bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampal connectivity in illiterate adults from Brazil
Authors: Resende Elisa de Paula França , Rosen Howard J , Friedlaender Clarisse Vasconcelos , Lara Vivian Proença , Santiago Ana Luisa Carvalho , Silva Lênio Lúcio Gávio , Brown Jesse A , Maciel Francisca , Grinberg Lea T , Caramelli Paulo
Published: December 2021

Background

The role of hippocampal connectivity for good memory performance is well known in persons with high educational level. However, it is understudied the role of hippocampal connectivity in illiterate populations.

Methods

Thirty‐nine illiterate adults underwent resting state functional MRI and an episodic memory test (Free and Cued Selective Reminding Test). We correlated the hippocampal connectivity at rest with the free recall scores. Analyzes were corrected for head motion and physiological BOLD signal.

Results

Participants were most female (66%) and black (79%) and the mean age was 49 years‐old (±13.9). The mean score on free recall was 27.2 (±10.7) out of 48 points. We found a significant correlation between the hippocampus and the right parahippocampal gyrus, right insula and right basal ganglia. However, we did not find an association between the hippocampal connectivity and the memory scores.

Conclusions

Illiterate adults have a significant correlation between the hippocampus and the right insula and basal ganglia. The lack of association with memory scores might be associated with low brain reserve in this group of individuals.
Childhood trauma and social resources moderate relationships between perceived discrimination and late‐life cognition in older African Americans
Authors: Pugh Erika , Divers Ross , Calamia Matthew
Published: December 2021

Background

Perceived discrimination (PD) is a common stressor for African Americans (AA) that has been linked to poorer cognition in old age, although factors that increase or decrease this association remain understudied. For example, a history of childhood trauma, for which African Americans are at greater risk, may affect later cognition by making individuals more stress reactive. In contrast, there may be other factors (e.g. socioeconomic status, access to cognitively stimulating resources) that buffer the negative association between PD and cognition. The purpose of this study was to examine these possible moderators of the association of PD with cognition in a sample of older AAs (n = 583),

Method

Data was obtained from the Minority Aging Research Study (MARS), a longitudinal, epidemiologic cohort study of cognitive decline and risk of AD in older (65+) AAs. Moderation analyses were conducted to identify the potential effects of childhood trauma and protective factors on the relationship between PD and cognition,

Result

Childhood trauma, specifically greater parental violence, increased the negative association between PD and perceptual speed. Additionally, both early childhood socioeconomic status and access to resources that support cognitive activities throughout one’s life decreased the negative association between PD and both global cognition and working memory,

Conclusion

In sum, experiencing childhood trauma significantly impacts the effects of PD on cognition in older AAs, representing a key target for interventions. Protective factors, particularly access to cognitively stimulating resources throughout one’s life, may represent an actionable target for promoting cognitive wellbeing in older AAs.
Fluid intelligence and its neural correlates in early onset mild cognitive impairment
Authors: Carbone Chiara , Bardi Elisa , Corni Maria Giulia , Fiondella Luigi , Salemme Simone , Vinceti Giulia , Tondelli Manuela , Molinari Maria Angela , Chiari Annalisa , Zamboni Giovanna
Published: December 2021

Background

Fluid intelligence refers to the ability of abstract reasoning, problem‐solving and other mental activities considered to be independent from learned knowledges and experience. It has been demonstrated that fluid intelligence is compromised in Mild Cognitive Impairment (MCI), but it also declines with ageing. We tested if fluid intelligence is also affected when MCI occurs before 65 years of age (i.e., in early‐onset MCI) and studied its specific functional and structural brain correlates independently from the effect of ageing.

Method

Eighty‐five subjects with early‐onset MCI (cognitive symptoms onset < 65 years) underwent extended neuropsychological assessment including Raven’s Coloured Progressive Matrices (RCPM), a culture‐free non‐verbal relational reasoning task that is considered a proxy of fluid intelligence. They also underwent multimodal Magnetic Resonance Imaging (MRI) protocol on a 3T scanner including high‐resolution T1 and sequences acquired at rest for functional MRI (fMRI). Performance at RCPM was related to regional grey matter volume using Voxel Based Morphometry (VBM) and to functional connectivity of resting‐state networks (RSNs) known to be related to cognition using independent component analysis.

Results

The median RCPM score was 27 (range 8‐36, with 36 being the maximum obtainable score). Among all 85 patients, only 11.8% (N=10) performed below the age and education‐corrected cut‐off. These patients also had significantly lower scores in almost all the remaining neuropsychological tests, suggesting that they were in a more severe stage of MCI (i.e., close to conversion). VBM results showed that, across all patients, decreased performance on RCPM was associated with focal atrophy in right fronto‐temporal and bilateral parietal areas (Figure 1). FMRI acquired at rest showed that better performance on RCPM was associated with lower functional connectivity in areas of the anterior DMN and with higher functional connectivity in areas of the left fronto‐parietal RSN (also indicated as the working memory RSN).

