bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropsychological and biomarker predictors of conversion to dementia in young‐onset Mild Cognitive Impairment
Authors: Carbone Chiara , Urbano Teresa , Beltrami Daniela , Tondelli Manuela , Gasparini Federico , Balboni Erica , Vinceti Giulia , Molinari Maria Angela , Marti Alessandro , Chiari Annalisa , Zamboni Giovanna 
Published: December 2023

AbstractBackgroundMild Cognitive Impairment (MCI) is a clinical condition that captures the stage between normal aging and dementia along the continuum of cognitive impairment. While it is usually thought to be precursor of Alzheimer’s Disease, when occurring at young ages (i.e., before 65 years old) it may increase the risk of all forms of neurodegenerative dementing diseases. We studied which neuropsychological and biomarker characteristics are predictors of conversion to dementia in a sample of patients with young‐onset MCI.MethodSubjects with a diagnosis of MCI and early‐onset of cognitive symptoms (< 65 yo) were recruited in a prospective longitudinal study. They underwent extended neuropsychological assessment, Magnetic Resonance Imaging with measurement of hippocampal volume, and lumbar puncture with measurements of cerebrospinal fluid (CSF) light‐chain neurofilaments (NFL), beta‐amyloid 1‐42, total‐ and phosphorylated‐tau. They were followed‐up clinically and repeated the neuropsychological evaluation at 18 months from the baseline. Statistical analyses were performed with Stata15. Each biomarker and neuropsychological variable were added in multivariate Cox regression models with age, sex, and education.Result84 young‐onset MCI patients were recruited. After 18 months, 26 converted to dementia while 58 remained stable (i.e., MCI). Preliminary analyses showed that baseline smaller bilateral hippocampal volumes, lower baseline MMSE scores, baseline worst performances in tests of language, verbal long‐term memory, and executive functions, as well as baseline elevated levels of CSF NFLs increased the risk of conversion to dementia. Among them, the higher risk was given by the Free and Cued Selective Reminding Test (FCSRT), the Corsi Supraspan, the Frontal Assessment Battery, and the CSF NFLs levels, as shown by spline regression analyses (Figure 1). Of note, the FCSRT delayed recall showed a U‐shaped relationship with the risk of conversion (i.e., not only low/bad performance but also high/good performance were both related to a higher risk of conversion) suggesting that the types of predicted conversion may be different.ConclusionOur results suggest that, in young‐onset MCI, a combination of CSF‐NFLs levels and baseline performance at long‐term memory tests may be predictive of conversion to dementia, either AD or FTD.
A compound that specifically recognises patient‐derived Alzheimer fibrils
Authors: Pedrola Júlia Aragonès , Dekker Françoise A , Mayer Guy , Garfagnini Tommaso , Friedler Assaf , Rüdiger Stefan G.D. 
Published: December 2023

AbstractBackgroundProtein aggregation is highly related to the development of Alzheimer’s Disease. The formation of extracellular beta‐amyloid plaques and intracellular neurofibrillary tangles, composed by Tau fibrils, leads to neuronal dysfunction and degeneration. Current diagnosis techniques, such as brain imaging and cerebrospinal fluid tests, can only determine the formation of the protein deposits, which happens to be too late. It is of great importance to visualize initial aggregation steps, which is a prerequisite for early diagnosis.MethodTau fibrils were extracted from AD patient‐derived brains or generated in vitro, and analysed by Flow Induced Dispersion Analysis with WH peptide.ResultsHere we present a method to monitor Tau fibrils size from the first aggregation steps. We designed WH peptide as a biocompatible, fluorescence‐labelled compound that specifically recognizes protein fibrils but not non‐amyloidic monomers, based on specific chemical properties, so called π‐stacking and H‐bonding interactions. These interactions are crucial for the recognition of aggregated species. In combination with Flow Induced Dispersion Analysis, a novel microfluidics technology, we determined the size of the aggregated species with sub‐microliter sample volumes. It is a key challenge in the field to study patient derived fibril. WH peptide labels Alzheimer’s Disease patient‐derived fibrils, which structurally differ from the in vitro generated ones, which allowed us to determine the size of the ex vivo fibrils.ConclusionWH peptide fluorescently labels Alzheimer’s Disease patient‐derived fibrils. WH peptide is biocompatible and could be further functionalized for imaging applications, which could be a basis for early‐stage diagnosis of Alzheimer’s Disease.
