bluuebunny/crossref_metadata_2025_split huggingface dataset:
Olfactory identification deficits are associated with cognitive decline in Chinese older adults: The Taizhou Imaging Study
Authors: Jiang Yanfeng , Tan Ziyi , Zhang Kexun , Zhu Zhen , Wang Yingzhe , Li Peixi , Jin Li , Dong Qiang , Cui Mei , Chen Xingdong 
Published: December 2020

AbstractBackgroundOlfaction function has emerged as a potential predictor of cognitive decline and dementia recently. We accessed the association of olfaction and cognitive function in a Chinese cohort.MethodParticipants in this study were part of the community‐based Taizhou Imaging Study. At the first wave of cognitive function follow‐up, 770 individuals underwent neuropsychological testing from July 2018 to August 2019, including four cognitive domains‐memory, executive function and attention, visuospatial function, and language. Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to assess participants’ global cognition. Among them, 686 participants underwent olfactory identification testing using 12‐item Sniffin’s Sticks test. Dementia and mild cognitive impairment (MCI) were adjudicated by a committee of experts, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV) and Petersen RC’s criteria, respectively. After data quality control, 684 participants were included in this analysis (Figure 1). Beta regression was used to evaluate the association between olfaction and cognitive function (continuous variables), logistic regression was used to assess the association between olfaction and cognitive status (categorical variable). Potential confounders were adjusted in two models: Model 1 was adjusted for age, sex, and years of education; Model 2 was additionally adjusted for smoking, alcohol consumption, body mass index, exercise, hypertension, diabetes, and hyperlipidemia.ResultA total of 54 (7.9%) individuals were diagnosed as dementia, 165 (24.1%) individuals were adjudicated as MCI (Table 1). In the fully adjusted Model 2, the associations remained significant (Beta = 0.062 and 0.093, respectively; both P <0.001) (Table 2). Olfactory identification scores were associated with domain‐specific cognitive function scores in Model 2 (visuospatial function: Beta = 0.072, P = 0.003; short delay recall: Beta = 0.120, P <0.001; long delay recall: Beta = 0.057, P = .010; language: Beta = 0.107, P <0.001). Moreover, we found olfactory identification was negatively associated with MCI in Model 2 (odds ration [OR]: 0.88; 95% confidence interval [CI]: 0.81, 0.96) and dementia (OR: 0.76; 95% CI: 0.66, 0.87) (Table 3).ConclusionOlfactory identification are associated with both global and domain‐specific cognitive function and could serve as a protector for cognitive decline.
Gait disturbances are associated with increased CSF tau levels in a memory clinic cohort
Authors: Muurling Marijn , Rhodius‐ Meester Hanneke FM , van Gils Mark , Frederiksen Kristian Steen , Bruun Marie , Hasselbalch Steen Gregers , Soininen Hilkka , Herukka Sanna‐Kaisa , Hallikainen Merja , Mattila Jussi , Teunissen Charlotte E. , Visser Pieter Jelle , Scheltens Philip , van Der Flier Wiesje , Lötjönen Jyrki , Pärkkä Juha , de Boer Casper 
Published: December 2020

