bluuebunny/crossref_metadata_2025 huggingface dataset:
Gait characteristics in preclinical Alzheimer’s disease: Preliminary results of the RADAR‐AD study
Authors: de Boer Casper , Muurling Marijn , Curcic Jelena , Kouzak Rouba , Verheij Herman , Nies Vera J.M. , Durudas Andre , Hannesdottir Kristin , Hinds Chris , Stavropoulos Thanos G. , Daskalova Yoanna , Owens Andrew P. , Wu Yuhao , Erdemli Gul , Stolk Pieter , Lucivero Federica , Narayan Vaibhav A. , Aarsland Dag , Visser Pieter Jelle ,   RADAR‐AD Consortium
Published: December 2021

Background

The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study is assessing functional decline in Alzheimer’s Disease (AD) using remote monitoring techniques (RMT’s). RMT’s allow for continuous and objective monitoring of function, potentially improving the sensitivity of assessment in AD. Gait is an important functional domain to maintain independent living. Yet, relatively little is known on gait impairments in the pre‐symptomatic stages of AD. Therefore, the aim of this study is to compare outcomes of in‐clinic gait assessments, using high frequency inertial measurement units, between healthy controls, preclinical AD patients, and cognitively impaired AD patients.

Method

We included early data from amyloid negative cognitively healthy participants (controls, n=9), amyloid positive cognitively healthy participants (preclinical AD, n=6) and amyloid positive cognitively impaired participants (n=3) participants (Table 1) from the RADAR‐AD study. Participants performed a one‐minute walking task, a one‐minute dual task (walking while counting backwards from 100) and timed up‐and‐go (TUG) task, while wearing GaitUp Physilog sensors1 on the left foot, right foot, and right hip. Metrics provided by the sensors include gait speed, steps per minute, double support time, and TUG task completion time.

Result

Regression analyses with models corrected for age, sex, and education revealed no between‐group differences on the main outcomes. However, the preclinical AD group showed several interesting near‐significant trends that warrant further investigation (Figure 1). This included an apparent smaller difference in gait speed between the walking task and dual task compared to controls (β=‐10.78 (5.8), p=0.09), accompanied by a smaller difference in steps per minute (β=‐9.27 (5.05), p=0.09), and a larger difference in double support time (β=14.32 (7.28), p=0.07).

Conclusion

Although no between‐group differences in gait outcomes were found in this initial data, early near‐significant trends in the preclinical AD group appears to show altered gait patterns in particular during the dual task. These preliminary findings will be further investigated on possible pathological causality of such behavior as our dataset increases. Inclusion in the RADAR‐AD study is ongoing, and subsequent analyses will include larger sample sizes, more in‐depth analyses of gait behavior, and associations with rating scales of mobility. Reference: [1] https://research.gaitup.com/physilog/
Trajectories of daytime sleepiness and sleep duration before diagnosis of dementia: A 14‐year follow‐up study
Authors: Cavaillès Clémence , Carriere Isabelle , Wagner Maude , Berr Claudine , Dauvilliers Yves , Jaussent Isabelle
Published: December 2021

Background

Sleep problems have been associated with an increased risk of dementia. However, the period in which sleep begins to deteriorate in the natural history of dementia remains unknown. The aim was to model and compare trajectories of several sleep measurements in the 14 years prior to diagnosis of dementia in subjects with dementia and matched controls.

Method

Data were collected from a large community‐dwelling elderly cohort (3‐City‐Montpellier) at baseline and at each follow‐up. Incident cases of dementia were systematically diagnosed and validated. Repeated measures of total sleep time (TST), time in bed (TIB), wake‐up time, bedtime and, daytime sleepiness (DS) were assessed via self‐questionnaire. Based on a nested case‐control study, sleep trajectories between cases and controls were performed using latent‐process mixed models and a backward timescale.

Result

Analyses were conducted on 205 cases and 813 matched controls. TST and TIB were higher among cases during all the follow‐up with a significant faster increase in cases. For TST, mean predicted values were ‐14 years before diagnosis and at year 0 (matching visit): 6.9 [95%CI= 6.6‐7.1] and 7.2 [95%CI= 6.9‐7.4] for controls and 7.0 [95%CI= 6.6‐7.3] and 7.9 [95%CI= 7.5‐8.2] for cases. Trajectories between both groups differed from 0 to ‐8.5 years before diagnosis. Bedtime trajectories decrease significantly over time in the two groups, more strongly in cases (mean predicted values at ‐14 years before diagnosis and at year 0 were 22.8 [95%CI= 22.7‐22.9] and 22.6 [95%CI= 22.5‐22.7] for controls and 22.7 [95%CI= 22.6‐22.9] and 22.2 [95%CI= 22.0‐22.4] for cases). A significant case‐control difference from 0 to ‐8.2 years prior to diagnosis was reported. In contrast, trajectories of wake‐up time and DS remained stable over time in both groups. Still, wake‐up time trajectories crossed at about ‐5 years before diagnosis. There were no significant case‐control differences in trajectories for DS.