Conclusion

In patients with early‐onset MCI fluid intelligence is relatively preserved, associated with lower atrophy in right fronto‐temporal and bilateral parietal regions, and with decreased functional connectivity in the anterior DMN and increased in the left fronto‐parietal network.
Remote diagnosis of dementia using AI methods on clock drawing images
Authors: Amini Samad , Zhang Lifu , Hao Boran , Gupta Aman , Song Mengting , Karjadi Cody , Au Rhoda , Paschalidis Ioannis
Published: December 2021

Background

Detection of any form of cognitive impairment is challenging and the subjects have to undergo numerous evaluations and clinical tests. Hence, it would be of great importance to design a reliable and accessible procedure by which patients may get diagnosed for dementia remotely. The capability of the Clock Drawing Test (CDT)as an effective cognitive assessment tool has motivated us to develop an online diagnostic tool by leveraging artificial intelligence techniques.

Method

Digital pen recordings of 3,263 normal subjects and 160 with dementia in the Framingham Heart Study (FHS) were collected, where all subjects have completed two analog clock drawings, one drawn on command and the other by copying. Using the idea of transfer learning, we first modified and trained a Convolutional Neural Network (CNN) pre‐trained on the ImageNet dataset to extract high level features of the CDT images, which generated a score associated with the likelihood of dementia for each patient. The proposed method integrates the scores of the CDT images and other demographic information. Therefore, the generated scores for both command and copy CDTs along with age were used to train a logistic regression model to classify individuals as demented or normal.

Result

We have evaluated the performance of the developed models by applying 5‐fold cross validation on the FHS dataset. On the test dataset, the model (modified pre‐trained CNN) based on command CDT images yielded an AUC of 0.81±0.043. The logistic regression model using age and the generated scores of command and copy CDTs, yielded an average AUC and average F1 score of 0.92±0.008 and 0.94±0.008, respectively.

Conclusion

Our method need not necessarily have access to digital biomarkers or clinical tests since the CDT can be completed using pen and paper, capturing the image using a smartphone. Hence, our method offers a cost‐effective and accurate screening tool to diagnose dementia and related diseases remotely.
Whole genome shotgun metagenomic sequencing to identify differential abundant microbiome features between dementia and mild cognitive impairment (MCI) in AD subjects
Authors: Jeong Sohyun , Huang Li‐Kai , Tsai Ming‐Ju , Liao Yi‐Tyng , Lin Yow‐Sien , Chang Chi‐feng , Chi Wei‐Kuang , Hu Chaur‐Jong , Hsu Yi‐Hsiang
Published: December 2021

Background

Previous studies demonstrated differential abundances of gut microbiota between Alzheimer’s disease (AD) and normal controls (NCs). However, gut microbiota distribution between dementia and amnestic mild cognitive impairment (aMCI) in AD subjects lacks clear data. With whole‐genome shotgun metagenomic sequencing (WGS), we aimed to identify differentially abundant microbiota as well as metabolic pathways between dementia and aMCI in AD subjects.

Method

Fecal samples from AD subjects were collected at Shuang‐Ho Hospital, Taipei Medical University, Taiwan and analyzed by WGS technique. 16S rRNA sequencing data from NCs were acquired from Taiwan Microbiome Database. Mini‐Mental State Examination (MMSE) and clinical dementia rating (CDR) scores, food frequency questionnaire, and other principal characteristics were collected along with fecal samplings. Alpha and β diversities were estimated by Chao1 and Shannon indices, and PCoA, respectively. We applied univariate tests (t‐test/Mann‐Whitney) and other modeling approaches (HAllA, MaAsLin, DESeq2, and LEfSe) to identify differential microbial biomarkers.

Result

A total of 48 AD (38 dementia and 10 aMCI) and 50 NC samples were analyzed. Alpha diversities at the taxonomy level of Family, Class, and Genus were significantly different between AD and NC. With the results commonly confirmed in the MaAsLin (age and sex‐adjusted) and other models, we found significantly increased abundances of phyla Firmicutes and Actinobacteria; but decreased abundances of Bacteroides and Acidobacteria in AD subjects (Figure 1). There was no significant difference in both α and β diversities between dementia and aMCI in AD subjects. However, lower MMSE (higher CDR) scores in the AD subjects were associated with higher abundances of strains in Blautia hydrogenotrophica, Anaerotruncus colihominis and Gordonibacter pamelaeae. In addition, metabolic pathway analyses by HAllA demonstrated microbial glucose and S‐Adenosyl‐L‐methionine (SAMe) pathways were associated with cognitive function scores (Table 1) and more enriched in aMCI (not significant).

