatric disorders.

The Department of Defense Blast Injury Research Program Coordinating Office held an International State-of-the-Science Meeting in 2015 to consider and reach consensus about the current body of knowledge relating to chronic traumatic encephalopathy (CTE) in the military. The two biggest future priority areas identified at that time related to the need for more research on CTE neuropathologic change (CTE-NC) and more research on clinical diagnostic criteria. Both have occurred and have yielded important findings. This commentary article addresses these two high priority recommendations, a decade after the state-of-the-science meeting, by reviewing recently published studies. We also add new data to the literature relating to CTE-NC in military veterans. We examined data from the Lieber Institute for Brain Development brain repository. Brain donors were 163 men with a mean age of 66 years at the time of death (range = 50-96), 70 of whom served in the military (42.9%), with 15 reportedly experiencing combat (9.2%). Tissue samples were screened to determine if they had definitive CTE-NC or 'features' of CTE-NC. No case had definitive CTE-NC. There were 4.3% of the civilian group who had 'features of CTE-NC' (4/93) and 7.1% of the veteran group had features of CTE-NC (5/70). Based on our review it is unclear how common CTE-NC is in military veterans; it is possible that it is uncommon. There are no validated clinical diagnostic criteria for CTE, and recent studies have illustrated that CTE-NC is not associated with depression, suicidality, anxiety, irritability, impulsivity, explosivity, verbal violence, physical violence, or substance abuse.

Transformative neuropathology is redefining human brain research by integrating foundational descriptive pathology with advanced methodologies. These approaches, spanning multi-omics studies and machine learning applications, will drive discovery for the identification of biomarkers, therapeutic targets, and complex disease patterns through comprehensive analyses of postmortem human brain tissue. Yet critical challenges remain, including the sustainability of brain banks, expanding donor participation, strengthening training pipelines, enabling rapid autopsies, supporting collaborative platforms, and integrating data across modalities. Innovations in digital pathology, tissue quality enhancement, harmonization of data standards, and machine learning integration offer opportunities to accelerate tissue-level "pathomics" research in brain health through cross-disciplinary collaborations. Lessons from neuroimaging, particularly in establishing common data frameworks and multi-site collaborations, offer a valuable roadmap for streamlining innovations. In this perspective, we outline actionable solutions for leveraging existing resources and strengthening collaboration -where we envision future opportunities to drive translational discoveries stemming from transformative neuropathology.

Per- and polyfluoroalkyl substances (PFAS), a large group of manmade chemicals, have been detected extensively in the blood of people living in developed countries. Although it has been suggested that PFAS exposure might be associated with harmful effects on the brain, few studies have assessed the presence of PFAS in brain tissues. This study aimed to evaluate the concentrations of a broad range of PFAS in paired postmortem human brain and serum samples and investigate brain-to-serum concentration ratios. A partitioning experiment using PFAS-fortified animal brain samples additionally investigated differences in distribution between lipid-rich brain and water for different PFAS. Out of the 43 PFAS analyzed, 5 were detected in all paired human brain and serum samples, 11 were found in all serum, and 7 were found in all brain samples. Two PFAS compounds were observed at notably higher detection frequencies in brain samples compared to serum. The brain-to-serum ratios of PFAS concentrations ranged from approximately 0.04 for perfluorohexanesulfonate (PFHxS) to 1.3 for N-methyl perfluorooctanesulfonamido acetic acid (N-MeFOSAA) with a clear increase in PFAS brain-to-serum ratios with the total number of carbons. There were no differences between the two cortical brain regions analyzed. Results underscore the necessity of a better understanding of individual PFAS, as the difference in their properties can influence their behavior within the human brain.

Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only for amyloid β (Aβ). In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (Aβ, tau, α-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing α-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (Aβ and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or α-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.