Conclusion

In prodromal dementia, TST and TIB increased, whereas bedtime was getting earlier and, wake‐up time and DS remained stable. Results suggest that optimal period for the management of sleep health to prevent dementia begins at least 8 years before the diagnosis of dementia.
Prediction of future Alzheimer’s disease dementia using plasma phospho‐tau combined with other accessible measures
Authors: Palmqvist Sebastian , Tideman Pontus , Cullen Nicholas , Zetterberg Henrik , Blennow Kaj , Stomrud Erik , Janelidze Shorena , Mattsson‐Carlgren Niklas , Hansson Oskar ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2021

Background

Plasma phospho‐tau (P‐tau) has shown a high diagnostic accuracy for Alzheimer’s disease (AD), but its performance in predicting development of AD dementia and what other measures to combine it with for an optimal predictive accuracy is less known. We examined this using plasma P‐tau combined with other easily accessible measures and compared the results to the clinical diagnostic prediction and to results obtained using cerebrospinal fluid (CSF) biomarkers.

Method

We included patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) who were consecutively recruited in the BioFINDER study (n=340). The results were validated in SCD and MCI participants in the ADNI study (n=543). Plasma P‐tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and MRI (cortical thickness in AD‐specific regions) were examined as predictors of progression to AD dementia within 4 years (2 and 6 years were secondary outcomes). The accuracy was determined using the area under the ROC curve (AUC) from logistic regression models.

Result

Within 4 years, plasma P‐tau217 predicted AD dementia accurately (AUC 0.83) in BioFINDER. A model consisting of plasma P‐tau217, memory, executive function, and APOE had higher accuracy (AUC 0.91, p<0.001). In ADNI, this model produced a similar AUC (0.90) using plasma P‐tau181 instead of P‐tau217. A cross‐validated version of this model using binary plasma P‐tau data (normal/abnormal) was implemented online for the prediction of the individual probability of progressing to AD dementia. Parsimonious models had similar accuracies for predicting AD dementia within 2 and 6 years (AUCs 0.90‐0.91 in both cohorts). Using CSF P‐tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy. In BioFINDER, the clinical diagnostic prediction by memory clinic physicians blinded to fluid biomarker data had significantly lower accuracy than all models (4‐year AUC 0.71).

Conclusion

Plasma P‐tau in combination with brief cognitive tests and APOE genotyping improves the predictive accuracy of whether a patient will progress to AD dementia or remain stable/progress to other dementias, compared to using just plasma P‐tau or to the clinical prediction. Plasma P‐tau combined with these measures may also facilitate recruitment for AD trials.
Repetitive transcranial magnetic stimulation ameliorates the pathology and cognitive dysfunction in a mouse model of Alzheimer's disease through increased drainage efficiency of meningeal lymphatic system
Authors: Jin Jian , Wang Yuling , Ye Xiaojing , Lv Rongke , Dai Weiping , Li Wenchang , Lin Wei Jye , Lin Yangyang
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high prevalence rate among elderly population. Given numerous studies that have shown promising outcomes in delaying or reversing the disease at preclinical stage, however, successful translation into clinical applications has been rare. Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive, painless technique that has been clinically proven to improve cognitive function in AD patients, but the underlying cellular and molecular mechanisms remain largely uninvestigated.

Method

5xFAD mice, an AD mouse model that overexpresses human familiar APP and presenilin 1 mutations under regulated expression of mouse neuronal‐specific Thy1 promotor, were stimulated by rTMS for 2 weeks. The stimulation contained a total of 4000 magnetic stimulation pulses given daily, which consisted of 100 burst trains and 40 pulses of each train at 20 Hz with a 5 sec intertrain interval. At the end of rTMS treatment, mice underwent memory tests including Y‐maze, novel object recognition and novel location recognition. A 10kD Dextran‐AlexaFluo647 tracer was injected into the cisterna magna compartment and mice were perfused 30 minutes later. Brains, meninges and deep cervical lymph nodes were resected for subsequent immunofluorescent analysis.

Result

5xFAD mice treated with high frequency rTMS for two weeks showed improved long‐term object and spatial memory, increased neuronal activity as revealed by the elevation of c‐fos‐positive neurons in the prefrontal cortex and the hippocampus, and reduced pathological features of AD, which included enhanced clearance of β‐amyloid deposit and reduced glial activation. Importantly, rTMS significantly enhanced the drainage of the intra‐cisterna magna injected tracer in 5xFAD mice, as revealed by tracer penetration and clearance in the brain parenchyma, dura mater, and deep cervical lymph nodes.

Conclusion

Our findings provide the novel mechanistic insight of the regulatory role of rTMS in the drainage efficiency of brain lymphatic system and the clearance of β‐amyloid in the 5xFAD mouse model, suggesting rTMS as a potential tool for the intervention of neurodegenerative and other disorders related to meningeal lymphatic dysfunction.
Social functioning and cognitive impairment among the oldest old
Authors: Lisko Inna , Ngandu Tiia , Solomon Alina , Kivipelto Miia , Kulmala Jenni
Published: December 2021

Background

Findings from observational studies support the benefits of social activities on cognition. The ability to carry out social activities is described by social functioning. However, only little data exists on the associations between social functioning and cognition among the oldest old. The aim of this study is to explore if social functioning is associated with cognitive impairment among the oldest old.

Method

The study uses cross‐sectional data from a Finnish population‐based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) 85+ study. Altogether 187 individuals aged 85+ provided data on health‐related quality of life, RAND‐36, from which the following question on social functioning was used: “During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting with friends, relatives, etc.)?“ Social functioning was divided into three categories: 1) Low (all the time or most of the time), 2) Moderate (some time), and 3) High (a little time or not at all). Cognitive impairment was defined as Mini‐Mental State Examination score < 25. Logistic regression model was used in the analyses which were adjusted for sex.