Conclusion

We identified significantly higher strains in AD subjects with lower MMSE (higher CDR) scores suggesting that these microbes may have deleterious effects to cognitive function. In addition, the findings of higher enrichment of microbial glucose and SAMe metabolism in aMCI compared to dementia may implicate their beneficial roles in cognitive function in AD subjects.
Closer correlations between florbetapir PET measurements of amyloid plaque burden using a cerebral white matter reference region and Alzheimer’s disease‐related hypometabolism
Authors: Wang Michele S , Bi Tingting B , Jing Naomi Y , Ausdemore Jake C , Kramer Harrison L , Chen Yinghua , Luo Ji , Weiner Mike W. , Landau Susan M. , Jagust William J. , Su Yi , Reiman Eric M. , Chen Kewei
Published: December 2021

Background

Alzheimer’s disease (AD) is associated with amyloid‐β (Aß) plaque deposition and a characteristic pattern of cerebral glucose hypometabolism. While a cerebellar reference region is commonly used to characterize cerebral Aβ burden, we demonstrated improvements in the ability of florbetapir PET to track Aβ burden using a cerebral white matter reference region (Chen, et al., 2015). Here, we compare associations between cerebral‐to‐reference region florbetapir PET standard value uptake ratios (SUVRs) using cerebral white matter versus cerebellar reference regions to two FDG PET indices of AD‐related cerebral hypometabolism: “hypometabolic convergence index” (HCI) and “statistical region‐of‐interest” (sROI) (Chen et al, 2010; 2011).

Method

We analyzed 1722 florbetapir and FDG PET scan pairs from the AD Neuroimaging Initiative, including 267 with probable AD dementia (pAD), 592 with MCI and 379 cognitively unimpaired (CU). Florbetapir SUVRs were computed using measures from the cerebral regions‐of‐interest with the cerebral white matter or cerebellar reference regions. HCI and sROI were generated from the FDG PET images. Pearson’s correlations and the Steiger statistical test were used to characterize and compare the extent to which florbetapir SUVRs using cerebellar versus cerebral white matter reference regions were associated with HCI or sROI in the overall group, the pAD, MCI and CU sub‐groups.

Result

Correlations between florbetapir SUVRs using the white matter reference region and HCI (0.59, 0.41, 0.45, and 0.40 in the overall, pAD, MCI and CU groups) were significantly stronger than those using the cerebellar reference region (0.40, 0.23, 0.26, and 0.20, P=1.1e‐16, 3.6e‐06, 1.3e‐09, and 1.0e‐11, respectively). Similarly, inverse correlations between florbetapir SUVR measurements using the white matter reference region and sROI measurements (‐0.51, ‐0.32, ‐0.38, and ‐0.28 in the overall, pAD, MCI and CU groups) were significantly stronger than those using the cerebellar reference region (‐0.34, ‐0.09, ‐0.24, and ‐0.13, P=2.0e‐15, 3.2e‐07, 1.7e‐0, and 4.0e‐07, respectively).

Conclusion

Florbetapir PET Aβ plaque measures are more closely associated with the AD‐related pattern of cerebral hypometabolism when SUVRs are generated using a white matter rather than cerebellar reference regions. Additional research is needed to examine if our results are generalizable for other Aβ PET tracers and longitudinal change measures.
Impact on cerebral cortical thickness of lifestyle multidomain intervention: The SUPERBRAIN study
Authors: Moon So Young , Kim Sohui , Choi Seong Hye , Hong Chang Hyung , Park Yoo Kyoung , Na Hae Ri , Song Hong‐sun , Kim Byeong‐Chae , Park Kyung Won , Park Hee Kyung , Choi Muncheong , Lee Sun Min , Chun Buong‐O , Lee Jong‐Min , Jeong Jee Hyang
Published: December 2021

Background

In the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored impact on cortical thickness of 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI).

Method

A total of 152 participants, aged 60‐79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 control) took brain MRIs at baseline and 24 weeks. We compared between each intervention and control groups in change of global/regional mean cortical thickness at 76 region‐of‐interest (ROI)s of the automated anatomical labelling (AAL); the total scale index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); and Serum brain‐derived neurotrophic factor (BDNF) levels. The changes in mean cortical thickness were compared using analysis of covariance with age, sex, education, and scan centers as covariates. ROI‐based analysis was controlled for multiple comparisons with a false discovery rate threshold of P < 0.05.