AbstractBackgroundGait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s Disease and other dementias. It is not clear however, which gait features are most informative and how these measures relate to Alzheimer pathology. In this study, we used in‐depth evaluation of gait in cognitively normal (CN) subjects, Mild Cognitive Impairment (MCI) patients, and dementia patients. We evaluated the associations between dynamics of gait, level of cognitive impairment and CSF biomarkers of Alzheimer’s pathology.MethodWe included CN participants (n=58), MCI patients (n=58) and participants with different types of dementia (n=26) of the multicenter PredictND cohort. Participants performed gait tests in two conditions: a normal walk task and a cognitively complex dual task. Gait was measured using tri‐axial accelerometers attached to the fifth lumbar vertebra (L5). Following principal component analysis, calculated gait features were clustered into four domains: pace, rhythm, time variability and length variability. Associations between gait domains, clinical diagnosis and CSF biomarkers (Aβ42, total tau, pTau) were examined using linear mixed models, included an interaction term with condition (normal and dual walk task) and were corrected for age, sex and center.ResultDementia patients showed gait disturbances in the pace domain ((p<0.05), Figure 1, first row), meaning that dementia patients walk slower and with a smaller step length compared to CN and MCI participants. Rhythm disturbances were associated with increased levels of CSF (p)tau in the dual task (Figure 1, third and fourth row). No associations were found with CSF Aβ42 levels in any gait domain (Figure 1, second row).ConclusionThese findings suggest that gait disturbances increase with level of syndrome diagnosis. Moreover, rhythm disturbances increase with higher levels of CSF total tau and pTau, providing evidence for a direct link with neurodegeneration. These results demonstrate that in‐depth gait analysis with accelerometers might be a potential helpful tool to support clinical diagnosis or can be used as clinical outcome tool in clinical trials.
Proprotein convertase subtilisin/kexin type 9 inhibitor exerts greater efficacy than atorvastatin on ameliorating cognitive impairment in high‐fat diet–induced obesity
Authors: Arunsak Busarin , Pratchayasakul Wasana , Amput Patchareeya , Chattipakorn Kenneth , Tosukhowong Theetouch , Kerdphoo Sasiwan , Jaiwongkam Thidarat , Thonusin Chanisa , Palee Siripong , Chattipakorn Nipon , Chattipakorn Siriporn C. 
Published: December 2020

AbstractBackgroundLong‐term consumption of a high‐fat diet (HFD) caused not only obesity with dyslipidemia but also caused brain pathologies which resulted in cognitive impairment. Atorvastatin, a recommended first‐line lipid‐lowering drug, had beneficial effects on metabolic control and mitigated brain pathologies in several models. However, the long‐term use of statin had many side effects which may result in discontinuation of statins for therapeutic treatment. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effectively therapeutic drug for lowering cholesterol level. PCSK9 inhibitor decreases low‐density lipoprotein receptor (LDLR) degradation, and consequently lowers of LDL levels in the circulation. However, there were only few studies that reported the effect of PCSK9 inhibitor on brain functions. In addition, the comparative effects of atorvastatin and PCSK9 inhibitor on brain functions and cognitive function in HFD‐induced obesity have not been elucidated. We hypothesize that PCSK9 inhibitor has greater effect than atorvastatin on improving brain function and cognitive function in HFD‐induced obesity.MethodTwenty Female Wistar rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline, and HFD rats were divided into two subgroups to receive either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. At the end of experimental protocol, metabolic parameters, brain function, and cognitive function were determined.ResultHFD‐fed rats developed obesity, dyslipidemia and insulin resistance. An increase in PCSK9 level, LDLR degradation, oxidative stress, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity, apoptosis, Alzheimer’s‐related proteins production in hippocampus, and cognitive decline were observed in HFD‐fed rats. Atorvastatin and PCSK9 inhibitor equally attenuated Alzheimer’s‐related proteins production and apoptosis in hippocampus of HFD‐fed rats. Interestingly, PCSK9 inhibitor had greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress level, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity and cognitive decline in HFD‐fed rats. Furthermore, PCSK9 inhibitor, but not atorvastatin, decreased the hippocampal PCSK9 and increased LDLR expression in HFD‐fed rats (p<0.05, Figure 1).ConclusionPCSK9 inhibitor exerted greater efficacy than atorvastatin in improving metabolic and brain function in HFD‐induced obesity.
Oligodendroglial alterations in FTD caused by C9orf72 expansion
Authors: Dolcet Sonia Sirisi , Querol‐Vilaseca Marta , Dols‐Icardo Oriol , Pegueroles Jordi , Montal Victor , Muñoz Laia , Torres Soraya , Blesa Rafael , Belbin Olivia , Fortea Juan , Clarimon Jordi , Lleó Alberto 
Published: December 2020