Hyposmia is one of the most prevalent non-motor symptoms of Parkinson’s disease and antecedes motor dysfunction by up to a decade. However, the underlying pathophysiology remains poorly understood. In this study, we investigated the mechanisms of dopamine metabolism in post-mortem olfactory bulbs from ten Parkinson’s disease and ten neurologic control subjects. In contrast to the loss of dopaminergic neurons in the midbrain, we observed an increase in tyrosine hydroxylase-positive neurons in the Parkinson’s disease olfactory bulb, suggesting a potential role for dopamine in the hyposmia associated with the condition. Using immunohistochemistry, high-performance liquid chromatography, western blot, and enzyme-linked immunosorbent assays, we demonstrate a reduction in catechol-O-methyltransferase catabolism of dopamine to homovanillic acid, potentially due to a depletion of the methyl donor substrate S-adenosyl methionine. We hypothesized that reduction in catechol-O-methyltransferase activity would result in increased dopamine occupation of the D2 receptor, and consequent inhibition of olfactory processing. Next, we conducted pharmacological interventions to modify dopamine dynamics in hyposmic tau knockout mice, which exhibit altered dopamine metabolism. Our hypothesis was supported by the observation that the D2 receptor antagonist haloperidol temporarily alleviated olfactory deficits in these tau knockout mice. This study implicates a potential role of catechol-O-methyltransferase-mediated dopamine metabolism in the early olfactory impairments associated with Parkinson’s disease.

The retrotrapezoid nucleus (RTN) of rodents is located ventral to the facial motor nucleus (7N) and consists of acid-sensitive neurons that activate breathing and mediate the central component of the ventilatory response to hypercapnia. In rodents, RTN neurons can be histologically identified by the presence of paired-like homeobox 2B positive nuclei (Phox2b +) and the absence of cytoplasmic choline acetyltransferase (ChAT-) and tyrosine hydroxylase (TH-). Up to 50

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (

Mitochondrial activity directs neuronal differentiation dynamics during brain development. In this context, the long-established metabolic coupling of mitochondria and the eukaryotic host falls short of a satisfactory mechanistic explanation, hinting at an undisclosed facet of mitochondrial function. Here, we reveal an RNA-based inter-organellar communication mode that complements metabolic coupling of host-mitochondria and underpins neuronal differentiation. We show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (PNPase) located in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, acquisition of neRNA by mitochondria leads to a collapse of proton motive force, suppression of ATP production, and a resultant amplification of autophagic flux that attenuates proteomic memory. Collectively, these events force the progenitor cells towards a “tipping point” characterised by emergence of a competing neuronal differentiation program. It appears that neuronal differentiation is a consequence of reprogrammed coupling of metabolomic and transcriptomic landscapes of progenitor cells, with mitochondria emerging as key “reprogrammers” that operate by acquiring and metabolising neRNAs. However, the documented role of mitochondria as “reprogrammers” of differentiation remains to be validated in other neuronal lineages and in vivo.

Poly-GA immunohistochemistry (A) on formalin fixed paraffin embedded cerebellum sections shows a similar distribution to p62 antibody (B) and reliably identifies neuronal cytoplasmic inclusions and neurites in cases with known C9orf72 repeat expansion. This is useful in the research setting where genetic testing has not been performed in life or suitable tissue is not avilable post-mortem.

AimsWe applied the 2021 consensus criteria for both chronic traumatic encephalopathy neuropathological change and traumatic encephalopathy syndrome in a small case series of six former elite-level Australian rugby code players.MethodsNeuropathological assessment of these cases was carried out at the Sydney and Victorian Brain Banks. Clinical data were collected via clinical interviews and health questionnaires completed by the participants and/or their next of kin, and neuropsychological testing was conducted with participants who were capable of completing this testing.ResultsAll cases exhibited progressive cognitive impairment during life. Chronic traumatic encephalopathy neuropathological change was identified in four out of the six cases. However, coexisting neuropathologies were common, with limbic-predominant age-related TDP-43 encephalopathy and ageing-related tau astrogliopathy seen in all cases, intermediate or high Alzheimer's disease neuropathological change seen in four cases and hippocampal sclerosis seen in two of the six cases.ConclusionThe presence of multiple neuropathologies in these cases complicates clinical diagnostic efforts for traumatic encephalopathy syndrome. It will be important for further clinicopathological studies on larger groups to report all neuropathological comorbidities found in cases diagnosed with either chronic traumatic encephalopathy neuropathological change and/or traumatic encephalopathy syndrome. In this clinicopathological case series of former Australian rugby code players, four of six had post mortem CTE-NC. All met current diagnostic criteria for TES and had multiple pathologies at post mortem. Future studies are needed to improve the specificity of the TES consensus diagnostic criteria for predicting the presence of CTE-NC, and we encourage future researchers to report all neuropathological comorbidities clearly in their clinicopathological studies. image