Result

Comparing with the control group, the total scale index score of RBANS was more significantly improved in both FMI group (p=0.002) and HMI group (p=0.013), respectively. The serum BDNF more significantly increased only in the FMI group (p=0.029). Mean global cortical thickness more significantly increased only in the FMI group (0.033±0.070 vs ‐0.003±0.040, p=0.035). ROI‐based analysis showed more significantly increased cortical thickness of the orbital, medial, medial orbital parts of right superior frontal gyrus, right olfactory cortex, right rectal gyrus, right anterior cingulate and paracingulate gyri, right middle temporal gyrus, medial orbital and dorsolateral parts of the left superior frontal gyrus, the orbital part of the left middle frontal gyrus, left middle occipital gyrus, and left middle temporal gyrus in the FMI group.

Conclusion

Significant differences between the FMI and control groups on changes in cortical thicknesses in at‐risk elderly without substantial impairment in the SUPERBRAIN suggest that group preventive strategies at the facility may be beneficial on cognition through structural neuroplastic changes in the brain areas which play a crucial role in processing social information.
Individual analysis of reminiscence from nostalgic music videos using text mining
Authors: Urabe Mie , Miyata Chiharu , Fukuda Hiroko , Yoneda Sho , Sakai Katsumi , Kato Yuka , Kitajima Kengo , Kashiwa Yukiko , Sawada Chikao
Published: December 2021

Background

Nostalgic music arouses positive changes in mood and social behavior of persons with dementia.(Barnetta L.,et al.,2006)Our research is an intervention using nostalgic music videos and reminiscence which provides stimulation to the emotions of a person with dementia, and positive emotions occur. In AAIC 2020, we presented this intervention. (Urabe, et al.,2020) The purpose of this study is to clarify the individual changes in narrative of reminiscence of a person with Alzheimer’s disease between the first and the last intervention using text mining.

Method

The participant with Alzheimer’s disease was a female (over 90 years old, MMSE: sixteen points ), and was in a psychiatric hospital in Japan, because of BPSD. We intervened four times using nostalgic music videos she liked, and listened to her memories of youth. We recorded her narrative and analyzed the words of her stories using text mining to see the changes caused by our intervention, and compared the results of the first intervention and the last. The participant’s language was Japanese, so her words were analyzed in Japanese to maintain accuracy. This study was approved by the ethical review board of Kyoto Prefectural University of Medicine and hospital where participant hospitalized.

Result

In the first intervention, the overall number of words were 1271, the number of sentences were 121, and the number of paragraphs were 102. In the last intervention, the total number of words were 2669, the number of sentences were 229, and the number of paragraphs were 150, and was significantly increased more than first intervention. In the co‐occurrence network, there were more connected co‐occurrence words in the last intervention than first intervention. The connections between this co‐occurrence network included three themes, these themes were memory, songs and work.

Conclusion

We were able to visualize the narrative of the participant with Alzheimer’s disease, and clarify the individual important keywords in the participant’s memories by using text mining. By reminiscing with nostalgic music videos, it increased the amount of language and revived memories for the patient with Alzheimer’s disease.
Amyloid‐β accumulation is independently related to executive function in cognitively unimpaired adults
Authors: Tideman Pontus , Stomrud Erik , Mattsson Niklas , Palmqvist Sebastian , Hansson Oskar
Published: December 2021

Background

The shift from a symptom‐based to a biological definition of Alzheimer’s disease (AD), within the NIA‐AA research framework, has highlighted the importance of biomarkers that are indicative of the neuropathological changes underlying AD. The independent associations of amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) need to be studied in deeply phenotyped cohorts. In the current study we investigated how the distinctive pathologies and neurodegeneration of AD, according to the AT(N) system, are related to cognition in four cognitive domains in CU adults.

Method

We included 316 CU individuals from the prospective BioFINDER‐2 study. The results were validated in CU participants from the ADNI study (n=376). All cases had CSF biomarkers (Aβ42 and P‐tau181), MRI (cortical thickness of AD‐susceptible regions), Aβ‐PET (neocortical uptake) and tau‐PET (entorhinal cortical uptake) as well as neuropsychological test data (including tests for i) memory, ii) executive function, iii) verbal function, iv) visuospatial function). Multivariable linear regression models, adjusted for age, sex and education, were performed, first using CSF Aβ42, P‐tau181 and cortical thickness and secondly using Aβ‐PET, tau‐PET and cortical thickness.

Result

In BioFINDER‐2, abnormal Aβ‐status was independently associated with executive function, regardless of biomarker (CSF Aβ42 β=0.128, p=0.024; Aβ‐PET β=0.124, p=0.049), but not memory or any other cognitive domains. Tau, on the other hand, was independently related to memory (CSF P‐tau181 β=0.132, p=0.018; tau‐PET β=0.189, p=0.002). Cortical thickness was independently associated with executive function (CSF‐based model, β= ‐0.161, p=0.013; PET‐based model, β= ‐0.186, p=0.005) and verbal function (CSF‐based model, β= 0.163, p=0.011; PET‐based model, β= 0.156, p=0.018). In a second step, only participants without evidence of tau pathology or neurodegeneration were included, again resulting in an association between Aβ and executive function (CSF Aβ42, β=0.189, p=0.005; Aβ‐PET, β=0.146, p=0.023), but not with other cognitive domains. Results were overall replicated in the ADNI cohort.