AbstractBackgroundThe most frequent genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is the hexanucleotide repeat expansion in the C9orf72 gene. Until now, three different mechanisms have been proposed to explain its pathogenic effects: i) loss of function of the C9orf72 protein, ii) toxic gain of function from sense and antisense C9orf72 repeat RNA, or iii) toxic gain of function from Dipeptide Repeat Proteins. Another important hallmark associated with C9orf72 mutations is the TDP43 accumulation in neurons and glia. As in other neurodegenerative diseases, neuroinflammation is a common feature in FTD; however, the specific role of the innate immune system in FTD associated to specific subtypes of the disease is unknown.MethodIn this study, we investigated changes in the pattern of different glial markers (GFAP, YKL‐40, Iba‐1 and MBP) using immunohistochemistry in the frontal cortex and hippocampus of a cohort of 23 cases diagnosed with C9‐FTD/ALS with TDP43 pathology (C9‐FTD), 8 cases diagnosed with sporadic‐FTD TDP43 (sFTD) and 9 healthy controls (HC). Different in‐house semi‐automated MATLAB algorithms were developed and were used to quantify the immunoreactivity of these different markers.ResultWe found a significant increase of GFAP, YKL‐40 and Iba1 immunoreactivity in C9‐FTD and in the sporadic group compared with a group of healthy controls both in frontal cortex and hippocampus. We also found a decreased of MBP protein immunoreactivity in the group of C9‐FTD samples, both in grey and white matter from the frontal cortex, compared to control and sporadic group of samples. In C9‐FTD group we found a negative correlation between MBP and TDP43.ConclusionThese results indicate that FTD caused by C9orf72 is associated with myelin loss likely caused by the mutation or its distinct pathology. Understanding these biological processes will help to identify specific pathways associated with this FTLD subtype and help in the development of new therapeutic strategies implicating oligodendroglial cells as a target to reduce the disease progression and improve quality of life of FTD with C9orf72 expansion patients.
Using the Locus Coeruleus as a biomarker in Alzheimer's disease
Authors: Beardmore Rebecca C , Darekar Angela , Holmes Clive , Boche Delphine , Nicoll James AR , Durkin Matthew , Hou Ruihua 
Published: December 2020

AbstractBackgroundNeuronal loss and tau aggregation in the Locus Coeruleus (LC) are suggested to be among the earliest pathologies in Alzheimer’s Disease (AD). However this remains to be investigated in vivo. Depletion of cortical noradrenaline (NA) concentration as a result of LC degeneration has proinflammatory effects on microglia and likely contributes to the neuroinflammatory changes observed in animal models of AD. However inflammatory changes within the human LC and the relation to inflammation seen in LC projection areas, e.g. the temporal cortex, has not been investigated.Method24 AD participants and 24 age and gender matched cognitively unimpaired subjects underwent a high resolution neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) scan to enable the LC to be visualised in vivo. A LC contrast ratio was generated by comparing maximum values in the anatomical location of the LC to a reference region in the adjacent pontine tegmentum. Additionally, immunohistochemistry is currently being performed to examine several inflammatory markers in the LC and temporal cortex of 60 human brains at varying stages of disease severity and in relation to the pathology.ResultIn the MRI study, the AD group had a lower LC‐CR compared to controls (p<0.05), which correlated with cognitive impairment. Inflammatory and neuropathological markers in the post‐mortem tissue are currently being quantified.ConclusionNM‐MRI may be useful as a biomarker for diagnosis in AD and suggests early degeneration of the LC. Tissue examination will characterise the inflammatory changes observed in patients in order to elucidate the pathological consequences of LC degeneration.
Race and sex differences in midlife changes in cerebral volume and perfusion
Authors: Moonen Justine E. , Nasrallah Ilya M. , Detre John A. , Dolui Sudipto , Erus Guray , Davatzikos Christos , Meirelles Osorio , Bryan R.N. , Launer Lenore J. 
Published: December 2020

