bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subacute plasma neurofilament light predicts neurodegeneration after moderate‐severe traumatic brain injury
Authors: Graham Neil S.N. , Zimmerman Karl A. , Moro Federico , Bourke Niall , Zetterberg Henrik , Heslegrave Amanda J. , Magnoni Sandra , Bertolini Guido , Garbero Elena , Nattino Giovanni , Oddo Mauro , Maillard Samia Abed , Miroz John‐Paul , Gradisek Primoz , Bernini Adriano , Chieregato Arturo , Fainardi Enrico , Baciu Camelia , Sharp David J. 
Published: December 2021

AbstractBackgroundTBI is an environmental risk factor for the development of dementia. Axonal injury is thought be a significant determinant of clinical outcomes post‐injury, which can now be assessed using novel techniques such as fluid biomarkers including plasma neurofilament light and advanced MRI assessment.MethodBIO‐AX‐TBI (Developing and Validating Blood and Imaging BIOmarkers of AXonal Injury Following Traumatic Brain Injury, NCT03534154) is a multi‐centre cohort study of patients after acute moderate‐severe TBI. Patients admitted to major trauma units underwent baseline clinical assessment, serial blood biomarker and MRI over one year, with detailed outcome ascertainment. Blood concentrations of neurofilament light (NFL), total‐tau, S100‐B, ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and glial fibrillary acidic protein (GFAP) were quantified.Result197 patients after TBI had acute blood biomarker assessment with clinical outcomes ascertained at 6 and 12 months. 95 healthy participants with imaging and blood biomarker workup were assessed, alongside 28 healthy controls with longitudinal neuroimaging and 24 trauma patients with extracranial injuries (non‐TBI trauma, ‘NTT’). TBI patients had significant elevations of blood biomarkers including NfL and tau compared with controls and NTTs. Diffusion tensor imaging (DTI) showed reduced fractional anisotropy in TBI patients, which remained abnormal into the chronic phase and correlated with subacute NFL. Grey matter atrophy rates were elevated in the first 6 months post injury and correlated with peak plasma tau levels, which additionally predicted cognitive performance. Abnormal chronic (6‐12) month white matter atrophy, particularly of the right internal capsule/posterior thalamic radiation, was predicted by subacute plasma NFL, which furthermore predicted functional outcome.ConclusionIn this longitudinal investigation, subacute plasma NFL was highly sensitive to axonal injury after TBI, predicted functional outcome at 6 and 12 months and predicted accelerated white matter atrophy in the chronic phase. Early plasma tau predicted grey matter atrophy post‐injury and 12 month cognitive function. Plasma NFL and tau appear to be a valuable non‐invasive means to diagnose significant injuries and identify those patients at high risk of chronic neurodegeneration, which may inform recruitment into clinical trials of anti‐neurodegenerative therapies in future.
Cardiorespiratory fitness and cognition in healthy elderly and MCI patients
Authors: Velde Pia Marie , Müller Patrick , Müller Notger , Hökelmann Anita 
Published: December 2021

AbstractBackgroundCurrent research indicates a positive impact of physical activity on healthy ageing, on brain plasticity and on the risk for dementia. Furthermore, several epidemiological, cross‐sectional and interventional studies have shown that cardiorespiratory fitness is associated with cognitive performance, especially regarding executive functions.MethodHere, we investigated the relationship between cardiorespiratory fitness and cognition in both healthy elderly (n=33; age: 68.8 ± 6.9) and in patients with mild cognitive impairment (MCI; n=27, age: 70.8 ± 6.1). Cardiorespiratory fitness was assessed using bicycle spiroergometry (cosmos torqualizer 600ef med; Germany) with an incremental step test. To determine the metabolic status, capillary blood samples were taken from the ear at rest (baseline), after each step and one, three and five minutes after the incremental step test was finished. The lactate concentration was measured with lactate scout sensors (SensLab GmbH Leipzig, Germany). Cognitive abilities were measured with the extended CERAD plus neuropsychological test battery (including Trial making test & verbal fluency S words).ResultStatistical analysis revealed significant between group differences in cognitive functions (e.g. MMSE, p<.001 TMT‐A, p<.001), but no significant differences in cardiorespiratory fitness (e.g. VO2peak, Wpeak, lactate). Furthermore, correlation analysis showed a significant correlation between VO2peak and MMSE in healthy elderly (p=.029, r=‐0.333)), but not in MCI patients (p=.317, r=‐0.096).ConclusionOur results indicate no differences in cardiorespiratory fitness between healthy elderly and MCI patients. However, cardiorespiratory fitness is associated with general cognition in healthy elderly. Why this correlation was not seen in MCI patients needs to be assessed in more detail in future research.
Language profile of primary progressive aphasia in a linguistically diverse cohort in India
Authors: Goyal Sheetal , Darshini K.J , Arshad Faheem , Varghese Feba Anna , Paplikar Avanthi , Vandana V.P , Ramakrishnan Subasree , Alladi Suvarna 
Published: December 2021