Conclusion

These findings suggest an independent relationship between early Aβ accumulation and worse executive function in CU individuals while tau is associated with memory. This finding contributes to our understanding of how cognitive deficits are manifested in early AD, especially in regard to Aβ accumulation.
Epidemiological impact of Alzheimer´s disease and other dementias in the Spanish‐Portuguese border region
Authors: Alonso‐Sardón Montserrat , Martín‐Delgado María Antonia , Pérez‐Martín Raixa Noemí , Ortega Eva González ,   NEUROQUALYFAM group
Published: December 2021

Background

Dementia has reached epidemic proportions and become a huge Public Health problem. Alzheimer’s disease (AD) is the most common type of dementia. In Spain, more than 800,000 people suffer from AD (Spanish Society of Neurology‐SEN). Age is the main risk marker for developing this disease. Its prevalence is three times higher in women than in men due to females’ higher life expectancy. The aim is to know the epidemiological profile and quantify the current scope of the AD and other dementias in the rural Spanish‐Portuguese border area, one of the most depopulated and aging regions in Europe.

Method

A cross‐sectional descriptive study was designed to estimate the prevalence of persons diagnosed with an ICD‐9‐CM or ICD‐10 code diagnosis of dementia in ten Basic Health Areas of the cross‐border rural area of province of Salamanca, Spain, during June‐July 2020 (39,354 inhabitants). The cases were recorded from the Electronic Clinical Record of Primary Care (MEDORA) by the Regional Health Management of Castilla y León.

Result

A total of 579 individuals suffer some type of dementia in the Spanish‐Portuguese border region, with a predominance of females (70%) vs. males (30%), and an age range of 38 to 109 years (Figure_1). AD was diagnosed in 307(53%) persons and other dementias in 272(47%). Gender distribution of the diagnoses is different in women and men (p<0.001) (Table_1). The mean(±SD) age was 85.2±7.6 years for women and 82.5±8.7 years for men (p<0.001). The mean(±SD) age of Alzheimer´s patients was lower, 83.7±7.1 vs. 85.2±8.9 (p=0.031) (Figure_2). The global prevalence of dementia was 1.47 per 100 inhabitants (0.78% in AD vs. 0.69% in other dementias). The prevalence of dementia was 2.12% in females and 0.85% in males. Prevalence range in the ten Basic Health Areas: from 2.98 (La‐Alberca) to 0.77 (Tamames) per 100 inhabitants. 26.4% of people with AD and other dementias in this region were institutionalized.

Conclusion

The prevalence data obtained confirm that AD and other dementias must be considered a public health problem in the rural Spanish‐Portuguese border region that represents a significant deterioration in the quality of life (QoL) in patients and their families.
Evaluation of the Elecsys NeuroToolKit panel in early Alzheimer's disease populations across six clinical trials
Authors: Rabe Christina , Thorne Nick , Voyle Nicola , Mertes Michaela , Mellino Gaspare , Quan Marian , Bittner Tobias
Published: December 2021

Background

We evaluated the Roche Elecsys® NeuroToolKit (NTK) assay panel of 12 cerebrospinal fluid (CSF) biomarkers in patients from a total of six clinical trials of crenezumab and gantenerumab in sporadic Alzheimer’s disease (AD), with respect to the correlations between individual biomarkers, and their associations with patient characteristics and disease severity. Additionally, we assessed their ability to measure and predict disease progression.

Method

CSF samples were collected at baseline and follow‐up (Phase II, 1.5 years; Phase III, 1 and 2 years) from a subset of patients enrolled in the Phase II ABBY (NCT01343966)/BLAZE (NCT01397578) studies of crenezumab in mild‐to‐moderate AD, the Phase III CREAD (NCT02670083)/CREAD 2 (NCT03114657) studies of crenezumab in prodromal‐to‐mild AD, the Phase III SCarlet RoAD (NCT01224106) study of gantenerumab in prodromal AD, and the Phase III Marguerite RoAD (NCT02051608) study of gantenerumab in mild AD. NTK assays included beta‐amyloid (1‐42), beta‐amyloid (1‐40), alpha‐synuclein, GFAP, IL‐6, neurogranin, neurofilament light chain (NfL), phospho‐Tau (181P), S100B, sTREM2, total Tau, and YKL‐40. Correlations between biomarkers, longitudinal changes in biomarkers, and correlation between baseline biomarker levels and cognitive progression were evaluated across all six studies.