AbstractBackgroundCross‐sectional demographic differences in MRI markers of brain health are well established, but less is known about differences in rates of change, particularly in mid‐life. We assessed demographic differences in midlife change of MRI measures of gray matter (GM) volume and perfusion, which are important early markers of late‐life cognitive decline. We also assess the extent to which cardiovascular risk factors explain demographic differences.MethodData are from a subsample attending the 25 and 30 year follow‐up MRI exams [n=478] of Coronary Artery Risk Development in Young Adults (CARDIA), a community‐based cohort study at 3 USA‐based centers. Structural 3T MRI was used to quantify total GM as percent of intracranial volume. GM cerebral blood flow (CBF, ml/100gr/min) was measured using pseudo‐continuous arterial spin labeling. To test for interaction between race and sex, multiple linear regression analysis was used entering MRI feature at follow‐up as dependent variable and as independent variables: MRI feature at baseline, center, age, sex, race and the interaction term(race*sex). Next, MRI features at follow‐up were compared amongst groups of race/sex with ANCOVA, adjusting for baseline MRI feature, center, age and additionally for cardiovascular health(CVH) according to the American Heart Association Life’s Simple 7(LS7) metric.ResultThe sample had mean baseline age 50.4(SD 3.5) years, 48.1% male, and 38.3% black. Over the 5‐year follow‐up period, GM volume and CBF significantly declined. Significant interaction between race and sex was observed for GM (P‐interaction=0.0041), such that black men demonstrated a significantly larger volumetric decline than black women, whereas no significant sex differences were observed in whites. Race*sex interaction was also observed for CBF (P‐interaction=0.023), such that men demonstrated a significantly larger decline in perfusion than women in both races, which associations were more pronounced in blacks. Adjustment for LS7‐CVH metric attenuated results slightly but reported associations remained significant.ConclusionOur results indicate sex/race specific patterns of midlife decline in cerebral GM volume and in perfusion, which were not fully explained by prevalent cardiovascular risk. Race/sex may be crucial variables in heterogeneity of early cerebral disease, an important marker of late‐life cognitive decline. Additional research is needed to identify the factors driving these associations.
The dynamic interplay between longitudinal subjective and objective cognitive decline along the early AD spectrum in the Harvard Aging Brain Study
Authors: Amariglio Rebecca , Chou Hsiang‐Chin Lori , Buckley Rachel F. , Papp Kathryn V. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. 
Published: December 2020

AbstractBackgroundApplying a biomarker‐based definition of Alzheimer’s disease (AD) (Jack et al., 2018) affords characterization of early, disease‐specific symptoms that are subtle, yet dynamic. Our previous work comparing cognitively‐unimpaired individuals with elevated amyloid (Ab+) to non‐elevated (Ab‐), shows increasing subjective cognitive decline, while neuropsychological performance decreases longitudinally. Here, we sought to directly examine longitudinal associations between subjective and objective cognitive decline along the early AD trajectory.Method224 cognitively‐unimpaired individuals at baseline from the Harvard Aging Brain Study, a community‐based sample, were followed up to 9 years with annual neuropsychological assessment (PACC) and a participant reported cognitive complaint questionnaire (STIDA). A second cognitive complaint questionnaire (CFI) was introduced several years into the study (mean=3.23 (1.65) years) and was administered to both the participant and a study partner annually thereafter. Ab‐PET using Pittsburgh Compound B was collected closest to the time of CFI. Previously established cut‐offs were used to determine Ab+/‐. Longitudinal trajectories of STIDA, PACC, and CFI (participant and study partner) were examined by Ab status.ResultPiecewise linear mixed models revealed initially increasing STIDA (0‐3.5years, t=2.17, p = 0.03) that plateaued in the remaining years (3.6‐9.1 years, t = 0.26, p = 0.80) in Ab+. Likewise, increasing STIDA corresponded with decreasing PACC in the first 3 years (r = ‐0.36, p = 0.001), but not in subsequent years (r = 0.11, p = 0.33). When examining cross‐sectional CFI (first collection of CFI) with retrospective PACC (mean= 3.23 years), higher participant CFI (r = ‐0.26, p = 0.03) and study partner CFI (r = ‐0.32, p = 0.006) were associated with steeper PACC decline in Ab+. Finally, comparison of concurrent slopes between longitudinal participant and study partner CFI, revealed a significant divergent pattern (t=‐2.50, p= 0.01), such that study partner CFI increases relative to slightly decreasing participant CFI over time.ConclusionAmong Ab+ individuals, participant report initially increases and tracks with objective decline. Over time, however, participant report begins to diminish as study partner report continues to increase. Our findings highlight the dynamic nature of subjective report in early AD, which has significant implications for clinically meaningful outcome measures in secondary prevention trials.
NIA‐AA AD framework stage 2: Performance in the community
Authors: Petersen Ronald C. , Wiste Heather J. , Machulda Mary M. , Geda Yonas E. , Kremers Walter K. , Therneau Terry M. , Knopman David S. , Mielke Michelle M. , Lowe Val J. , Jack Clifford R. ,   Mayo Clinic Study of Aging
Published: December 2020

