Glenda M. Halliday

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.

Background: Blood biomarkers are needed to facilitate new therapeutic trials and improve management of behavioral variant frontotemporal dementia (bvFTD). Since altered white matter integrity is characteristic of bvFTD, this study aimed to determine if plasma levels of myelin-enriched glycolipids are altered in bvFTD and correlate with white matter integrity. Methods: Nineteen glycolipids were quantified in bvFTD (n = 31) and control (n = 26) plasma samples. White matter integrity was assessed using magnetic resonance imaging (MRI)-derived fiber tract density and cross-section (FDC). Results: Eleven lipids were significantly lower in bvFTD compared to control subjects, and seven were inversely correlated with disease duration, with C22:0 hexosylceramide most strongly correlated. FDC was lower in frontotemporal white matter tracts of bvFTD compared to control subjects, and plasma C22:0 hexosylceramide was significantly correlated with FDC of these tracts in bvFTD but not control subjects. Conclusions: Circulating glycolipids may be a valuable biomarker of myelin integrity and disease progression in FTD. Blood biomarkers are needed for behavioral variant frontotemporal dementia (bvFTD).Plasma hexosylceramides are reduced in bvFTD cases compared with normal controls.Plasma hexosylceramides correlate with disease duration in bvFTD.Plasma hexosylceramides correlate with brain white matter integrity in bvFTD.Plasma glycolipids have potential as biomarkers of disease progression in bvFTD.

Biological definitions of neurological diseases are now becoming a reality, although still in the research phase. This development will recategorize neurological diseases, providing objective diagnostics and the promise of therapeutics that target biological mechanisms - similar to the strategy that has proven successful in tumours and other conditions. In this Perspective article, we discuss this development for dementias with dominant Lewy pathology, as the availability of biological assays for this pathology has sparked new interest in a single disease diagnosis for all individuals positive for α-synuclein. On the basis of current evidence, we argue that an α-synuclein assay alone is unlikely to be a specific criterion for a spectrum of clinical syndromes with Lewy pathology or a definitive diagnostic marker for Lewy body dementia. We advocate that one biological assay will not reflect the complex spatiotemporal features of brain pathology. Diverse sequential mechanisms underpin the highly heterogeneous phenotypes and clinicopathological processes of Lewy body dementias. Disease modification, if possible, will be most effective when it targets the early underlying mechanisms, especially those leading to aggressive phenotypes.

There is increasing interest in the role of platform trials, where several investigational products targeting disease modification in Parkinson's Disease can be assessed in parallel. Indeed, several initiatives are currently gearing up across North America and Europe to conduct such studies. However, to date, little attention has been paid to ongoing efforts that already exist in Australia and look soon to expand across to New Zealand as part of greater collaboration. This viewpoint will highlight some of these ongoing efforts addressing the challenges and potential solutions for delivering successful studies.

Background: Multiple system atrophy (MSA) is a neurodegenerative disease pathologically characterized by the presence of glial cytoplasmic inclusions (GCI) composed of α-synuclein aggregates. In Parkinson's disease, increases in monounsaturated fatty acids (MUFA) in phospholipid membranes promote α-synuclein binding, aggregation, and toxicity, and the inhibition of stearoyl-CoA desaturase (SCD), the enzyme responsible for synthesizing MUFA, alleviates α-synuclein toxicity. However, little is known about phospholipid MUFA or SCD in the context of MSA pathology. Objective: To determine whether phospholipid MUFA and SCD levels are altered in MSA brain and related to α-synuclein pathology. Methods: Phospholipid MUFA levels in the disease-affected motor cortex white matter (MWM) and disease-unaffected superior occipital cortex (SOC) of postmortem MSA and control brain were analyzed using liquid chromatography-mass spectrometry. Brain GCI, α-synuclein, and SCD were analyzed using immunofluorescence, Western blotting, and quantitative polymerase chain reaction (qPCR). Serum SCD was analyzed using ELISA. Results: MUFA in phosphatidic acid, phosphatidylcholine, and phosphatidylethanolamine were elevated in MSA MWM compared with control MWM by 3.9%, 8.8%, and 9.5%, respectively, whereas none were altered in SOC. MUFA were strongly associated with α-synuclein only in MWM. SCD mRNA and protein expression were decreased only in MSA MWM compared with control MWM. Conclusions: These findings suggest a prevalence of MUFA dysregulation in specific regions of MSA brain, resulting in MUFA levels remaining high despite decreases in SCD expression. Our study has provided new insights into an unrecognized pathway in MSA and opened a new area of research for better understanding MSA pathogenesis. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.