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Ageing is a major risk factor for most neurodegenerative diseases, including Parkinson’s disease (PD). Progressive age-related dysregulation of the immune system is termed immunosenescence and is responsible for the weakened response to novel antigens, increased susceptibility to infections and reduced effectiveness of vaccines seen in the elderly. Immune activation, both within the brain and periphery, is heavily implicated in PD but the role of immunosenescence has not been fully explored. Studies to date provide some evidence for an attenuation in immunosenescence in PD, particularly a reduction in senescent CD8 T lymphocytes in PD cases compared to similarly aged controls. Here, we discuss recent evidence of age-related immune abnormalities in PD with a focus on T cell senescence and explore their potential role in disease pathogenesis and development.

The genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.

Misfolded α-synuclein oligomers are closely implicated in the pathology of Parkinson's disease and related synucleinopathies. The elusive nature of these aberrant assemblies makes it challenging to develop quantitative methods to detect them and modify their behavior. Existing detection methods use antibodies to bind α-synuclein aggregates in biofluids, although it remains challenging to raise antibodies against α-synuclein oligomers. To address this problem, we used an antibody scanning approach in which we designed a panel of 9 single-domain epitope-specific antibodies against α-synuclein. We screened these antibodies for their ability to inhibit the aggregation process of α-synuclein, finding that they affected the generation of α-synuclein oligomers to different extents. We then used these antibodies to investigate the size distribution and morphology of soluble α-synuclein aggregates in serum and cerebrospinal fluid samples from Parkinson's disease patients. Our results indicate that the approach that we present offers a promising route for the development of antibodies to characterize soluble α-synuclein aggregates in biofluids.

The human genome contains numerous duplicated regions, such as parent-pseudogene pairs, causing sequencing reads to align equally well to either gene. The extent to which this ambiguity complicates transcriptomic analyses is currently unknown. This is concerning as many parent genes have been linked to disease, includingGBA1,causally linked to both Parkinson’s and Gaucher disease. We find that most of the short sequencing reads that map toGBA1, also map to its pseudogene,GBAP1. Using long-read RNA-sequencing in human brain, where all reads mapped uniquely, we demonstrate significant differences in expression compared to short-read data. We identify novel transcripts from bothGBA1andGBAP1, including protein-coding transcripts that are translatedin vitroand detected in proteomic data, but that lack GCase activity. By combining long-read with single-nuclear RNA-sequencing to analyse brain-relevant cell types we demonstrate that transcript expression varies by brain region with cell-type-selectivity. Taken together, these results suggest a non-lysosomal function for both GBA1 and GBAP1 in brain. Finally, we demonstrate that inaccuracies in annotation are widespread among parent genes, with implications for many human diseases.

Aggregation of α-synuclein plays a key role in the development of Parkinson’s disease. Soluble aggregates are present not only within human brain but also the CSF and blood. Characterizing the aggregates present in these biofluids may provide insights into disease mechanisms and also have potential for aiding diagnosis. We used two optical single-molecule imaging methods called aptamer DNA-PAINT and single-aggregate confocal fluorescence, together with high-resolution atomic force microscopy for specific detection and characterization of individual aggregates with intermolecular β-sheet structure, present in the CSF and serum of 15 early stage Parkinson’s disease patients compared to 10 healthy age-matched controls. We found aggregates ranging in size from 20 nm to 200 nm, in both CSF and serum. There was a difference in aggregate size distribution between Parkinson’s disease and control groups with a significantly increased number of larger aggregates (longer than 150 nm) in the serum of patients with Parkinson’s disease. To determine the chemical composition of the aggregates, we performed aptamer DNA-PAINT on serum following α-synuclein and amyloid-β immunodepletion in an independent cohort of 11 patients with early stage Parkinson’s disease and 10 control subjects. β-Sheet aggregates in the serum of Parkinson’s disease patients were found to consist of, on average, 50% α-synuclein and 50% amyloid-β in contrast to 30% α-synuclein and 70% amyloid-β in control serum [the differences in the proportion of these aggregates were statistically significant between diseased and control groups (P = 1.7 × 10−5 for each species)]. The ratio of the number of β-sheet α-synuclein aggregates to β-sheet amyloid-β aggregates in serum extracted using our super-resolution method discriminated Parkinson’s disease cases from controls with an accuracy of 98.2% (AUC = 98.2%, P = 4.3 × 10−5). Our data suggest that studying the protein aggregates present in serum can provide information about the disruption of protein homeostasis occurring in Parkinson’s disease and warrants further investigation as a potential biomarker of disease.