Result

According to these preliminary results, individuals with low social functioning were 7 times more likely to have cognitive impairment as compared to individuals with high social functioning (Odds ratio [OR] 7.46, 95% Confidence Interval [CI] 2.16–25.75). No differences in cognitive impairment were found between individuals with moderate social functioning as compared to high social functioning (OR 0.68, 95% CI 0.26–1.84).

Conclusion

Lower social functioning appears to be associated with cognitive impairment among the oldest old. These results need further exploration. Causality behind the found association should be examined and if supporting social activities particularly among cognitively impaired would carry health benefits.
Clinical experience with polygenic risk score in subjects with early cognitive concerns
Authors: Sauer Justin , Ballard Clive , Gibson Alex , Daunt Paula , Pither Richard
Published: December 2021

Background

There is mounting evidence that lifestyle interventions and behavioural changes play a significant role in maintaining cognition and function, as well as preventing dementia. Consequently, it is important that clinicians confronted with subjects with early cognitive concerns, have appropriate tools available to assist in diagnosis and to facilitate risks management appropriately. The application of polygenic risk score (PRS) tests has the potential to contribute towards management planning and to reduce the burden of testing in subjects with low overall risk.

Methods

This retrospective analysis considered the application of genoSCORETM in a small cohort of patients seen over a six month period in a London Memory Clinic. The test was offered to selected patients in the clinic with MCI not clinically attributable to dementia, or cognitively normal individuals concerned about their risks of dementia. The impact upon clinical management and lifestyle modification was reviewed. genoSCORE, a polygenic risk score algorithm, was developed by Cytox to assess genetic risk for the future development of Late‐Onset Alzheimer’s disease (LOAD).

Results

Patients receiving the genoSCORE test included those with early MCI, subjective memory complaints and a small number concerned about their risk of dementia. In each case, a medical history was taken and individuals assessed using the Addenbrooke’s Cognitive Examination, conducted either in clinic or remotely. genoSCORE polygenic risk score was easy to conduct and well received. The results stimulated individuals at risk of developing LOAD to make lifestyle adjustments and thereby potentially modifying their dementia risk.

Conclusions

In this study, the genoSCORE PRS test provided a valuable assessment of genetic risk of individuals most likely to decline cognitively decline towards AD and as such, contributed significantly to clinical management decisions. The ease and effectiveness of home sampling of saliva as source DNA for the PRS test was a major factor and well aligned with the continuing need for remote consultations in the light of COVID‐19 concerns. Further larger‐scale studies to determine the full clinical and associated economic impact of the genoSCORE PRS test are required.
Brain donation for research: Features of the brain donors from the InveCe.Ab population‐based cohort
Authors: Davin Annalisa , Rolandi Elena , Poloni Tino Emanuele , Medici Valentina , Vaccaro Roberta , Cirrincione Alice , Cereda Cristina , Guaita Antonio
Published: December 2021

Background

Research on brain tissue is essential to understand the biological mechanisms underlying neurodegenerative diseases and brain aging processes.Brain donation for research is influenced by many factors both in clinical and non‐clinical samples. The aim of the present study is to explore the features associated with the decision to join the brain donation program of the Abbiategrasso Brain Bank (ABB) in the context of a population‐based study on brain aging.

Method

The longitudinal cohort study InveCe.Ab enrolled participants aged 70‐75 years and residing in Abbiategrasso (MI). During the second follow‐up of the study (2014), the participants fill a questionnaire to investigate attitudes through brain donation for research purpose (N=1010). We compared socio‐cultural aspects and questionnaire responses between participants who adhere to brain donation (N=163; 16,1%) and those who refuse (N=847) using Student’s t Test and chi‐squared test when appropriate. Variables showing significant differences in the group comparisons were included in a logistic regression model with brain donation status (yes/no) as the dependent variable.

Result

The groups were comparable for age and sex, while ABB donors were significantly more educated (donors: 7,74, non‐donors: 6,70; p=0,000), more frequently prone to organ donation (donors: 93,4%; non‐donors: 64,3%, p=0,000) and to cremation (donors: 76,8%; non‐donors: 44,8%; p=0,000). Among those who were favorable for brain donation in the questionnaire, only 43,6% actually signed up for brain donation (p=0,000). Moreover, brain donation was associated with friends relationship satisfaction (donors: 96,5%; non‐donors: 91,4%; p=0,023) and better self‐reported health (donors: 83,3%; non‐donors: 73,4%; p=0,028), despite no difference between groups was found in the number of chronic disease (p=0,49). Finally, in the multivariable model, being prone to organ donation was the main factor associated with actual registration for brain donation. The availability for cremation remained significant only for males.