AbstractBackgroundThe accurate characterization of language and semantic memory deficits is crucial for diagnosis of primary progressive aphasia (PPA). In a linguistically diverse society like India, assessment with linguistically appropriate and culturally relevant tools is essential but challenging. This study aimed at developing language and culture specific tests to diagnose PPA and profile cognitive‐linguistic characteristics of a diverse cohort of PPA in India.MethodBased on typical characteristics of Indian languages: free‐word order, rich system of morphology and case‐marking that are features that differentiate Indian languages from English, a language‐specific assessment battery was developed in seven languages: Hindi, Bengali (Indo‐Aryan languages) and Kannada, Telugu, Malayalam and Tamil (Dravidian languages). In the background of the importance of case‐markers in the syntax of Indian languages, a unique syntax assessment test was specifically developed. To evaluate semantic memory, the Indian Semantic Memory battery was developed using stimuli appropriate for a pan‐Indian cultural context. All patients underwent assessment of language proficiency and comprehensive cognitive evaluation by examiners proficient in the language of testing.Result36 patients with PPA: 22 with semantic variant (svPPA), 12 nonfluent variant (nfvPPA) and 2 logopenic variant (lvPPA) participated. The cohort consisted of proficient speakers of seven Indian languages. A particular difficulty in the appropriate use of case markers on the new test of syntax was revealed in nfvPPA compared to svPPA. Further, the core diagnostic feature of ‘agrammatism’ for PPA in English‐speaking nfvPPA was not as dramatic in Indian patients owing to the morphological richness of Indian languages, leading to reduced contrast between fluent versus non‐fluent aphasia. Consistent with diagnosis, a significant reduction in fluency was demonstrated in nfvPPA (p< 0.006 on fluency tasks). Semantic memory was significantly affected in svPPA as revealed on non‐verbal tasks i.e., word‐picture matching (p<0.02)and semantic association task(p<0.01) of Indian Semantic Battery.ConclusionUsing language and culture specific assessment batteries tailored to the Indian context, a comprehensive clinical characteristics in PPA subtypes were identified. The need to re‐define agrammatism with respect to Indian languages with additional weightage to the use of case markers that assist in identifying the PPA subtype was a novel finding.
Astaxanthin‐s‐allyl cysteine diester attenuated high glucose‐induced oxidative stress toxicity in neuronal cells through protection of mitochondria in vitro
Authors: Loganathan Chitra , Sakayanathan Penislusshiyan , Thayumanavan Palvannan 
Published: December 2021

AbstractBackgroundCognitive dysfunction associate with diabetes is related to high glucose‐induced oxidative stress toxicity in neuronal cells. Hence, identifying compounds that protect the neuronal cells against high glucose toxicity is important to overcome cognitive deterioration under diabetic condition. Astaxanthin‐s‐allyl cysteine diester (AST‐SAC) was synthesized by esterification of AST from the source H. pluvialis with SAC, an allyl sulfur compound found in aged garlic extract. AST‐SAC has shown antidiabetic effect in in vivo rat model. Hence, in the present study the effect of AST‐SAC against high glucose‐induced oxidative stress toxicity in neuronal cell line in in vitro was studied.MethodAST‐SAC was pre‐treated to neuronal cell line and high glucose toxicity was induced. The cell viability, reactive oxidant species generation, antioxidant status and apoptosis induction was studied. Further, mitochondrial membrane potential, mitochondrial oxidative phosphorylation activity and antioxidant status of mitochondria was measured.ResultHigh glucose‐induced toxicity increased oxidative stress and decreased over all antioxidant status of the neuronal cells. Due to which functions (membrane potential and oxidative phosphorylation) and antioxidant status of mitochondria were reduced. All these dysfunction cumulatively lead to the induction of apoptosis in neuronal cells. However, AST‐SAC pretreatment has protected the neuronal cells against high glucose‐induced apoptosis through reduction of oxidative stress and protection of mitochondrial function.ConclusionOverall AST‐SAC attenuated high‐glucose toxicity induced neuronal injury in in vitro through preservation of mitochondrial function.
The mediating role of inflammation in the relationship between α‐synuclein and cognitive functioning
Authors: Dabiri Sanaz , Ruiz Mara Ramirez , Obisesan Thomas O. , Ntekim Oyonumo , Mwendwa Denée T. , Ngwa Julius S. , Campbell Alfonso L. ,   for the Alzhemer's Disease Neuroimaging Initiative
Published: December 2021