ObjectiveTo explore the possibilities of radioligands against the mitochondrial outer membrane translocator protein (TSPO) as biomarkers for mitochondrial disease, we performed brain PET-MRI with [11C]PK11195 in 14 patients with genetically confirmed mitochondrial disease and 33 matched controls.MethodsCase–control study of brain PET-MRI with the TSPO radioligand [11C]PK11195.ResultsForty-six percent of symptomatic patients had volumes of abnormal radiotracer binding greater than the 95th percentile in controls. [11C]PK11195 binding was generally greater in gray matter and significantly decreased in white matter. This was most striking in patients with nuclear TYMP or mitochondrial m.3243A>G MT-TL1 mutations, in keeping with differences in mitochondrial density seen postmortem. Some regional binding patterns corresponded to clinical presentation and underlying mutation, even in the absence of structural changes on MRI. This was most obvious for the cerebellum, where patients with ataxia had decreased binding in the cerebellar cortex, but not necessarily volume loss. Overall, there was a positive correlation between aberrant [11C]PK11195 binding and clinical severity.ConclusionThese findings endorse the use of PET imaging with TSPO radioligands as a noninvasive in vivo biomarker of mitochondrial pathology.Classification of EvidenceThis study provides Class III evidence that brain PET-MRI with TSPO radioligands identifies mitochondrial pathology.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods:N = 42 patients with probable PSP and N = 39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N = 9 patients who also had post-mortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: N = 10 patients were classified in stage I/II, N = 26 in stage III/IV, N = 5 in stage V/VI, while N = 1 was not classifiable. An explorative sub-staging identified N = 2 patients in stage I, N = 8 in stage II, N = 9 in stage III, N = 17 in stage IV and N = 5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion:18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.

Background Immune involvement is well-described in Parkinson’s disease (PD), including an adaptive T lymphocyte response. Given the increasing prevalence of Parkinson’s disease in older age, age-related dysregulation of T lymphocytes may be relevant in this disorder, and we have previously observed changes in age-associated CD8+ T cell subsets in mid-stage PD. This study aimed to further characterise T cell immunosenescence in newly diagnosed PD patients, including shifts in CD4+ and CD8+ subpopulations, and changes in markers of cellular ageing in CD8+ T lymphocytes. Methods Peripheral blood mononuclear cells were extracted from the blood of 61 newly diagnosed PD patients and 63 age- and sex-matched controls. Flow cytometric analysis was used for immunophenotyping of CD8+ and CD4+ lymphocyte subsets, and analysis of recent thymic emigrant cells. Telomere length within CD8+ T lymphocytes was assessed, as well as the expression of the telomerase reverse transcriptase enzyme (hTERT), and the cell-ageing markers p16INK4a and p21CIP1/Waf1. Results The number of CD8+ TEMRA T cells was found to be significantly reduced in PD patients compared to controls. The expression of p16INK4a in CD8+ lymphocytes was also lower in patients versus controls. Chronic latent CMV infection was associated with increased senescent CD8+ lymphocytes in healthy controls, but this shift was less apparent in PD patients. Conclusions Taken together, our data demonstrate a reduction in CD8+ T cell replicative senescence which is present at the earliest stages of Parkinson’s disease.

Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson's disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson's and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuroglial tau pathology. A new staging system for PSP pathology postmortem has been described and validated. We used a data-driven approach to test whether postmortem pathologic staging in PSP can be reproduced in vivo with

While [18F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of ‘off-target’ [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson’s disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [18F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [18F]-AV-1451 binding between Parkinson’s disease and controls. Substantia nigra [18F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society—Unified Parkinson’s Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson’s disease groups. Despite the reduction of substantia nigra [18F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson’s disease. Further investigations in longitudinal cohorts are warranted.

Parkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain. Electronic supplementary material The online version of this article (10.1186/s40478-020-01083-5) contains supplementary material, which is available to authorized users.

Parkinson’s disease (PD) is a common neurodegenerative disorder. While a number of nonmotor manifestations arise, the typical clinical features involve a movement disorder consisting of bradykinesia, resting tremor, and rigid­ity, with postural instability occurring at a later stage. The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. Environmental influences such as smoking, caffeine consumption, and pesticide exposure have been postulated to alter the risk of PD development, although the role of these remains unclear. The movement disorder arises due to the loss of dopaminergic neurons of the substantia nigra pars compacta, with the pathological hallmark being intracel­lular aggregates of α-synuclein, in the form of Lewy bodies and Lewy neurites. Several processes have been implicated in PD, including mitochondrial dysfunc­tion, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood.

IntroductionEvidence suggests the immune system contributes to Parkinson’s disease (PD) aetiopathogenesis and this represents a tractable target for disease-modifying therapy. As ageing is a risk factor for PD, it is relevant to investigate age-related immune changes (immunosenescence) in PD.MethodsBlood samples were collected from 20 early PD patients and 20 controls. T- and B-cell senescence subsets were identified using flow cytometric immunophenotyping. CMV/EBV serostatus was ascertained given its well-documented effect on immunosenescence.ResultsCD4+ TEMRA cells, T-cell senescence markers, were reduced in PD cases versus controls (p=0.046). This was not driven by differences in age or CMV/EBV serostatus across groups. CMV positivity was associated with increased CD4+ TEMRA cells as expected in controls, but not in PD cases. Switched memory B-cells were lower in patients versus controls (p=0.040). No changes were observed in the CD8+ T-cell pool.ConclusionsThese findings suggest that the senescent ‘shift’ induced by viral infection and ageing is atypical in PD. Reductions in senescent lymphocytes may favour the passage of activated lymphocytes across the blood brain barrier, promoting central inflammation and neurodegeneration. Pragmatically, this study shows that immune abnormalities occur in early-stage disease, adding urgency to the search for immune-modulating therapies in PD.