Conclusion

Despite a positive attitude through brain donation in nearly half of the respondents, only a minority of older adults actually engage in a brain donation program. Being prone to organ donation was the main factor associated with brain donation subscription. The donors were more educated, with a positive attitude through their health and their relationships with friends.
Young‐onset dementia in memory clinics in the Netherlands: PRECODE‐GP
Authors: Rhodius‐Meester Hanneke FM , Leeuwis Anna E , Van Gils Aniek M , Bakker Christian , Peetoom Kirsten , Bouwman Femke H , Pijnenburg Yolande AL , de Vugt Marjolein , van der Flier Wiesje M ,   the PRECODE‐GP Consortium
Published: December 2021

Background

The disease trajectory of patients with young onset dementia differs from older patients, as do healthcare requirements. To improve specialized care, more insight in young onset dementia is crucial. The aim of PRECODE‐GP is therefore 1) to conduct an (annual) inventory of the diagnostic workup in all memory clinics in the Netherlands, and 2) to set up a prospective nationwide database including newly diagnosed younger patients with dementia.

Methods

PRECODE‐GP is part of the PRECODE project, a collaboration between four Dutch Alzheimer centers, Knowledgecenter Dementia at Young Age, Nivel and Alzheimer Nederland. Governance is embedded in the Dutch Memory Clinic Network. Memory clinics are asked annually to fill out a survey on their current diagnostic workup. Eligible patients (<70 years; any type of dementia) are identified by local specialists and recruited via an informed consent procedure providing consent for future linkage to other datasets. Demographics, test results and (etiological) diagnosis are collected in an online database.

Results

PRECODE‐GP was initiated in July 2019 and has been approved in 36 memory clinics, approval procedure is ongoing in additional 10 clinics. Based on the annual survey (filled out by 21 clinics), standard imaging of the brain occurs in almost half of memory clinics and neuropsychological examination in one third. CSF is performed when deemed necessary by the clinician. A median 250(141‐396) new patients visited the memory clinics yearly, of whom 111(74‐180)(48%) were diagnosed with dementia and 12(4‐36)(6%) were <70 years. To date, 201 young onset dementia patients (age 62±8, 51% female, MMSE 22±5) are included in our prospective database, diagnosed with 140(69%) Alzheimer’s dementia (AD), 29(14%) frontotemporal dementia (FTD), 14(7%) dementia with Lewy Bodies (DLB) and 18(9%) other dementia types. Patients with FTD were youngest (61±6 years), subjects with DLB were most often male (79%), in AD MMSE was lowest (21±5).

Conclusion

We took the first step to include patients with young onset dementia via all Dutch memory clinics. As a next step, we plan to link data to existing registries, to gain valuable knowledge on disease trajectories. All needed to improve quality of life for patients with young onset dementia.
Exploration of the cognitive functions of females in a mouse model of chronic neuroinflammation
Authors: Wagnon Ingrid Marguerite , Niedermayer Garry , Chesworth Rose , Muench Gerald Wolfgang , Karl Tim , Gyengesi Erika
Published: December 2021

Background

Chronic neuroinflammation has been identified as a common feature of many neurodegenerative diseases, such as Alzheimer’s disease (Kempuraj et al., 2016). Sex has been shown to strongly influence the development as well as the clinical expression of neurodegenerative and neuroinflammatory diseases . The GFAP‐IL6 mouse is a useful model to study chronic neuroinflammation and its consequences. These mice exhibit increased levels of neuroinflammatory markers, neurodegeneration, as well as motor deficits (Campbell et al., 1993; Chiang et al., 1994; Gyengesi et al., 2019). Although previous studies have identified some cognitive impairments in these animals (Heyser et al., 1997), more work is needed to fully characterised this model at a behavioural level.

Method

Cognitive tests exploring anxiety such as the elevated plus‐maze (EPM), light/dark box, and spatial learning and memory such as the Barnes maze and Y‐maze, were performed on female GFAP‐IL6 mice and their litter mate control wild‐type (WT) from 12 months of age. Tests were recorded using AnyMaze® and results analysed in IBM SPSS® software with one or two‐way ANOVAs. This study was completed with immunochemistry and RT‐qPCR in brain regions implicated in anxiety, learning and memory.

Result

We found that the GFAP‐IL6 mice travelled a significantly higher percentage of distance in the opened arm of the EPM than the WT (WT=9.48%, GFAP‐IL6=18.03%, p<0.01), and a lower percentage in the closed arm than the WT (WT=63.13%, GFAP‐IL6=53.70%, p<0.05). No genotype effect was found in the preference for the light compartment during the light/dark box test. In the Y‐maze, the GFAP‐IL6 mice spent a significantly lower percentage of time in the novel arm compared to the WT (WT=45.06%, GFAP‐IL6=27.97%, p<0.01). During the acquisition phase of the Barnes maze, all mice were able to learn the location of the escape hole. However, there was a significant effect of genotype (p<0.01), with the GFAP‐IL6 mice exhibiting higher latencies to enter the escape hole than the WT. No significant difference was found during the probe test

Conclusion

These results suggest that female GFAP‐IL6 mice exhibit a less anxious phenotype but seem to present impaired spatial memory compared to female WT.
Plasma and cerebrospinal fluid neurofilament light protein concentrations are differentially associated with biomarker evidence of neurodegeneration in a community‐based population of 70‐year‐olds
Authors: Dittrich Anna , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Zettergren Anna , Simrén Joel , Schöll Michael , Westman Eric , Skoog Ingmar , Kern Silke
Published: December 2021

Background

Neurofilament light protein (NfL) is the best‐established fluid biomarker for general neurodegeneration, predicting poor outcome in cognitive function across neurodegenerative dementias. Currently, there are few studies examining the correlation of plasma and cerebrospinal fluid (CSF) NfL with other fluid and imaging biomarkers for neurodegeneration.

