bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stress and Alzheimer’s disease: Linking salivary cortisol to biomarkers of neurodegeneration and cognitive decline in a memory clinic cohort
Authors: Daniilidou Makrina , Hagman Göran , Holleman Jasper , Sindi Shireen , Brinkmalm Ann , Zetterberg Henrik , Blennow Kaj , Solomon Alina , Sandebring‐Matton Anna , Kivipelto Miia 
Published: December 2021

AbstractBackgroundPsychosocial stress has been shown to affect cognitive performance negatively and to increase the risk of developing dementia. Cortisol, a hormone thought to mediate several of the effects of chronic stress, has been shown to be elevated in Alzheimer’s disease (AD) patients. Interestingly, cortisol induces inflammatory responses that are detrimental to brain function. However, the relationship of this hormone with AD pathology, neuroinflammation, synaptic degeneration and neuronal survival is not well understood. The aim of this study is to investigate the interconnection of cortisol with CSF biomarkers of AD pathology, inflammation and synaptic dysfunction and with the serum neurotrophic factor BDNF and its precursor, proBDNF.MethodCross‐sectional analyses were performed on data from a total of 158 memory clinic patients with subjective cognitive decline (SCI, n=55), mild cognitive impairment (MCI, n=62) and Alzheimer’s disease (AD, n=41), from the Karolinska University Hospital in Sweden. Six timepoint diurnal salivary cortisol measurements, serum BDNF (both mBDNF and proBDNF) and the following CSF analytes were quantified: a neuroinflammation marker (chitinase‐3‐like protein 1 (YKL‐40)), markers of synaptic degeneration (synaptotagmin‐1, neurogranin and SNAP‐25) and AD pathology markers (Aβ1‐42, t‐tau and p‐tau). Linear regression models were performed for all participants and for each diagnostic subgroup, to examine the relationship between cortisol and the biomarkers, adjusting for age, sex, education and diagnosis. ANOVA, or Kruskal‐Wallis tests were applied to compare marker levels between the diagnostic groups.ResultPositive associations were observed between salivary cortisol and CSF t‐tau, neurogranin and SNAP‐25. Salivary cortisol was also associated with lower peripheral proBDNF levels in the AD group. Increased awakening cortisol was associated with lower proBDNF levels in all participants, while a similar association could be observed for bedtime cortisol in the AD group only. There was no relationship between cortisol and YKL‐40, however YKL‐40 was associated with the synaptic markers. SNAP‐25 and neurogranin were higher in AD compared to SCI and MCI participants, confirming results from previous reports.ConclusionOur findings support an association of cortisol hypersecretion with neurodegeneration, synaptic dysfunction and the reduction of proBDNF in the periphery, which needs further investigation.
Demographics and clinical risk factor(s) variations in mortality of Alzheimer's disease in Taiwan: A 15‐year national population‐based study
Authors: Liu Chih‐Ching 
Published: December 2021

AbstractBackgroundIdentifying variation in the demographics and clinical risk factor(s) of the mortality for Alzheimer's disease (AD) has public health applications for projecting the future burden of disease. However, very few nationwide studies have been conducted on this topic in Asia countries. This study describes age‐, sex‐ and comorbidities‐ specific mortality in Taiwan as well as assesses the disparity of demographics and clinical factor(s) on the mortality of AD.MethodThis is a population‐based cohort study. The data of onset AD aged ≧40 years were acquired from the Taiwan National Health Insurance Research Database entries between 2000 and 2002.We used proportional hazards models to assess the effect of demographic and clinical factor(s) on 15 years of mortality after AD onset, Kaplan–Meier method for median survival times. We also further investigated survival time in incident AD by age‐, sex‐ and comorbidities‐stratified analyses.ResultThe median survival time during 15 years after first‐diagnosis of AD was 7.69 (95%CI :7.46‐7.90) years for overall, 6.37(95%CI :6.06‐6.65) years for men and 8.81(95%CI :8.49‐9.12) years for women. Predictors of mortality based on proportional hazards models included older age, males, and some specific clinical factors, including hypertension, diabetes mellitus, heart disease, and chronic obstruction pulmonary disease (COPD). Regardless of any gender, the survival time was shortest in subjects aged ≧80 years, especially in those with heart disease, diabetes mellitus, and COPD.ConclusionThe significant demographics and clinical risk factor(s) variations in AD mortality. Public health interventions should consider these differences in health care resources.