AbstractBackgroundThe NIA‐AA Research Framework for Alzheimer’s disease (AD) includes consideration of two clinical schemes for staging AD: (1) traditional cognitively unimpaired (CU) to MCI to dementia and (2) a new numeric staging (1‐6) for individuals who are on the Alzheimer’s continuum.MethodThe Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We analyzed CU persons who had completed three consecutive clinical visits and calculated measures for cross‐sectional categories: objective cognitive impairment and function and measures for change including subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (NBS). We calculated the frequencies for Stage 2 by varying the cutoffs for each of the measures above and assessed stability of this stage over 15 months.ResultThe frequency of Stage 2 varied from 5‐48% depending upon the age of the participants and the cutoff scores used. Membership in Stage 2 required abnormal SCD, ΔOBJ, or ΔNBS and having only ΔOBJ abnormal was the primary reason for inclusion in Stage 2 (45‐62%) followed by 10‐21% having only SCD abnormal. The stability of Stage 2 over 15 months ranged from 31‐65% with 5‐13% progressing to Stage 3 or higher and 22‐43% percent reverting to Stage 1.ConclusionStage 2 was characterized as a transitional period between CU and MCI and could be operationalized with a variety of measures. The staging scheme performed well considering the variables evaluated and cutoff scores employed.
Determinants of cognitive decline and dementia in stage 2: The SCIENCe project
Authors: van Der Flier Wiesje ,   Alzheimer Center Amsterdam
Published: December 2020

AbstractBackgroundWe initiated the SCIENCe cohort to study the earliest brain changes leading to Alzheimer’s disease in individuals with subjective cognitive decline (SCD). We aimed to identify which individuals are most likely to progress to dementia using imaging and non‐imaging markers.MethodsSCIENCe is an ongoing memory clinic cohort, enrolling cognitively normal individuals with SCD. In addition to the standardized diagnostic work‐up (medical exam, neuropsychology, MRI, and lumbar puncture) we offer amyloid PET to participants. Patients are followed annually. Incident dementia was used as outcome. We classified 693 individuals with SCD (60±9yr, 41%F, MMSE 28±2) according to ATN based on CSF, PET and MRI. We measured plasma abeta42/40 ratio with SIMOA. We used Cox proportional hazards models to determine associations with risk of dementia, and to develop prognostic models, providing individualized risks.ResultsCompared to A‐T‐N‐ (56%), participants in the Alzheimer continuum (A+; 18%) had an increased risk of dementia (HR=17, 95%CI 3.6‐79), while the risk in the non‐AD pathologic change profiles (27%) was not increased (HR=3, 95%CI 0.6‐18). Within the A+ profiles, abnormal T and N further increased the risk of dementia. Using Cox regression to develop prognostic models (n=481), we found that the model including CSF biomarkers had a Harrell’s c of 0.82. Using CSF biomarkers, the prognostic model reclassified 58% of individuals with uncertain outcome based on demographics only, as either high or low risk. Finally, in 241 participants with paired CSF and plasma amyloid measurements, we found that both lower CSF abeta42 and lower plasma ab42/40 ratio were associated with steeper rate of cognitive decline. On visual inspection, effect sizes of CSF and plasma amyloid associations with cognitive decline were in the same order of magnitude.ConclusionIn individuals with SCD, only 18% could be labeled as stage 2 Alzheimer’s disease, based on positive amyloid markers. Those with stage 2 AD are at increased risk of dementia, even more so when there is additional tau pathology and/or neurodegeneration. In the future, it is feasible that biomarkers could be used for individualized risk profiling, and blood based biomarkers could offer a reasonable alternative for CSF and/or PET.