Method

The sample (n= 287) was derived from the Gothenburg H70 Birth cohort 1944 study, conducted in 2014‐2016. CSF NfL, total‐Tau (t‐Tau), phospho‐Tau (p‐Tau), neurogranin, CSF/serum albumin ratio and plasma NfL were measured and brain magnetic resonance imaging (MRI) was conducted. Participants were examined with comprehensive neuropsychiatric and somatic examinations, and dementia was diagnosed according to DSM III criteria. In linear models adjusted for age and sex, NfL was examined in relation to other demographics, cognitive tests, CSF biomarkers and MRI measurements. Sub analysis were also performed on participants with or without β‐Amyloid pathology, defined as a CSF β‐Amyloid 42 ≤ 530 pg/mL.

Result

NfL in plasma and CSF presented a moderate correlation (Spearman’s R=0.41, p<0.001). P‐NfL was associated with worse delayed memory recall (p=0.019), smaller hippocampus volume (p=0.001), larger white matter lesion volume (p=0.004), as well as CSF levels of β‐amyloid 42 (p=0.043), β‐amyloid 42/40 (p=0.049), β‐amyloid 42/t‐Tau (p=0.007), CSF NfL (p<0.001) and BMI (p<0.001). CSF NfL was associated with t‐Tau (p=0.001), p‐Tau (p<0.001), neurogranin (p=0.014), albumin ratio (Qalb) (p=0.001), P‐NfL (p<0.001), and BMI (p=0.033). In participants with prevalent β‐amyloid 42 pathology, P‐NfL was associated with β‐amyloid 42 (p=0.009), β‐amyloid 42/40 (p=0.043), β‐amyloid 42/t‐Tau (p=0.010) and CSF NfL (p<0.001). In participants without β‐amyloid 42 pathology, P‐NfL associated with BMI (p<0.001), smaller hippocampus volume (p=0.007) and CSF NfL (p<0.001).

Conclusion

Although CSF NfL and P‐NfL concentrations are correlated, the biomarker measured in the two sample types presents distinct associations with biomarker evidence of AD pathology and neurodegeneration. P‐NfL was associated with several markers that are characteristic of AD, whereas CSF NfL demonstrated more associations with synaptic and neurodegeneration.
Informant‐reported subjective cognitive decline is specifically relevant in MCI patients: Association with cognition, amyloid deposition and neurodegeneration
Authors: Kuhn Elizabeth , Perrotin Audrey , Touron Edelweiss , Dautricourt Sophie , Vanhoutte Matthieu , Vivien Denis , De la Sayette Vincent , Chetelat Gaël ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2021

Background

Informant‐reported subjective cognitive decline (I‐SCD) have been associated with objective cognitive decline and biomarkers of Alzheimer's disease (AD) in previous studies. However, we lack a comprehensive overview of these associations across the entire clinical continuum of the Alzheimer's syndrome allowing to stress whether there is a clinical stage where this measure is particularly relevant. This study aims at describing the relationships of I‐SCD to cognition and multimodal neuroimaging data within two independent cohorts.

Method

We used data from 110 participants from IMAP+, and, as an independent replication cohort, from 731 participants from ADNI. All participants were divided into four clinical groups (IMAP+/ADNI): controls (N=32/157), subjective cognitive decline (SCD; N=25/84), mild cognitive impairment (MCI; N=35/369) and dementia (N=18/121). We first compared the I‐SCD score between groups and assessed its relationship to cognition within each clinical group cross‐sectionally and longitudinally (over 2.5 years). We then assessed the voxelwise relationships between the I‐SCD score and neuroimaging measures of amyloid deposition (Florbetapir‐PET) and neurodegeneration, i.e. atrophy (T1‐MRI) and hypometabolism (FDG‐PET), across the four clinical groups. These analyses were performed in IMAP+ and replicated in the ADNI cohort.

Results

The I‐SCD score was higher from one clinical group to another within both cohorts (p?0.001, except SCD‐MCI p=0.15 in IMAP+). Interestingly, this measure was associated with cognition and AD biomarkers specifically within the MCI patients. The relation was such that higher I‐SCD was associated with lower memory and global cognition cross‐sectionally and over time (Figure 1), higher amyloid deposition (global SUVr and voxelwise) and higher neurodegeneration (Figure 2). The same findings were recovered in both cohorts, except for neurodegeneration where the links were significant in ADNI only.

Conclusion

Our findings reveal that the cognitive decline reported by the informant is particularly meaningful at the MCI stage, when the corresponding self‐reported score is contaminated by decreased awareness. The strong and consistent links with cognition and AD biomarkers found here reinforce the validity and clinical relevance of this finding and suggest that this measure should be used in clinical trials to identify MCI patients at higher risk to develop cognitive decline and/or AD.
INSPIRATION: Study design and preliminary results of a crosssectional risk AD‐profiling study
Authors: Zeyen Philip , Sannemann Lena , Escher Claus , Müller Theresa , Jessen Frank
Published: December 2021

Background

Estimates suggest that between 30% and 40% of all AD cases are attributable to potentially modifiable risk factors such as hypertension, midlife obesity, diabetes mellitus, depression, social isolation, physical inactivity, smoking, low level of education, and hearing loss (Barnes and Yaffe 2011; Livingston et al. 2020; Luck and Riedel‐Heller 2016). In addition, other risk factors for AD such as stress and sleep disturbances have been identified in recent years (Escher et al. 2019; Sindi et al. 2018). The Individual risk profiling for Alzheimer's disease and dementia prevention (INSPIRATION) study aims to explore the frequency and distribution of risk factors for AD in the participants of an Alzheimer Prevention Registry in order to establish individualized risk profiles and aid the development of personalized prevention programs.