Stimulation of cerebral angiogenesis and neurogenesis with transcatheter intracerebral laser photobiomodulation therapy during dementia in patients with Alzheimer's and Binswanger's disease
Authors: Maksimovich Ivan V 
Published: December 2021

AbstractBackgroundThe research investigates stimulation of cerebral angiogenesis and neurogenesis with Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) in patients with dementia with Alzheimer's disease (AD) and Binswanger's disease (BD).Materials & MethodsExamined 120 patients suffering from dementia. Accomplished: CDR assessment, Tomography Dementia Rating scale (TDR), MMSE, cerebral CT, MRI, SG, rheoencephalography (REG), cerebral MUGA. We chose 48 patients suffering from AD aged 34‐80 (mean age 67.5), 17 men (35.42%) and 31 women (54.58%). The patients were subdivided according to dementia severity: preclinical stage (TDR‐0 dementia level) ‐ 4, mild stage (TDR‐1 dementia level) ‐ 16, moderately severe stage (TDR‐2 dementia level) ‐ 21, severe stage (TDR‐3 dementia level) ‐ 7 patients. 17 patients with BD aged 58‐81 (mean age 78) were selected, 11 men (64.71%) and 6 women (35.29%). According to dementia severity, the patients were subdivided: mild stage (dementia level CDR‐1) ‐ 9, moderately severe stage (dementia level CDR‐2) ‐ 5 patients. In hospital setting, all patients underwent Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT).ResultsAll 48 (100%) patients with AD showed cerebral microcirculation improvement, as well as a 10‐20% increase in cerebral temporal lobes volume, which indicates cerebral neurogenesis development and tissue regeneration. The process was accompanied by dementia level decline and cognitive functions restoration. As a result, patients were transferred to the milder TDR stage group. Depending on the initial dementia severity, the obtained positive effect has been observed for 2‐10 years. All 17 (100%) patients with BD showed cerebral microcirculation improvement and cerebral involutional changes decline, which indicates neurogenesis development and tissue regeneration. The process was accompanied by dementia level decline and cognitive functions restoration. The resulting positive effect has been observed for over 10 years.ConclusionsDespite the differences in the etiology of AD and BD, Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) is an effective treatment for dementia during these diseases. The method improves cerebral blood flow; it stimulates neurogenesis and tissue structure restoration, which lead to dementia decline and cognitive functions improvement. The resulting effect lasts for a long time.
In vivo Braak‐staging using 18F‐Flortaucipir‐tau‐PET as a predictive marker for future cognitive decline in Alzheimer’s disease
Authors: Biel Davina , Brendel Matthias , Rubinski Anna , Buerger Katharina , Janowitz Daniel , Dichgans Martin , Franzmeier Nicolai 
Published: December 2021

AbstractBackgroundThe development of in vivo amyloid (Aβ) and tau biomarkers has greatly facilitated diagnosing AD (Jack et al., 2018), however, reliable prognosis of AD‐related cognitive decline remains a critical yet unmet challenge. Here, especially tau biomarkers may offer great potential for individualized risk prediction of clinical AD progression, since the progressive spread of tau tracks clinical status more closely than Aβ deposition (Ossenkoppele et al., 2016; Wang et al., 2016). Thus, positron emission tomography (PET) of tau may be a better predictor for future cognitive decline and clinical progression than amyloid‐PET. Here, we examined whether tau‐PET‐based Braak‐staging outperforms amyloid‐PET as a predictor of future cognitive decline and clinical progression in older adults with and without cognitive impairment.MethodWe included 396 cognitively normal to AD dementia subjects with Flutemetamol/Florbetapir‐amyloid‐PET, Flortaucipir‐tau‐PET and longitudinal cognitive assessments. Annual change rates in global cognition (i.e. MMSE, ADAS13) and episodic memory (i.e. ADNI‐MEM) were calculated via linear mixed models. We determined global amyloid‐PET (i.e. Centiloid) plus global and Braak‐stage‐specific tau‐PET SUVRs, which were stratified as positive(+)/negative(‐) at pre‐established cut‐offs. Using Braak‐stage‐specific binarized tau‐PET SUVRs, we classified subjects as BraakI+/BraakI‐IV+/BraakI‐VI+/Braakatypical+. In bootstrapped linear regression, we assessed whether global tau‐PET explained more variance in subsequent cognitive decline than Centiloid. Using ANCOVAs, we tested whether advanced Braak‐stage predicted faster future cognitive decline. All models were controlled for age, sex, education, clinical diagnosis, and baseline cognition. Lastly, we determined Braak‐stage‐specific conversion risk to mild cognitive impairment (MCI) or dementia.ResultHigher global tau‐PET SUVR at baseline explained more variance in subsequent cognitive decline across ∼2 years of follow up compared to baseline amyloid‐PET, consistently for MMSE, ADAS13, and memory (all p<0.001; Fig. 1). The association between global tau‐PET and subsequent cognitive changes remained consistent when additionally controlling for baseline amyloid‐PET. Advancing Braak‐stage was associated with gradually worsening future cognitive decline, independent of Centiloid (p<0.001; Fig. 2), and elevated clinical conversion risk to MCI or AD dementia (e.g. 15.38% for BraakI+, 23.81% for BraakI‐IV+, 45.45% for BraakI‐VI+; Fig. 3).ConclusionTau‐PET clearly outperforms amyloid‐PET in predicting future cognitive decline, where tau‐PET‐based Braak‐staging may be used for estimating patient‐specific risk for clinical AD progression.
Correlation of frontal atrophy and CSF tau levels with neuropsychiatric symptoms in patients with cognitive impairment: A memory clinic experience
Authors: Ramusino Matteo Cotta , Perini Giulia , Vaghi Gloria , Fabbro Beatrice Dal , Capelli Marco , Picascia Marta , Franciotta Diego , Farina Lisa , Ballante Elena , Costa Alfredo 
Published: December 2021

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are a distressful condition. We aimed to investigate the BPSD distribution in subjects with cognitive impairment, and the potential correlations between BPSD and neurodegeneration in terms of cerebrospinal fluid (CSF) tau and brain atrophy.MethodOne‐hundred patients with mild cognitive impairment (MCI) or dementia (Alzheimer’s disease; Lewy‐body disease, LBD; frontotemporal dementia; vascular dementia) underwent a complete diagnostic workup, including 3T‐MRI and/or CT and CSF. Cortical atrophy was assessed with medial temporal atrophy (MTA), posterior atrophy (PA) and global cortical atrophy‐frontal lobe (GCA‐F) scales. BPSD were rated using Neuropsychiatric Inventory (NPI), and BPSD clusters were defined according to the European Alzheimer Disease Consortium.ResultDelusions, hallucinations and psychosis cluster were differently distributed among the diagnostic groups (p<0.05, p<0.001, and p<0.05), with LBD patients showing higher scores for hallucinations (vs MCI, p<0.001, and AD, p<0.05) and psychosis cluster (vs MCI, p<0.05). In primary dementias, we found a negative correlation between NPI total score and tau levels (p=0.08), confirmed by beta regression (p<0.01), while a positive non‐significant relationship was observed in MCI. Higher GCA‐F scores were associated with delusions and apathy (p<0.05, on both hemispheres) and to hallucinations (left: p<0.01, right: p<0.05). GCA‐F scores were positively correlated with psychosis cluster (right: p<0.05), and agitation/aggression (left: p<0.05). Conversely, nighttime disturbances were positively correlated with both GCA‐F and MTA scores (left: p<0.01; right: p<0.05).ConclusionOur results suggest that psychotic symptoms are significantly more represented in LBD patients, and that CSF tau and frontal atrophy are associated with the occurrence and severity of BPSD in clinical practice. Longitudinal studies are however required to ascertain their actual predictive value.