Result

All biomarkers except IL‐6 positively correlated with each other; the highest correlations were between total Tau, phospho‐Tau (181P), and neurogranin (Spearman’s rho >0.9). NfL, GFAP, YKL‐40, and sTREM2 biomarkers positively correlated with patient age. Analyses of ABBY, BLAZE, CREAD, and CREAD2 showed consistent findings across all studies. Levels of NfL, GFAP, and α‐synuclein biomarkers increased at the 1 year and 1.5‐year timepoints. NfL correlated with disease severity and progression in the prodromal‐to‐mild population. Additionally, results from NTK measurements in SCarlet RoAD and Marguerite RoAD CSF samples will also be presented.

Conclusion

The NTK provided robust data and sufficient measuring range for the biomarkers tested. Further evaluation of these biomarkers is needed to understand their potential utility for clinical trials as pharmacodynamic biomarkers or for selecting patient populations. Elecsys is a trademark of Roche.
Association between tooth loss and cognitive performance: 11‐year follow‐up cohort study
Authors: Asher Sam , Stephen Ruth , Ngandu Tiia , Koskinen Seppo , Suominen Anna Liisa , Solomon Alina
Published: December 2021

Background

Emerging evidence suggests tooth loss to adversely affect cognition. This study assessed association between tooth count and cognitive performance over 11 years.

Method

This study included 6537 participants (2933 males, 3604 females), aged 30‐99 years old (mean 53.4 years) from Finnish Health 2000 and 2011 Surveys. Tooth count was assessed clinically in 2000. Cognitive status was assessed either in 2000, 2011 or both, through battery of cognitive tests including Mini‐Mental Scale Examination (MMSE, short version, max 16‐points), Immediate word recall, Delayed word recall and Verbal Fluency (number of animals correctly listed). Cognitive tests were dichotomized according to median. Number of remaining teeth were categorized into 0, 1‐9, 10‐19 and ≥20. Logistic regression analyses were adjusted for age, gender, years of education, cardiovascular risk factors (FINRISK score), homocysteine, vitamin D and alcohol consumption.

Result

In cross‐sectional analyses at baseline, lower tooth count was associated with lower cognitive tests scores. 10‐19 versus ≥20 teeth was associated with lower MMSE, and immediate and delayed recall scores. 1‐9 teeth was associated with lower MMSE score. Having 0 teeth was associated with lower MMSE and immediate recall scores.

In longitudinal analysis significant associations were observed between 10‐19 teeth in 2000 and lower MMSE and immediate recall scores in 2011. No association was observed between tooth count and verbal fluency in either cross‐sectional or longitudinal analyses (Table 1). Similarly, no association was observed for tooth count and decline in any cognitive test score over 11 years.

Conclusion

Preliminary results indicate that tooth loss may be linked to lower cognitive performance. Having 10‐19 versus ≥20 teeth appears to be particularly important. Individuals with 10‐19 teeth might have active or current periodontitis which could explain the observed associations. In contrast, individuals with low number of remaining teeth (0 or 1‐9) might not have periodontitis or lower burden of periodontal inflammation. The impact of periodontitis on cognition needs to be assessed in future studies. Acknowledgements: The authors wish to acknowledge Juho Vainio Foundation (Finland), Finnish Brain Foundation (Finland) & Päivikki and Sakari Sohlberg Foundation (Finland), Finnish Dental Society Apollonia and Finnish Dental Association.
Cerebrospinal fluid levels of 8‐isoprostane, a marker of oxidative stress, are elevated in patients with Alzheimer’s disease compared to healthy subjects: Does the malfunction in the cell’s powerhouse lead to Alzheimer’s disease?
Authors: Jensen Camilla Steen , Kellberg Amanda Oliva , Hasselbalch Steen Gregers , Simonsen Anja Hviid
Published: December 2021

Background

Oxidative stress may play an important role in the pathology of Alzheimer’s disease (AD). 8‐Isoprostane is a prostaglandin (PG)‐F2‐like compound belonging to the F2 Isoprostane class that is produced in vivo by the free radical‐catalyzed peroxidation of cells membrane arachidonic acid. 8‐Isoprostane is a biomarker of oxidative stress, and could possibly be a surrogate marker of the mitochondrial health in AD.

Method

We measured concentrations of cerebrospinal fluid (CSF) 8‐isoprostane from 113 subjects ranging from healthy subjects (HS, n=25) , to Mild Cognitive Impairment with positive AD biomarkers (MCI+, n=16), AD( n=40), and non‐AD dementia (non‐AD, n=32). Analysis was done using 8‐isoprostane Enzyme‐linked immunosorbent assay from Cayman Chemicals (Cayman Chemicals, MI, USA).

Result

Patient characteristics can be seen in Table 1. Analyzing the CSF levels of 8‐isoprostane, a significant difference between 8‐isoprostane concentrations among the groups (ANOVA) was found. Post‐hoc test (t‐test) revealed a difference between the HS and AD groups (Figure 1).