Full complement activation is associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease.
Authors: Hondius David , Veerhuis Robert , Li Ka Wan , van Nifterick Anne M , Kuiperij H. Bea , Verbeek Marcel M. , Smit August B. , Rozemuller Annemieke J.M. , Hoozemans Jeroen 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is the most common form of dementia and mainly characterized by the accumulation the amyloid β (Aβ) peptide in the parenchyma and often around the blood vessels of the brain. The accumulation of Aβ in vessels walls is referred to as cerebral amyloid angiopathy (CAA). In a subset of AD cases CAA is observed in both capillaries and larger vessels which is designated as CAA type‐1. CAA type‐1 is associated with an increased neuroinflammatory response involving activated microglia and increased oxidative stress, which supposedly results in loss of blood‐brain barrier (BBB) integrity in CAA. Complement activation is an integral part of neuroinflammation associated with parenchymal Aβ deposits and CAA. However, a direct comparison of the complement activation in relation to plaque pathology and CAA type‐1 has not been made.MethodUsing immunohistochemistry we performed a semi‐quantitative analysis on the expression and localization of complement factors C1q, C3, C4 and the membrane attack complex (MAC) in post mortem cortical brain tissue derived from AD cases with severe occurrence of CAA type‐1, AD cases without CAA and non‐demented control cases. In addition, label free quantitative mass spectrometry was applied to quantify complement components in whole cortical tissue lysates.ResultThe complement factors C1q, C3 and C4 were found to be associated with CAA type‐1. No clear differences were observed in level of occurrence of C1q, C3 and C4 between AD cases with CAA type‐1, AD cases without CAA and non‐demented control cases. Interestingly, a subset of the AD cases with CAA type‐1 displayed MAC in affected vessels, whereas this was not observed in AD cases without CAA or control cases. Mass spectrometry analysis revealed an increase in C9, the primary component of MAC, in CAA type‐1 but not in AD without CAA.ConclusionEarly complement factors are present in all AD cases while the presence of MAC is restricted to a subset of CAA type‐1 cases, indicating full‐blown complement activation in CAA type‐1 but not in AD without CAA.
Back‐translation of clinical tau‐aggregation inhibitor trials to experimental models: negative interactions of dementia therapies
Authors: Riedel Gernot , Melis Valeria , Schwab Karima , Klein Jochen , Niewiadomska Grazyna , Niewiadomski Wiktor , Wischik Claude M , Harrington Charles R 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) has attracted considerable interest in novel therapies. Two Phase III trials by TauRx Pharmaceuticals (TRx‐005, TRx‐015) failed to attain their endpoints. A significant number of recruits, however, remained on symptomatic treatment and a post‐hoc analysis confirmed this sub‐cohort was selectively resilient against the tau aggregation inhibitor hydromethylthionine (HMT; previously termed LMT). By contrast, drug‐naïve patients were highly sensitive to the novel therapy and showed little decline over 18‐month. We here back‐translated this study to the preclinic.MethodsExperiments used female tau transgenic Line 1 mice (L1) aged 6‐8 months previously characterised for cognitive impairments, tau pathology, and sensitivity to the tau aggregation inhibitor HMT. Here, multiple groups and doses of drugs were chronically administered (up to 11 weeks) with pre‐exposure to the acetylcholine esterase inhibitor rivastigmine followed by add‐on of HMT. Drugs were also dosed singly.Results(i) Tested for spatial learning in the water maze, L1 mice were significantly impaired and benefitted from exposure to HMT. By contrast, combination therapy with rivastigmine precluded some of the benefits of HMT while rivastigmine alone was non‐efficacious.(ii) Chronic drug administration was followed by tissue harvest and histological preparation of sections through 6 brain regions (3 x cortical, 3x basal forebrain) and labelling of 6 presynaptic structural (3) and functional proteins (3. Reduced protein levels were found in cortex; they were heightened by HMT, but abnormally altered in the presence of rivastigmine (single and combination therapy).(iii) Chronic drug administration was followed by in vivo brain dialysis from hippocampus for acetylcholine at rest and under behavioural challenge. L1 showed a lowering of cholinergic neurones in the basal forebrain, but no difference in acetylcholine levels at rest; a heightening of choline levels was observed to HMT alone at rest and challenge, but not to combinations with rivastigmine.ConclusionWe successfully back‐translate the clinical trials on HMT into the preclinic using L1 tau transgenic mice . Data suggest not only a reduced cognitive efficacy of HMT in subjects pre‐exposed to the choline esterase inhibitor rivastigmine, but also offer mechanistic explanations for potential interactions at presynaptic function and for transmitter release.