Method

Cross‐sectional assessment of healthy study participants aged 50 or older recruited through a local volunteer Alzheimer Prevention Registry is performed to determine the prevalence of key risk factors. This protocol includes established questionnaires and medical examination. Data is collected on demographics, medical history, family history, physical activity, diet, BMI, waist circumference, hearing loss, smoking and drinking habits, presence of depression, anxiety, stress, resilience, and loneliness. In addition, we perform neuropsychological testing and blood sampling for ApoE determination and AD‐biomarker testing. The aim is to enroll 200 individuals.

Result

Preliminary results in 32 participants indicate that the three most frequent risk factors were non‐adherence to recommended diets (i.e. Mediterranean diet) in 84.4% of the subjects, obesity in 68.8% with a mean BMI of 27.6 kg/m2 (22.3‐41.6kg/m2, min./max.), and sleep problems in 50% of the subjects. The full set of assessed risk factor will be presented

Conclusion

The INSPIRATION study aims to understand the prevalence of modifiable AD risk factors, in order develop a tool box of interventions for personalized strategies to prevent AD in a population, which is particularly interesting in dementia prevention.
Plasma neurofilament light chain (NfL) relates to preclinical changes in cognition, structural white matter integrity and markers of cerebral small‐vessel disease: A population‐based study
Authors: van Arendonk Joyce , Wolters Frank J. , Neitzel Julia , Vinke Elisabeth J. , Vernooij Meike W. , Ikram M. Arfan , Ghanbari Mohsen
Published: December 2021

Background

Neurofilament light chain (NfL) is known as a promising biomarker for risk stratification and disease monitoring of dementia due to Alzheimer’s disease, but the underlying pathophysiological substrates remain largely elusive. Moreover, it is uncertain whether NfL levels are able to capture changes in cognitive performance prior to the onset of clinical cognitive decline. We studied the relation of plasma NfL with cognition and structural brain imaging markers in a general population without dementia.

Method

Plasma level of NfL was measured using the Simoa NF‐light™ assay in 4,207 dementia‐free participants of the population‐based Rotterdam Study cohort (mean age 71.6 years, 57% women). Participants underwent repeated cognitive assessment, and a subset of 970 had brain MRI. We used linear and logistic regression (cross‐sectional) and mixed‐effects models (longitudinal) to determine the association of plasma NfL with (changes in) cognition and brain tissue volumetry, white matter integrity and markers of cerebral small‐vessel disease (lacunes, white matter hyperintensities and microbleeds).

Result

At baseline, higher plasma NfL level was significantly associated with a worse cognitive performance (g‐factor: β=‐0.06 95%CI ‐0.12;0), and more specifically with lower test scores on the Stroop 3 test (β=‐0.07 95%CI ‐0.12;‐0.01), and Perdue Pegboard (β=‐0.12 95%CI ‐0.18;‐0.06). Similarly, among 2,850 participants with repeated cognitive assessment, baseline NfL level was significantly associated with a stronger decline in cognition (g‐factor (β=‐0.02 95%CI ‐0.04;0), driven by faster decline on Stroop 1 & 2 tests (β=‐0.03 95% ‐0.04;‐0.01, β=‐0.03 95%CI ‐0.05;‐0.02, Figure 1). In participants with brain MRI, NfL level was significantly associated at baseline with larger volumes of white matter hyperintensities (β= 0.12 95%CI 0.04;0.20), more lacunar infarcts (OR= 1.69 95%CI 1.20;2.39), and worse fractional anisotropy (β=‐0.10 95%CI ‐0.18;‐0.02) and mean diffusivity (β=0.09 95%CI 0.02;0.16), but not with grey matter volumes. Plasma NfL level was not significantly related to progression of structural brain changes over time (n=738).

Conclusion

In this large community‐dwelling population, higher plasma NfL levels are associated with accelerated cognitive decline and larger burden of white matter pathology. These findings suggest NfL as a predominant biomarker of axonal rather than neuronal damage in monitoring of disease progression and treatment effects.
Association between SCD‐Plus features and GDS factors in subjective cognitive decline and healthy controls in the studies DELCODE and SILCODE
Authors: Hu Xiaochen , Chen Ji , Jiang Xueyan , Daamen Marcel , Wang Xiaoqi , Lee Hwee Ling , Spottke Annika , Düzel Emrah , Peters Oliver , Buerger Katharina , Teipel Stefan J. , Laske Christoph , Boecker Henning , Wagner Michael , Han Ying , Jessen Frank
Published: December 2021

Background

A previous study showed a subjective cognitive decline (SCD) related factorial score derived from the geriatric depression scale (GDS, 30 items) to predict cognitive decline within a group of healthy elderlies in interaction with amyloid status[1]. On the other hand, several features associated with SCD (SCD plus), including subjective decline in the memory domain, concerns about cognitive decline, onset within five years and over 60 years old, and cognitive performance worse than other people, have been proposed to increase the likelihood of preclinical AD in subjects with SCD[2]. Here, we test the association between SCD plus features and GDS factorial scores in two independent cohorts from Germany and China.