Conclusion

In conclusion 8‐isoprostane may be a good surrogate marker of cellular oxidative stress and may be used to evaluate mitochondria’s role in AD pathology in vivo.
Slowing as a multidomain and vascular geriatric syndrome: Apathy symptoms, gait speed and information processing speed in a geriatric memory clinic population
Authors: de Schraaf Sara AJ Van , Meester Hanneke FM Rhodius‐ , Aben Laurien , Sizoo Eefje M , Peters Mike JL , Trappenburg Marijke C , Hertogh Cees MPM , Klein Martin , Muller Majon
Published: December 2021

Background

The occurrence of slowing in mood, thinking and walking increases with age. It is, however, unclear if and how slowing in mood, thinking and walking, are interrelated and whether slowing is associated with the presence of cerebral small vessel disease (CSVD).

Method

For this study, we included 566 geriatric outpatients (49% female; age 79 ±6 years) from the Amsterdam Aging Cohort. Patients underwent brain imaging, a comprehensive geriatric assessment and a neuropsychological assessment. Three slowing aspects were investigated: apathy symptoms, processing speed and gait speed. CSVD measures included white matter hyperintensities (WMH), lacunes, and microbleeds. Associations between the slowing aspects and of cerebral small vessel disease with the slowing aspects were analyzed using multiple linear regressions and Poisson regressions for count data. To test the occurrence of CSVD in the population increased with accumulation of slowing aspects, using predefined cut‐offs, logistic regressions were used.

Result

Of the total population, 18% had two or more impaired slowing aspects below predefined cut‐offs. Cross‐sectional regression analyses showed that lower gait speed was associated with lower information processing speed (B = ‐.36, 95% CI = ‐.48 to ‐.23) and more apathy symptoms (B = ‐.18, 95% CI = ‐.27 to ‐.09), independent of age, sex, education level, depressive symptoms and sedative medication. Increased WMH volume was associated with worse slowing outcomes: gait speed (B = ‐0.49, 95% CI = ‐0.71 to ‐0.28), processing speed (B = ‐0.36, 95% CI = ‐0.55 to ‐0.18) and apathy (Incident Rate Ratio = 1.29, 95% CI = 1.05 to 1.57, p <.05). Moreover, patients with a higher number of impaired slowing aspects had a higher odds of having a larger volume of WMH (Fazekas ≥ 2; ORs 1.69 to 3.47) or having more than three microbleeds (ORs 2.73 to 3.79).

Conclusion

This study provides further evidence that slowing in mood, thinking and walking are closely related and more present in patients with cerebral small vessel disease. Longitudinal data is needed to unravel the direction of the complex relationship between cerebral small vessel disease and mental, cognitive and physical slowing.
Screening of new BACE‐1 inhibitors from marine animals: Molecular interaction and pharmacokinetic studies to find new drug prototypes
Authors: Romanek Thabatta Giuliani Monclus , De Blasio Paola , Sciani Juliana Mozer
Published: December 2021

Background

One cause of the Alzheimer's disease (AD) is the amyloid plaques accumulation, generated after an endoproteolytic cleavage of APP by secretases (WAKABAYASHI; STROOPER, 2008). Secretase inhibitors have been studied, but failed in clinical trials due to high toxicity and/or efficacy (HUNG; FU, 2017). So far, the main clinical treatment for AD is the administration of cholinesterase inhibitors that only increases the patient's survival in a few years (GAN et al., 2004). Molecules from natural products have been used as prototypes in the development of new drugs, and species from marine habitat have provided compounds of therapeutic interest, none of them applied to AD (MALVE, 2016). Thus, the objective of this work was to find new druggable β‐secretase (BACE1) inhibitors among molecules described from marine animals, aiming a new prototype for amyloid plaques decrease.

Method

Molecules from marine animals were searched in scientific articles and prepared for docking, conducted by Swiss Dock server, to predict molecular interaction with BACE1 (PDB code 2VKM). Results were analyzed by UCSF Chimera, and molecules were selected if they were positioned in the enzyme active site, with distance lower than 3 Å and binding energy lower than ‐6 kcal/mol. Selected molecules were analyzed for their pharmacokinetics properties (PK) and druggability using the SwissADME server.

Result

From 48 molecules, 3 were selected by molecular docking. Psammaplin A (PsA) is one of them, extracted from the poriferous Aplysin and known for its antibacterial and antitumor activities (SELEGHIM et al, 2007). It had favorable binding energy (−9.71 kcal/mol) and short distance between the ligand and the protein (1,923 and 2,615 Å2); however, its PK was not suitable for a drug. On the other hand, 1H‐Benzo[de][1,6]naphthyridine and Sebastianine A had lower binding energy as well (−6.76 and −6,98 kcal/mol, respectively) and favorable PK: logP ∼2.5, high gastrointestinal absorption, brain‐blood barrier permeant, low ability to inhibit liver enzymes and no violation of the Lipinski’s rules, characteristics to be druggable.