Developing a psychoeducational programme for family caregivers of people living with late stage dementia
Authors: Waddington Claire , Zimmermann Nikki , Crutch Sebastian J , Stott Joshua , Brotherhood Emilie V , Support Rare Dementia 
Published: December 2023

AbstractBackgroundFamily caregivers often find it difficult to access information and support in the later stages of dementia. They may have difficulties attending in‐person support groups due to caring responsibilities. If caregivers are able to attend these groups, the information and support is often targeted towards the earlier stages of dementia.MethodAn eight session psychoeducational programme was developed in order to enable caregivers to access peer support and information from professionals with expertise relevant to the later stages of dementia. The programme sessions are held over Zoom and include the following topics: sensory stimulation, nutrition diet and swallowing, legal matters, care in the home and care homes, palliative care and pain management, funeral planning and brain donation. Sessions are co‐facilitated by health and social care professionals with relevant expertise, including a speech and language therapist, dietitian, solicitor and palliative care practitioner. Themes and session content have been co‐created through partnership working between facilitators and programme participants.ResultThe programme has been completed by four groups of caregivers (n = 26). All participants care for someone living with a rare or young onset form of dementia, and include those caring at home as well as caregivers of people living in a care or nursing home. Participants have reported a number of positive outcomes from attending the programme, with one participant stating: ‘Joining this late stage carers group – I was a bit worried about it… it’s absolutely one of the best things I could have done. In some respects, I wish I could have joined this earlier’. The programme is currently being evaluated using a time and cost survey to determine ongoing feasibility.ConclusionThere is a need for accurate and timely access to information and support for family caregivers of people living with dementia in the later stages. Online psychoeducational programmes provide the opportunity for caregivers to access both peer and professional support in their own homes. The development of this programme has benefited from ongoing and iterative input from both caregivers and professionals in the dementia support field.