Method

The 15‐items GDS(GDS15) and the SCD plus score, which was assessed with the SCD‐interview[3] and which summarizes SCD plus features, were obtained from two cohorts, the DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE, 230HC/361SCD), and the Sino Longitudinal Cognitive Impairment and Dementia Study(SILCODE, 99HC/135SCD). Non‐negative matrix factorization[4, 5] was applied to the GDS items from the two cohorts separately with the number of factors ranging from 2 to 9. The optimal number of factors, in terms of stability and generalizability, was identified by using cross‐validation in 5.000 split‐half analyses in each cohort. Partial correlations between SCD plus scores and individual loadings on each factor derived from the optimal factor structure were calculated, controlling for age, sex, education years, and the loadings on other factors.

Result

For both cohorts, the three‐factorial‐solution revealed the best generalizability (lowest out‐of‐sample increased reconstruction error of individual GDS scores), as well as good stability of item‐to‐factor assignment. Partial correlations revealed significant association of SCD plus score with two factors in the DELCODE cohort (positive mood:r=‐0.20,p=1x10‐6;cognition/anxiety:r=0.41,p=8.1x10‐25), and with two factors in the SILCODE cohort (positive mood:r=‐0.18,p=0.007; memory problem:r=0.51,p=2.6 x 10‐16)(figure 1).

Conclusion

The present work corroborate the previous finding [1] that a SCD related factor can be derived from GDS. Furthermore, we demonstrated that the individual loadings on this factor are strongly associated with SCD plus features in two independent cohorts. Interestingly, the item assigned to the SCD related factor are different between two cohorts.
Gamma phase synchronization during olfactory stimulation as a marker for Alzheimer’s disease
Authors: Afzal Arshia , Sedghizadeh Mohammad Javad , Aghajan Hamid , Vahabi Zahra
Published: December 2021

Background

Altered gamma oscillations have been observed in patients of Alzheimer’s disease (AD). A large number of studies have linked the quality of gamma oscillations in the frontal cortex to the performance of memory retrieval tasks. Synchronization of gamma oscillations has a strong correlation with cognitive functions (Fell et al., Nature Reviews Neuroscience 2011), and deficit in gamma synchronization in the frontal cortex has been reported as a marker for AD (Sedghizadeh et al., PLOS One 2020). In this study, we examine the phase synchronization of gamma oscillations in the EEG data recorded from the frontal cortex during olfactory stimulation as a marker for AD.

Method

Twenty‐four elderly participants (13 Normal and 11 mild AD patients) participated in this study. The cognitive status of the participants was quantified using the MMSE test. Then, each participant underwent an olfactory stimulation session consisting of 120 trials of 2s stimuli presentation with a random selection of two odors (lemon as the frequent and rose as the rare odor) followed by 8s of rest. EEG data were simultaneously recorded and pre‐processed for artifact and noise removal and trial averaging. To analyze gamma band synchronization, the phase‐locking value (PLV) for lower gamma oscillations (35‐45Hz) was calculated between the Fz and Cz electrodes. Fig. 1 illustrates the measurement and processing flow.

Result

Our study shows that the PLV is significantly higher for normal participants compared to AD patients (Fig. 2). Also, the phase difference between the Fz and Cz electrodes in the lower gamma band remains unchanged across trials for normal participants while it widely varies between ‐180 and 180 degrees for AD patients (Fig. 3).

Conclusion

This study shows that there is a significant difference between normal participants and AD patients in terms of the synchronization of gamma oscillations in the frontal cortex in response to olfactory stimulation. These results suggest that the PLV between the Fz and Cz electrodes under olfactory stimulation can be used as a marker for AD diagnosis.
Evidence exclusive labels in cognitive research cause unstable prevalence estimates over time
Authors: Richardson Connor Duncan , Stephan Blossom CM , Robinson Louise , Brayne Carol , Matthews Fiona E , Function Cognitive , Studies Ageing
Published: December 2021

Background

While age specific prevalence of dementia has recently declined in some high‐income countries it is unclear whether or how the milder end of the spectrum, including Mild Cognitive Impairment might also have changed across generations. This is likely to vary according to how cognitive impairment has been defined, including exclusion criteria. Previous findings from the Cognitive Function and Ageing Studies (CFAS) show prevalence of mild impairment has either increased or remained stable depending on the criteria used, while more severe impairment has decreased over time. Whether different subtypes of MCI used in contemporary studies have different time trends are not known.

Method

Data are from the English sites of the population representative Cognitive Function and Ageing Studies (CFAS). In 1991 7,635 participants were interviewed in CFAS I in Cambridgeshire, Nottingham and Newcastle with 1457 being diagnostically assessed. In the same geographical areas, the CFAS II investigators interviewed 7,796 individuals in 2011. Using consensus criteria, the population was categorised into MCI and ‘other cognitive impairment no dementia’ OCIND. Each cognitive group was further subtyped by the domain of cognition into amnestic (aMCI and aOCIND), non‐amnestic (naMCI and naOCIND) and multi‐domain (mMCI and mOCIND) groups, memory complaints were included as an OCIND subtype. Prevalence estimates for each were calculated using multinomial logistic regression, adjusted for age, sex and education. Results were standardized to the age‐sex specific UK and global population.