Clinical studies indicate that traumatic brain injury (TBI) is linked to an increased risk of dementia during life. However, studies involving neuropathologically-confirmed cases have shown conflicting results. This study was aimed at assessing a large brain bank cohort to identify any association between TBI and the presence of pathologies underlying the most commonly found dementias, Alzheimer’s disease (AD) and Lewy body disease (LBD). 636 cases were assessed for this study (average age 76.2). Cases with a history of TBI were identified using donor records held at the Sydney Brain Bank. We use the term "TBI” to include a single or multiple TBIs, as well as repetitive mild neurotrauma that may be subconcussive (N = 109). Amyloid plaque and alpha synuclein pathologies were identified by immunohistochemistry. Neurofibrillary tangles were identified using modified Bielschowsky silver staining. Pathology was assessed according to current neuropathological diagnostic criteria. Multivariate regression statistics were used to assess the effect of TBI, age and gender on amyloid plaque (A score), neurofibrillary tangles (B score) and Lewy pathology stages. Multinomial logistic regression was used to examine the effect of TBI on pathological diagnosis. TBI was not significantly associated with increased amyloid (p = 0.05) or Lewy pathology stages (p = 0.65), however the odds of having a higher neurofibrillary tangle stage increased by 75% in the TBI group (p = 0.009)(Figure 1). Gender was not a significant predictor of amyloid (p = 0.29), neurofibrillary tangle (p = 0.89) or Lewy pathology (p = 0.15). Not unexpectedly, age was a significant predictor of AD pathologies, including amyloid (p = <0.0000001) and neurofibrillary tangle (p = 0.00002) stages, although age was not a significant driver of Lewy body pathology (p = 0.1). There was no association between TBI and overall diagnosis of AD neuropathologic change or LBD (p = 0.12). In this elderly neurodegenerative cohort, age remains a risk factor for AD, but not LBD pathology. Gender did not have a significant association with these pathologies in this cohort. TBI did not increase the risk of AD but did increase the frequency of neurofibrillary tangles, suggesting that abnormal tau protein accumulation following TBI is an important long-term consequence that may contribute to poor brain aging and future neurodegeneration.

Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological events suggests the existence of programmable non-linear elements in the underlying signalling pathways. Here, we review the network topology of key signalling pathways with a focus on redox-sensitive proteins, including PTEN and Ras GTPase, that reshape the connectivity profile of signalling pathways in response to an altered redox state. While this network-level impact of redox is achieved by the modulation of individual redox-sensitive proteins, it is the population by these proteins of critical nodes in a network topology of signal transduction pathways that amplifies the impact of redox-mediated reprogramming. We propose that redox-mediated rewiring is essential to regulate the rate of transmission of biological signals, giving rise to a programmable cellular clock that orchestrates the pace of biological phenomena such as development and aging. We further review the evidence that an aberrant redox-mediated modulation of output of the cellular clock contributes to the emergence of pathological conditions affecting the human brain.

The glutamate modulator, riluzole, extends survival in amyotrophic lateral sclerosis (ALS) and was recently assessed in a clinical trial for Alzheimer’s disease (AD). 1 This trial found that riluzole-treated patients with AD had a significantly reduced decline of cerebral glucose