Prevalence of Concomitant Pathologies in Parkinson\u27s Disease: Implications for Prognosis, Diagnosis, and Insights into Common Pathogenic Mechanisms

Pathologies characteristic of Alzheimer\u27s disease (i.e., hyperphosphorylated tau and amyloid-β (Aβ) plaques), cardiovascular disease, and limbic predominant TDP-43 encephalopathy (LATE) often co-exist in patients with Parkinson\u27s disease (PD), in addition to Lewy body pathology (α-synuclein). Numerous studies point to a putative synergistic relationship between hyperphosphorylation tau, Aβ, cardiovascular lesions, and TDP-43 with α-synuclein, which may alter the stereotypical pattern of pathological progression and accelerate cognitive decline. Here we discuss the prevalence and relationships between common concomitant pathologies observed in PD. In addition, we highlight shared genetic risk factors and developing biomarkers that may provide better diagnostic accuracy for patients with PD that have co-existing pathologies. The tremendous heterogeneity observed across the PD spectrum is most likely caused by the complex interplay between pathogenic, genetic, and environmental factors, and increasing our understanding of how these relate to idiopathic PD will drive research into finding accurate diagnostic tools and disease modifying therapies

Rare histotype of sporadic Creutzfeldt-Jakob disease, clinically suspected as corticobasal degeneration

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease that can mimic other neurological disorders. We present a case of sCJD in a 64-year-old man that presented with corticobasal syndrome and survived for 3 years. He presented initially with dementia, hemiparkinsonism and alien limb phenomenon and was diagnosed with corticobasal degeneration, ultimately progressing to immobility and akinetic mutism. With a normal MRI 1 year before onset, his neuroimaging 1 year later revealed abnormal DaTscan, cortical and hippocampal atrophy with ventricular dilatation on MRI, and diffusion-weighted cortical ribboning and thalamic hyperintensity. Postmortem, the patient’s brain was collected by the Parkinson’s UK Tissue Bank. Prion protein immunohistochemistry revealed widespread diffuse microvacuolar staining without kuru-type plaques. Hyperphosphorylated tau was only found in the entorhinal cortex and hippocampus. This case highlights the clinical heterogeneity of sCJD presentation and the important inclusion of CJD in the differential diagnosis of atypical presentations of neurodegenerative disease

Particle production and equilibrium properties within a new hadron transport approach for heavy-ion collisions

The microscopic description of heavy-ion reactions at low beam energies is achieved within hadronic transport approaches. In this article a new approach SMASH (Simulating Many Accelerated Strongly-interacting Hadrons) is introduced and applied to study the production of non-strange particles in heavy-ion reactions at $E_{\rm kin}=0.4-2A$ GeV. First, the model is described including details about the collision criterion, the initial conditions and the resonance formation and decays. To validate the approach, equilibrium properties such as detailed balance are presented and the results are compared to experimental data for elementary cross sections. Finally results for pion and proton production in C+C and Au+Au collisions is confronted with HADES and FOPI data. Predictions for particle production in $\pi+A$ collisions are made.Comment: 30 pages, 30 figures, replaced with published version; only minor change

Prevalence, distribution, and severity of cerebral amyloid angiopathy differ between Lewy body diseases and Alzheimer’s disease

\ua9 The Author(s) 2024.Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies

Associations between multimorbidity and neuropathology in dementia: Consideration of functional cognitive disorders, psychiatric illness and dementia mimics

\ua9 The Author(s), 2024. Published by Cambridge University Press on behalf of Royal College of Psychiatrists.Background Multimorbidity, the presence of two or more health conditions, has been identified as a possible risk factor for clinical dementia. It is unclear whether this is due to worsening brain health and underlying neuropathology, or other factors. In some cases, conditions may reflect the same disease process as dementia (e.g. Parkinson\u27s disease, vascular disease), in others, conditions may reflect a prodromal stage of dementia (e.g. depression, anxiety and psychosis). Aims To assess whether multimorbidity in later life was associated with more severe dementia-related neuropathology at autopsy. Method We examined ante-mortem and autopsy data from 767 brain tissue donors from the UK, identifying physical multimorbidity in later life and specific brain-related conditions. We assessed associations between these purported risk factors and dementia-related neuropathological changes at autopsy (Alzheimer\u27s-disease related neuropathology, Lewy body pathology, cerebrovascular disease and limbic-predominant age-related TDP-43 encephalopathy) with logistic models. Results Physical multimorbidity was not associated with greater dementia-related neuropathological changes. In the presence of physical multimorbidity, clinical dementia was less likely to be associated with Alzheimer\u27s disease pathology. Conversely, conditions which may be clinical or prodromal manifestations of dementia-related neuropathology (Parkinson\u27s disease, cerebrovascular disease, depression and other psychiatric conditions) were associated with dementia and neuropathological changes. Conclusions Physical multimorbidity alone is not associated with greater dementia-related neuropathological change; inappropriate inclusion of brain-related conditions in multimorbidity measures and misdiagnosis of neurodegenerative dementia may better explain increased rates of clinical dementia in multimorbidit