AbstractBackgroundAccumulating evidence suggests that α‐synuclein is associated with poor cognitive functioning and plays a role in the pathophysiology of AD. High accumulation of α‐synuclein eventually leads to neuronal death and the initiation of inflammatory cascades. Prior research suggests inflammation plays a role in the development and acceleration of cognitive decline. Moreover, recent studies suggest VEGF may be involved in the development of AD. Therefore, this study examined whether α‐synuclein in cerebrospinal fluid (CSF) was associated with cognitive functioning among older adults. We also determined whether this relationship was influenced by elevated levels of pro‐inflammatory cytokines TNFα, IL‐6, soluble IL‐6 receptor along with VEGF.MethodUsing a cross‐sectional Alzheimer’s Disease Neuroimaging Initiative (ADNI; n= 148) sample, we examined the relationship between CSF measured α‐synuclein and participants' performance on MMSE and ADAS‐Cog 13 at baseline. Mediation analyses while adjusting for age, education, APOEe4, and GDS scores were utilized.ResultParticipants in the current sample were largely males (58.3%), Caucasian (95.5%), average education of 15.5 (SD = 2.97) years and average age 74.4 (SD = 7.51). We observed that higher accumulation of α‐synuclein was associated with lower performance on the MMSE (β =‐.41, SE=1.54, p<.001). This relationship was also mediated by VEGF (β =.27, SE=2.15, p=.025) and IL‐6r (β =.22, SE=1.66, p<.026). In addition, α‐synuclein was associated with poorer performance on the ADAS‐Cog 13 (β =0.34, p=.005) and mediated by VEGF (β =‐.19, SE=4.13, p=.025) after adjusting for age, education, APOEe4, and depressive symptoms.ConclusionOur findings suggest that α‐synuclein can be used as an additional biomarker for poor cognitive functioning. VEGF and IL‐6 soluble receptors were significant mediators in the relationship between α‐synuclein and cognitive functioning. However, this study observed that pro‐inflammatory cytokines TNFα and IL‐6 did not mediate this relationship. If confirmed in prospective analyses, these findings can further inform the pathologic cascade and early diagnosis of AD.
Memory decline is not normal, healthy brain aging
Authors: Pardo Jose V. , Nyabwari Shantal M. , Lee Joel T ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