Telephone survey to identify factors predicting willingness to enroll in biomarker studies and disclosure‐related outcomes
Authors: Clark Lindsay R , Erickson Claire M , Chin Nathaniel A , Jonaitis Erin M , Edwards Dorothy Farrar , Zuelsdorff Megan , Gleason Carey E 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) diagnostics is evolving rapidly, moving toward biomarker‐based diagnoses characterized by amyloid, tau, and neurodegeneration. To clarify benefits and risks of using this framework with cognitively unimpaired adults, particularly those from groups under‐represented in AD biomarker research, we developed a 30‐minute telephone survey to identify factors predicting willingness to enroll in biomarker studies and hypothetical disclosure‐related outcomes.MethodExisting scales were modified for telephone administration to assess experience/concern about AD, perceived health, health locus of control, brain health social norms, trust in medical research, and experiences of discrimination. Five hypothetical scenarios assessed willingness to participate in biomarker studies with or without results disclosure. Three open‐ended items provided qualitative data on willingness to participate and share results with others. Forty‐one items assessed reasons for learning results and potential reactions following a hypothetical elevated result. Descriptive statistics were used to evaluate response patterns. Thematic analysis of open‐ended items was conducted using an inductive coding method.ResultCognitively unimpaired participants (N=334) included 148 Black/African Americans and 186 non‐Hispanic Whites; aged 45‐89; Table 1). Most participants had cared for someone with dementia (73%), desired to know if they will develop AD (82%) and trust medical research (mean RAQ‐7 = 30/35) (Table 2). Approximately 50% were very or extremely willing to participate in biomarker studies regardless of results disclosure; however, African Americans were less willing to participate if results were not disclosed. Common themes related to willingness to participate and learn results included wanting to know if at personal risk or to prevent/plan for AD and wanting to support science or help others. Misgivings/anxiety about knowing biomarker and concerns about invasiveness or lack of a cure for AD were common themes for those less willing (Table 3).ConclusionThis survey assesses AD‐relevant, health, and experiential factors, willingness to participate in biomarker research, and disclosure‐related outcomes. Initial results suggest understanding risk, prevention/planning behaviors, and helping others are reasons for participating and learning biomarker results. Results may also inform recruitment of African Americans into biomarker studies. Future analyses will investigate factors predicting potential positive (e.g., planning, risk‐reducing behavior) and negative (psychological distress/stigma) disclosure outcomes.
Diffusion tensor imaging findings in empirically derived incident MCI subtypes
Authors: Machulda Mary M. , Lundt Emily S. , Mester Carly T. , Albertson Sabrina M. , Pillai Sheela Kumari Raghavan , Reid Robert I. , Schwarz Christopher G. , Graff‐Radford Jonathan , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Kremers Walter K. , Jones David T. , Petersen Ronald C. , Bondi Mark W. , Vemuri Prashanthi 
Published: December 2021

AbstractBackgroundEarly changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.MethodParticipants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.ResultAll MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p<0.001; Figure 1).ConclusionWe found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.
Analyzing the future time perspective scale in the baseline period in the Anti‐Amyloid treatment in Asymptomatic Alzheimer's Disease (A4) Study
Authors: Stites Shana D. , Dedhia Mehek , Grill Joshua D. , Karlawish Jason 
Published: December 2021

AbstractBackgroundLearning an Alzheimer’s disease (AD) biomarker result can impact a person’s expectations for their future. We assessed the behavior of the Future Time Perspective (FTP) scale in a sample of cognitively unimpaired older adults undergoing AD biomarker testing and disclosure.Method5665 participants who were screened for a multisite randomized preclinical AD trial learned their result of an amyloid PET scan: 1182 elevated and 3310 not elevated. Each completed the FTP scale before and after learning the result. The FTP is a 10‐item scale that measures perceived remaining time. Items are rated on a 7‐point scale. Correlations, factor analysis, within‐subject comparisons, and polytomous analyses explored relationships between FTP and amyloid status. In multinomial logistic regression (MLR) analyses, the base outcome was no FTP change (50th%tile interquartile range of change score distribution). Decreased FTP was the lowest quartile of change score distribution while increased FTP was the upper quartile.ResultsUsing items that showed high uniqueness scores (<0.40) and low ceiling effects (<20% endorsing maximum scale scores), we examined a 3‐item FTP subscale (FTP‐3, score range 1 to 7). Mean change in persons with elevated amyloid was 0.12 (95%CI 0.06 to 0.18) and 0.20 (95%CI 0.17 to 0.24) in those with a not elevated result.In MLR analysis, the mean in the decreased FTP‐3 group was ‐0.89 points (95%CI ‐0.92 to ‐0.86), while the mean increased FTP‐3 was 1.26 (95%CI 1.22 to 1.29). Elevated amyloid results (0.22, 95%CI 0.06 to 0.39) and better self‐rated cognitive function (CFI, ‐0.03, 95%CI ‐0.05 to 0.01) made decreased FTP‐3 more likely than no FTP‐3 change. In the same analysis, lower MMSE scores (‐0.08, 95%CI ‐0.14 to ‐0.03) made increased FTP‐3 more likely than no FTP‐3 change.ConclusionThe 3‐item FTP scale offers an option for a brief measure with limited ceiling effects. Additionally, while mean FTP change due to AD biomarker result disclosure is small (mean=0.18), our findings from polytomous analysis support the hypothesis that AD biomarker result knowledge may have notable effects on FTP (∼2SD). FTP warrants further study in preclinical AD with attention to associations with disease progression, well‐being, and life plans.