Neurodegenerative brain changes are associated with area deprivation in the United Kingdom: findings from the Brains for Dementia Research study

Socioeconomic disadvantage is associated with greater risk of dementia. This has been theorised to reflect inequalities in cognitive reserve, healthcare access, lifestyle, and other health factors which may contribute to the clinical manifestation of dementia. We aimed to assess whether area deprivation in the United Kingdom was associated with greater risk or severity of the specific neurodegenerative diseases which lead to dementia in a multi-centre cohort with autopsy assessment. Participants underwent clinical assessment prior to brain tissue donation post-mortem. Each then underwent detailed, standardised neuropathological assessment. National area deprivation statistics were derived for each participant’s neighbourhood, for use as a predictor in binary and ordinal logistic models assessing the respective presence and severity of staging of key neuropathological changes, adjusting for theorised confounders. Individuals from among the 20% most deprived neighbourhoods in the United Kingdom had significantly higher neurofibrillary tangle and neuritic plaque staging, and increased risk of cerebral amyloid angiopathy. These findings were not explained by a greater risk of diabetes or hypertension, APOE genotype, alcohol misuse or tobacco smoking, sex, or age differences. A sensitivity analysis conditioning on baseline cognitive impairment did not meaningfully change the observed association. Socioeconomic disadvantage may contribute to dementia incidence through a greater severity of specific neuropathological changes (neurofibrillary tangles, neuritic plaques, and cerebral amyloid angiopathy), independent of other indirect influences. Mechanisms through which deprivation is associated with these require further exploration

Associations between multimorbidity and neuropathology in dementia: a case for considering functional cognitive disorders, psychiatric illness, and dementia mimics

Cognitive impairment in older people has a variety of underlying causes. In addition to neurodegenerative causes such as Alzheimer's disease, a dementia-like cognitive disorder may appear due to non-degenerative factors. Multimorbidity has been previously associated with clinical dementia risk, though whether this was due to greater risk of dementia-related neuropathology, or other factors that mimic dementia, was unclear. We provide evidence that physical multimorbidity is not associated with greater pathological changes at autopsy. Other factors related to multimorbidity and cognitive impairments may be important targets for investigation, such as functional cognitive disorders, primary psychiatric disorders (depression, anxiety, psychosis) and polypharmacy

Nuclear alpha-synuclein is present in the human brain and is modified in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is pathologically defined by the cytoplasmic accumulation of alpha-synuclein (aSyn) within neurons in the brain. Predominately pre-synaptic, aSyn has been reported in various subcellular compartments in experimental models. Indeed, nuclear alpha-synuclein (aSynNuc) is evident in many models, the dysregulation of which is associated with altered DNA integrity, transcription and nuclear homeostasis. However, the presence of aSynNuc in human brain cells remains controversial, yet the determination of human brain aSynNuc and its pathological modification is essential for understanding synucleinopathies. Here, using a multi-disciplinary approach employing immunohistochemistry, immunoblot, and mass-spectrometry (MS), we confirm aSynNuc in post-mortem brain tissue obtained from DLB and control cases. Highly dependent on antigen retrieval methods, in optimal conditions, intra-nuclear pan and phospho-S129 positive aSyn puncta were observed in cortical neurons and non-neuronal cells in fixed brain sections and in isolated nuclear preparations in all cases examined. Furthermore, an increase in nuclear phospho-S129 positive aSyn immunoreactivity was apparent in DLB cases compared to controls, in both neuronal and non-neuronal cell types. Our initial histological investigations identified that aSynNuc is affected by epitope unmasking methods but present under optimal conditions, and this presence was confirmed by isolation of nuclei and a combined approach of immunoblotting and mass spectrometry, where aSynNuc was approximately tenfold less abundant in the nucleus than cytoplasm. Notably, direct comparison of DLB cases to aged controls identified increased pS129 and higher molecular weight species in the nuclei of DLB cases, suggesting putative pathogenic modifications to aSynNuc in DLB. In summary, using multiple approaches we provide several lines of evidence supporting the presence of aSynNuc in autoptic human brain tissue and, notably, that it is subject to putative pathogenic modifications in DLB that may contribute to the disease phenotype