Sphingomyelin 14:0 – the link between obesity and neuroinflammation
Authors: Mcmanus Roisin M. , Gorki Frederike , Asmann Nils , Griep Angelika , Thiele Christoph , Latz Eicke 
Published: December 2023

AbstractBackgroundOur laboratory has demonstrated that the consumption of a Western‐type diet (WD), triggers sterile inflammation and long‐term epigenetic reprogramming of myeloid cells, altering their immune response (Christ et al 2018). However, the precise molecular trigger mediating these changes was unknown. We have recently identified that during these WD conditions, there is an increase in circulating sphingomyelin 14:0 (S14), which was associated with atherosclerotic disease progression. As obesity, WD and atherosclerosis are all risk factors for Alzheimer’s disease (AD) and dementia, we set out to determine whether S14 was the signaling factor linking these conditions with AD development.MethodSerum samples were obtained from obese patients for lipidomic analysis. Mice were fed a high‐fat diet mimicking WD for a period of 8 weeks, before samples were obtained for lipidomic analysis. Microglia and macrophages were prepared from wildtype, TLR4−/−, Trif−/− and MyD88−/− mice to assess whether myeloid cells recognize S14, and the molecular pathways triggered by the lipid. Cells were prepared for RNA sequencing, to determine the genes and networks induced by S14. These genes and pathways were confirmed at a protein level by western blot and flow cytometry, and at a functional level using real‐time metabolic, and phagocytic assays. Results were confirmed in human myeloid cells.ResultLipidomic analysis confirmed that obese patients have increased circulating levels of S14, which were associated with inflammatory markers and cardiovascular disease. In vitro, we found using RNAseq that S14 triggers an extensive increase in pro‐inflammatory genes and pathways. We confirmed that S14 binds to TLR4/MD2 triggering NFkB activation and the release of TNFα in macrophages and microglial cells. S14 also reduced metabolic function and altered phagocytic capacity in microglia.ConclusionWe have found that S14, a lipid increased during obesity and WD conditions, is a novel TLR4 ligand that can activate macrophages and microglia triggering sterile inflammation. This pathway is conserved between murine and human cells. Critically, S14 reduced microglial phagocytosis, and rewired cellular metabolism. Together, our data shows for the first time that S14 is an immune stimulus, capable of triggering the innate immune responses and inflammation associated with dementia progression.
Long COVID‐19 symptoms in people with Dementia or Mild Cognitive Impairment
Authors: Tsapanou Angeliki , Zoi Panagiota , KALLIGEROU FAIDRA , Blekou Patra , Sakka Paraskevi 
Published: December 2023

AbstractBackgroundLong COVID is broadly defined as signs, symptoms, and conditions that continue or develop after initial COVID‐19 or SARS‐CoV‐2 infection. What is its impact though on people with Mild Cognitive Impairment (MCI) or dementia?MethodSelf‐reported questionnaire was used for the report of the Long‐Covid 19 symptoms, regarding the duration, the exact symptoms, and the amount of the effect. People with MCI or dementia or their caregivers regarding patients’ health were recruited from the Athens Alzheimer’s Association.ResultOur sample consisted of 56 participants. Twenty‐two (39.3%) had the diagnosis of MCI, while 34 were people with dementia. Most of the people reported symptoms of Long Covid‐19 for 3‐4 weeks. Significant were all the symptoms reported (problem in breathing, fatigue, sore throat, and psychological distress/ depression), with the majority of the people answered the questionnaire reporting fatigue as the major disturbance. This was followed by the “Psychological distress/ depression”. The symptoms affected people significantly, with almost 40% reporting “Quite enough” disturbance.ConclusionLong Covid‐19 is reported to be similar to other geriatric syndromes, in that the exact mechanism that leads to the symptoms is complex and not clearly understood. Therefore, the diagnosis and the management of the Long Covid‐19 symptom requires a more holistic and comprehensive approach.