AbstractBackgroundIt is generally accepted that memory decline is a cardinal feature of aging even in those who are healthy and cognitively intact. However, recent work indicates that as many as 1/4 cognitively unimpaired older adults have significant amyloid deposits and as many as 8% meet the biological definition of Alzheimer's disease (AD; i.e., A+T+; Therriault et al. 10.1212/WNL.0000000000011416). Therefore, studies of cognitive aging before the advent of AD biomarkers may have included a significant number of older adults with preclinical AD skewing findings toward abnormal values.MethodBaseline data from cognitively intact older adults with subthreshold whole‐brain amyloid (A‐) were downloaded from the ADNI website (LONI: http://adni.loni.usc.edu/). The scores from the Logical Memory I & II tests (recall of items for story presented verbally; immediate and delayed) were selected because these place minimal demands on executive function that can also become impaired with age. These volunteers (N = 155) were 59–93 years old (mean age 74 years, SD 6.6; 77 females). The relationship between memory and age was tested for significance.ResultThere was no significant correlation between age and immediate or delayed scores on the Logical Memory Test (r ∼ 0.1; d.f. 153).ConclusionEven into ninety years of age, older adults show cross sectionally no relationship between age and logical memory. However, age‐related deficits may surface in neuropsychological tests that are more demanding or that tax multiple brain systems such as executive functions. The lack of correlation of age with memory converges with recent studies, both cross‐sectional and longitudinal, examining other cohorts of cognitively intact, amyloid‐negative, older adults with more comprehensive testing of memory (Lim et. al. 2018: 10.1001/jamaneurol.2017.4325; Tomassen et al., 2020: 10.1002/alz.045112; Pelkmans et al. 2021: 10.1002/acn3.51273). Support: VA Merit I01CX000501; NIH ADNI U19 AG024904.
BIOFACE: A prospective study of risk factors, cognition and biomarkers in a cohort of individuals with early‐onset mild cognitive impairment at Fundació ACE
Authors: Antonio Ester Esteban‐De , Pérez‐Cordón Alba , Gil Silvia , Cano Amanda , Orellana Adelina , Alegret Montserrat , Espinosa Ana , Alarcón‐Martín Emilio , Valero Sergi , Martínez Joan , Montrreal Laura , de Rojas Itziar , Sotolongo‐Grau Oscar , Martín Elvira , Vivas Assumpta , Chiari Marta Gómez , Tejero Miguel Angel , Tarraga Lluis , Ruiz Agustin , Marquié Marta , Boada Mercè ,   BIOFACE Study Group
Published: December 2021

AbstractBackgroundThe diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) is based on either cerebrospinal fluid (CSF) or neuroimaging biomarkers (Albert et al, 2011). Currently, several non‐invasive and cheaper blood‐based biomarkers are being investigated, including neuronal‐derived plasma exosomes (NPEs) (Winston et al, 2016). The role of neuroinflammation, oxidative stress and early vascular changes, prior to the onset of amyloidosis, has been described in the pathogenesis of AD (Iturria‐Medina et al, 2016) and vascular‐related proteins can be traced in plasma and NPEs using proteomics. However, these changes have not been studied in early onset MCI (EOMCI), that is, when symptoms begin under the age of 65 (Rossor et al, 2010).ObjectiveTo describe the rationale, study design and baseline characteristics of the BIOFACE cohort, a two‐year prospective observational study on EOMCI conducted at Fundació ACE in Barcelona, Spain. The study goal is to characterize different clinical, neuropsychological and biomarker phenotypes and to investigate CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.MethodParticipants underwent neurological and neuropsychological batteries and multimodal biomarkers including brain MRI, APOE genotyping, plasma and NPEs, saliva, CSF, non‐invasive arterial peripheral testing, anthropometrics and neuro‐ophthalmological examinations. In the final visit, participants will undergo brain MRI, lumbar puncture and blood extraction for NPEs.ResultNinety‐seven patients with EOMCI were recruited. Most participants were women (59.8%). Mean age at symptom onset was 57 years; mean MMSE score was 28 with a mean of 12.13 years of education. First degree and presenile family history of dementia was present in 60.8% and 15.5%, respectively. Depressive and anxiety disorders, along with vascular risk factors, were the most frequent comorbidities. Syndromic diagnoses were established: possible amnestic MCI (n=32), possible non‐amnestic MCI (n=33), probable amnestic MCI (n=16) and probable non amnestic MCI (n=16). CSF biomarkers (ATN classification): A+ (n=15), A‐T/N+ (n=13), A‐T‐N‐ (n=57).ConclusionBIOFACE is a two‐year observational study of cognition and biomarkers that will shed light on the physiopathology and the potential utility of plasma proteomics and NPEs as non‐invasive early diagnostic and prognostic biomarkers in individuals with early onset MCI.
Neuropsychiatric symptoms in patients with possible vascular cognitive impairment: Does sex matter?
Authors: Exalto Lieza G. , Boomsma Jooske , Sep Yoni C.P. , Leeuwis Anna E. , Prins Niels D. , Scheltens Philip , Biessels Geert Jan , van der Flier Wiesje M ,   TRACE‐VCI study group
Published: December 2021