Clinical, cognitive and biomarker profiles in dominantly‐inherited versus sporadic early‐onset Alzheimer’s disease
Authors: Llibre‐Guerra Jorge J , Iaccarino Leonardo , Li Yan , Edwards Lauren , McDade Eric , Strom Amelia , Gordon Brian A. , Mundada Nidhi , Schindler Suzanne E. , Tsoy Elena , Fagan Anne M , La Joie Renaud , Benzinger Tammie L.S. , Soleimani‐Meigooni David N. , Aschenbrenner Andrew J. , Miller Zachary A. , Wang Guoqiao , Kramer Joel H , Hassenstab Jason , Rosen Howard J. , Morris John C. , Miller Bruce L. , Xiong Chengjie , Perrin Richard J. , Rabinovici Gil D. , Bateman Randall J. 
Published: December 2021

AbstractBackgroundApproximately 5% of Alzheimer disease (AD) occurs before the age of 65, known as early onset AD (EOAD); 5‐10% of the patients with EOAD are caused by dominantly inherited mutations (DIAD) and the remainder appear to be sporadic EOAD (sEOAD). The extent to which clinical presentations, cognitive and biomarker profiles in DIAD and sEOAD overlap remains unknown.MethodsWe compared the clinical presentation, cognitive performance and cerebrospinal fluid (CSF) AD biomarker concentrations in DIAD and sEOAD. We included all DIAD symptomatic (CDR>0) participants (n=92) from the Dominantly Inherited Alzheimer Network (DIAN) cohort and 120 sEAOD symptomatic participants from the UCSF Alzheimer’s Disease Research Center. All EOAD cases were amyloid‐positive via PIB‐PET. All participants completed clinical measures, a battery of cognitive tests and CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau). Baseline differences in clinical and biomarkers variables between sEOAD and DIAD were compared using t‐tests, and differences in the rates of decline on clinical and cognitive measures were compared using linear mixed effects models.ResultsDIAD participants had an earlier age at symptom onset compared to the sEOAD group (42.9y (±8.1) and 54.8y (±5.1) respectively, p<0.001). The sEOAD group showed a lower performance on executive measures, including verbal fluency (p=0.001), Trail making test (p=0.001) and digit span (p<0.001). CSF Aβ‐42 levels were significantly lower in DIAD compared to sEOAD participants (242.0 pg/ml [IQR=164.5, 318.8] vs 295.0 pg/ml [IQR=243.9, 364.1] respectively, p=0.014). Ptau‐181 levels were higher in the DIAD cohort (p=0.003), but no significant differences were found for t‐tau levels (p=0.11). Longitudinal analyses did not reveal significant differences in the rates of functional (CDRTM‐SB) and cognitive (MMSE) decline between two groups.ConclusionsAlthough sporadic and inherited EOAD differed in AD core pathological CSF biomarkers concentrations and baseline cognitive profiles, the rates of functional and cognitive changes were similar across these groups. These findings provide unique insights into the similarities and differences between DIAD and sEOAD and may inform the design of future clinical trials.