Novel EEG tools to predict early cognitive impairments in Parkinson’s disease
Authors: Segura Masha Burelo , Bray Jack , Gagnon Jean‐François , Platt Bettina 
Published: December 2023

AbstractBackgroundParkinson’s disease (PD) is a neurodegenerative disorder mainly characterised by motor symptoms but often also associated with dementia, increasing in likelihood with duration of disease. Electroencephalography (EEG) can aid in the early diagnosis of those at risk of developing dementia. Therefore, we analysed EEG recordings across conscious states from PD patients with and without cognitive symptoms (Latreille et al in 2016, https://doi.org/10.1093/brain/aww018).MethodBaseline data (REM sleep, NREM sleep, WAKE) from 38 PD patients (15 with and 23 without mild cognitive impairment) and 27 healthy subjects provided power spectra (qEEG), relative band power, as well as dominant frequency and its standard deviation to investigate markers for cognitive impairment. At follow‐up (an average 4.5 years after baseline), 11 patients developed dementia (PDD). Connectivity measures for left and right occipital and central electrodes were obtained as described in Crouch et al, 2018, https://doi.org/10.1038/s41598‐018‐19707‐1.ResultqEGG analyses confirmed previous reports of enhanced theta power during REM, NREM and WAKE for patients who developed PDD. A reduction in alpha power during WAKE was observed for MCI and PDD groups when compared to controls. Alpha rhythms generally decrease with age, alongside enhanced theta power, and this outcome may contribute to the global cognitive status of patients. A reduced and less variable dominant frequency was evident for MCI and PDD patients during WAKE, indicative of reduced flexibility of the network. Finally, rPDC detected disease‐specific changes, such as enhanced cross‐hemispheric connectivity in PDD in the alpha band during NREM sleep that indicate a lack of dynamism in the network. Also noted was the diminished interhemispheric communication in delta power between both central and occipital channels in PDD during WAKE.ConclusionTogether, we here confirm that changes of theta and alpha power are optimal discriminatory biomarkers for PD with cognitive decline (with MCI and at risk of dementia). Also, spectral and rPDC analyses indicate that dementia in PD is preceded by a loss of dynamism in EEG activity during MCI stages, both at the electrode and network level.
A retinal tauopathy with a characteristic molecular pattern points to the existence of a “Primary retinal tauopathy”
Authors: Walkiewicz Grzegorz , Ronisz Alicja , Van Ginderdeuren Rita , Lemmens Sophie , Bouwman Femke H. , Hoozemans Jeroen , Morrema Tjado , Rozemuller Annemieke J.M. , de Ruyter Frederique J. Hart , De Groef Lies , Stalmans Ingeborg , Thal Dietmar Rudolf 
Published: December 2023

AbstractBackgroundPathogenic processes characteristic of neurodegenerative brain diseases, such as accumulation of phosphorylated Tau protein (pTau), can also be detected in the retina. Given the advanced state of retinal imaging technology and its potential to aid in the clinical diagnosis of Alzheimer’s disease (AD), it is imperative to investigate the part the retina plays in neurodegenerative diseases of the brain, as well as the associated eye‐specific degenerative processes.MethodsRetinas from 129 individuals who underwent eyeball resection/evisceration for severe ophthalmological conditions and from 35 post‐mortem donors with or without AD were analyzed. Paraffin‐embedded sections from cross‐sectioned retinas were stained with antibodies against different pTau species and Gallyas staining to detect neurofibrillary tangles. Retinal pTau accumulation, its distribution over the retinal layers, and molecular composition were determined neuropathologically and correlated with visual performance, age, and the presence of dementia.ResultsRetinal pTau pathology showed a consistent topographical expansion pattern that allowed distinguishing four stages: Stage 0: no pTau pathology; Stage 1: thread‐like pTau in the outer plexiform layer; Stage 2: additional cytoplasmic pTau in the inner nuclear layer; Stage 3: thread‐like pTau also in the inner plexiform layers. Antibodies against pTauS202/pT205 (AT8), pTauT231 (AT180), and anti‐MC‐1 Tau showed comparable results. Neurofibrillary tangles were not found. The stage of retinal tauopathy was correlated with age (r = 0.176, p = 0.024, n = 164), the underlying ophthalmologic diseases (p = 0.001; β = 0.292), and independently associated with vision impairment (p = 0.030; β = 0.192) in a linear regression model. Cases with a clinical diagnosis of dementia were associated with slightly higher stages of retinal tauopathy (binary logistic regression: p = 0.026; odds ratio (OR) = 1.685 [95% C.I.1.066‐2.664), although some demented cases were free of pTau pathology.ConclusionsThese results point towards the existence of a primary retinal tauopathy (PReT). It differs in its molecular composition from cerebral tauopathies by the lack of argyrophilic inclusions and the predominance of 3‐repeat Tau. However, PReT may be a prerequisite for developing AD pathology in the retina. Altogether, these findings support the presence of retinal neurodegenerative changes that may reflect changes in the brain.FundingSAO/FRA 2020/017