AbstractBackgroundEmerging evidence shows sex differences in manifestations of neuropsychiatric symptoms (NPS) in memory clinic patients. NPS are common in patients with vascular cognitive impairment (VCI) affecting quality of life and caregiver burden, however sex differences are largely unknown. We aimed first to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and second to investigate the association between different NPS and substantial cognitive decline stratified by sex.MethodWe included 737 memory clinic patients (age 68.1±8.4; 45% female) from the prospective TRACE‐VCI cohort study with possible VCI; cognitive complaints and vascular brain injury (moderate/severe white matter hyperintensities (n = 398), microbleeds (n = 317), lacunar (n = 167) and non‐lacunar (n = 85) infarct(s), macrobleeds (n = 14)). Dementia was diagnosed in 405 and MCI in 197 patients. NPS were measured using the 12‐item Neuropsychiatric Inventory (NPI) and dichotomized as present ≥1. Substantial cognitive decline was defined as change of CDR ≥1 or institutionalization (available for n=571 without advanced dementia at baseline). The association between NPS and cognitive decline was assessed with Cox proportional hazard models in females and males separate, adjusted for other NPS, age and clinical diagnosis.ResultWe found no difference in age nor distribution of clinical diagnoses between the sexes. Males more often presented with agitation (29% versus 17%) and irritability (58% versus 46%), while females more often presented with anxiety (32% versus 25%, all p<0.05), the other 9 NPS (delusions, hallucinations, aggression, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, sleep/night‐time disturbances and appetite and eating abnormalities) did not differ between the sexes. During follow‐up, occurrence of substantial cognitive decline was comparable between males (14%) and females (15%). In males, substantial cognitive decline was higher in the presence of apathy (HR 2.5, 95%CI;1.2‐5.4) and aberrant motor behavior (HR 2.2, 95%CI;1.1‐4.6) and lower in the presence of appetite and eating abnormalities (HR 0.4, 95%CI;0.2‐0.9). In females, none of the NPS were associated with substantial cognitive decline.ConclusionPattern and predictive value of NPS differs by sex in memory clinic patients with VCI. Acknowledgment of these differences could direct interventions.
Longitudinal changes of multiple CSF phosphorylated tau sites in dominantly inherited Alzheimer disease
Authors: Barthelemy Nicolas R. , Li Yan , Sato Chihiro , Horie Kanta , McDade Eric 
Published: December 2021

AbstractBackgroundRecent analyses of tau phosphorylation in cerebrospinal fluid (CSF) from dominantly inherited Alzheimer disease (DIAD) patients have pinpointed early modification of phosphorylated tau (p‐tau) at 217 (pT217) occurring simultaneously with emergence of amyloid plaques. This has opened new perspective in diagnosing AD pathology at preclinical stages using ptau in CSF and plasma. Tau is phosphorylated at many sites in brain and a subset of them is detectable in CSF. To date, we have investigated four p‐tau sites and demonstrated the modifications of pT217, pT181 and pT205 start respectively 21, 19 and 13 years before estimated year to symptom onset (EYO) when pS202 remained unchanged. We extend the list of monitored ptau sites in the DIAN cohort to ten tau residues.Method589 CSF samples from 370 participants in DIAD families were analyzed by tau immunopurification and multiplex‐targeted mass spectrometry using nanoLC‐Q‐LTQ‐Orbitrap instrument. We measured phosphorylation occupancy and ptau level at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231. For each ptau, we calculated area under curve (AUC) of receiver operating characteristic (ROC) to detect amyloidosis as measured by PiB‐PET. We determined phosphorylation amount and rate of change over the course of the disease based on EYO.ResultThe most to least sensitive phosphorylated sites for detecting amyloidosis in mutation carriers were T217, T181, T153, T111, T231, S208 and T205 with AUC ranging from 0.96 to 0.87. T175, S199 and S202 were not significantly modified. For the newly investigated sites pT111, pT153, pS208 and T231, we found significant hyperphosphorylation compared to non‐carriers at EYOs ranging from ‐22 to ‐19 years. Longitudinal analyses of pT153, pS208 and pT231 demonstrated a decreasing of the phosphorylation after symptoms as previously observed for pT217 and pT181. Separately, pT111 continued to increase after onset.ConclusionThis study corroborates the distinct response of tau residues to hyperphosphorylation over AD process. We confirm pT217 is the earliest abnormally modified phosphorylated site in AD amongst the 10 sites investigated in CSF. Our results support the use of pT153, pT111 pT231 and pS208 as additional ptau biomarkers for the diagnosis of asymptomatic AD.