Result

Between 1991 and 2011 naMCI declined substantially (10.5% versus 6.3%), mMCI increased very slightly (5.9% versus 6.3%) while aMCI, whilst relatively rare, more than doubled in prevalence (1.2% versus 2.6%). In terms of OCIND, the prevalence of naOCIND has dropped (from 17.6% to 13.9%), aOCIND has increased (3.8% to 4.9%) while mOCIND has more than doubled (from 5.7% to 11.2%).

Conclusion

Between 1991 and 2011 naMCI declined substantially (10.5% versus 6.3%), mMCI increased very slightly (5.9% versus 6.3%) while aMCI, whilst relatively rare, more than doubled in prevalence (1.2% versus 2.6%). In terms of OCIND, the prevalence of naOCIND has dropped (from 17.6% to 13.9%), aOCIND has increased (3.8% to 4.9%) while mOCIND has more than doubled (from 5.7% to 11.2%).
The NeuroMET project: Metrology and innovation for early diagnosis and accurate stratification of patients with neurodegenerative diseases
Authors: Quaglia Milena , Cano Stefan , Fillmer Ariane , Flöel Agnes , Giangrande Chiara , Göschel Laura , Lehmann Sylvain , Melin Jeanette , Teunissen Charlotte E.
Published: December 2021

Background

The NeuroMET project aims are to develop: 1) a “NeuroMET memory metric” metrologically validated with clinical laboratory data that will be implemented into a app for delivery of cognitive tests 2) 7T magnetic resonance imaging and spectroscopy protocols and measurement uncertainty frameworks to be implemented into clinic and applied to larger studies; 3) reference measurement procedures and liquid chromatography based methods for t‐tau; p‐tau; α‐synuclein, NF‐L to underpin standardisation initiatives; 4) new clinical methods for quantification of synucleins and differentiation of synucleopathies for subsequent validation with support from the metrological infrastructure; and 5) construct specification equations to serve as reference for memory task difficulty and person memory ability

Method

Multiple approaches: LC‐MS and GC‐MS from different manufactures; 7 and 3 Tesla MRI and MRS (Siemens); RT‐QUIC; immunoassays (Simoa, MSD and Eurimmune); Rasch Measurement Theory analysis and principal component regression. All data are acquired for healthy controls, subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease patients recruited at Charitè.

Result

1) The most promising memory test items from legacy cognitive assessments data (focussing on blocks, numbers and word lists) from the NeuroMET patient cohort were selected to be used for the development of the NeuroMET Memory Metric. Construct specification equations were developed to serve as reference for memory task difficulty and person memory. 2) 7 T MRI and MRS protocols were developed. Those are applied to the project cohort and a framework for the definition and improvement of measurement uncertainty is designed. 3) A t‐tau primary calibrator characterization was finalized and the material shared with the IFCC‐CSF WG to be used for a round robin study. 4) A α‐synuclein reference measurement procedure was finalized and a hydrogen deuterium exchange mass spectrometry method developed to monitor the stability of the protein in different solvents and storage conditions. This methods will underpin the development of a liquid chromatography mass spectrometry method and a RT_QUIC method for synucleopathies

Conclusion

Multidisciplinary reference methods and frameworks for the definition of measurement uncertainty to be applied to facilitate uptake of new technology, to underpin the definition of clinical thresholds and ultimately to enable early diagnosis and patient stratification
Sex‐differences in neural responses to experimental pain in Alzheimer's disease
Authors: Failla Michelle D , Iversen Wm. Larkin , Atalla Sebastian W , Cowan Ronald L , Monroe Todd B
Published: December 2021

Background

People with Alzheimer’s disease (AD) generally receive less analgesic medications and verbally report pain less frequently than age‐matched healthy controls (Scherder 2005). Studies have also shown that people with AD exhibit differences in neural responses to acute experimental pain relative to controls (Monroe 2017). Several studies demonstrate that women report more pain than men and are at a greater risk for mismanagement of pain irrespective of cognitive status (Fillingim 2009). Thus, this study aimed to investigate sex differences in the neurophysiological response (fMRI) to experimental thermal pain in people with AD when compared to controls. We hypothesized that women with AD would have increased activation in brain regions related to the cognitive and emotional processing of pain.

Method

The sample consisted of 73 adults (age 65‐97), 36 adults with AD and 37 adults in a healthy control comparison group. In this study, 52.05% of the participants were female, matched across age and AD status. Experimental thermal perceptions for mild and moderate pain were collected prior to scanning. Stimuli were applied to the thenar eminence of the right hand. During fMRI, percepts were passively delivered during four runs, trials included 16 seconds of stimulus with 24 seconds of rest. Whole brain analysis for a sex by diagnostic group interaction was explored mild and moderate pain conditions. Standard SPM12 approaches were used for all analyses.

Result

We found significant main effects of both AD and sex in each pain condition indicating significant differences in brain activation for both males and females with AD compared to male and female controls (all p’s < 0.05), however there was no significant sex by AD group interaction in either contrast comparison.

Conclusion

While there are significant effects of both sex and AD on neural responses to pain, there was no significant evidence of a unique effect of sex on neural responses in AD. This work suggests that differences in pain responses by sex is relevant to consider in addition to disease specific effects. Sex differences seen in healthy cohorts may not persist to the same degree the Alzheimer’s disease brain.