Conclusion

Using molecular docking, 3 molecules were selected as potential inhibitors of BACE1, being two of them druggable and good prototypes for the treatment of AD.
Evaluating the relationship between vascular endothelial growth factor (VEGF) and cognitive improvements following exercised‐primed transcranial direct current stimulation (tDCS) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)
Authors: Song Bing Xin , Herrmann Nathan , Gallagher Damien , Rapoport Mark , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Oh Paul I. , Marzolini Susan , Kiss Alex , Swardfager Walter , Liu Celina , Vieira Danielle , Kim Doyoung , Koo Grace KY , Lanctôt Krista L.
Published: December 2021

Background

VEGF has been associated with memory decline in neurodegenerative diseases. As an angiogenesis biomarker, VEGF should be analyzed to better understand the variable treatment response from tDCS, a non‐invasive brain stimulation, and the priming effect of exercise on tDCS for memory improvements in MCI and AD. Using blinded data from an ongoing clinical trial (EXPRESS), we aimed to evaluate the ability of serum VEGF to predict improvements for recall memory in MCI and mild AD patients.

Method

Participants were enrolled in a five‐week, randomized, blinded tDCS clinical trial to receive either exercise and sham tDCS, exercise and tDCS, or exercise‐education only and tDCS intervention. Exercise groups included a three‐week ramp‐up period. Participants were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) criteria for major or mild neurocognitive disorder due to AD or mixed AD/vascular disease (etiology). VEGF serum concentrations were measured from blood samples at screening. Recall memory was assessed using the Word Recall Task from the Alzheimer's Disease Assessment Scale‐Cog (ADAS‐Cog) at screening, baseline and endpoint (2 weeks from baseline). Analysis of variance (ANOVA) evaluated recall memory and VEGF concentrations at screening between the two etiology groups. Multiple linear regression analysis determined the association between VEGF concentrations (pg/mL) and recall memory score improvements over treatment period (Δrecall).

Result

In 17 participants (58.8% male, 70.6% MCI, mean(±SD) age 72.8±7.2, years of education 17.1±2.0, VEGF 332.4±157.5, Δrecall 0.5±0.9), six participants (35.3%) were diagnosed as AD etiology only and eleven participants (64.7%) were mixed vascular/AD etiology with no differences in recall memory [F(1,15)=0.019,p=0.893] or VEGF concentrations [F(1,15)=1.488,p=0.241] between these two groups at screening. The regression analysis found that VEGF and etiology predicted Δrecall [F(2,14)=7.103,p=0.007,R2=0.504]. Controlling for etiology, VEGF concentrations were associated with Δrecall [B(SE)=‐0.003(0.001),p=0.039]; Δrecall decreased 0.003 for each pg/mL of VEGF.

Conclusion

In this pilot sample, lower serum VEGF concentrations at screening predicted greater recall memory improvements when controlling for etiology. After un‐blinding, longitudinal analysis and a larger sample size will allow further examination of VEGF’s predictive and monitoring capacity as a biomarker for recall memory and other cognitive responses to exercise‐primed tDCS.
Relationship between CDR Sum of Boxes and ADAS‐COG derived from historical clinical trials
Authors: Mitchell Emma , d'Amico Valeria , Geerts Hugo
Published: December 2021

Background

Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS‐Cog) has traditionally been used for monitoring cognitive function in AD clinical trials, while Mini‐Mental Score Evaluation (MMSE) usually is determined at baseline. Recently however, Clinical Dementia Rating Sum of Boxes (CDR‐SOB) has become increasingly popular. We sought to define a relationship between these three clinical scales based on outcomes in clinical studies where these three scales have been used on the same patient groups.

Method

We used Certara’s CODEx (Clinical Outcomes Database Explorer) Alzheimer database, consisting now of summary endpoints in 240 clinical trials with 651 study arms (over 83300 patients) from 290 publications. 65 datasets were identified where patients were evaluated both with ADAS‐Cog and CDR‐SOB, 53 datasets for MMSE and CDR‐SOB and 167 datasets for MMSE and ADAS‐Cog.

Result

Strong correlation (r2=0.8817) was observed for the relationship CDR‐SOB = 0.3105 ADAS‐Cog ‐1.1159 (p=2.2E‐16). Similarly, the relationship between ADAS‐Cog = ‐1.90881 MMSE + 62.27423 had a correlation coefficient of 0.801. Finally the linear relationship between CDR = ‐0.62806 MMSE + 18.50328 had a correlation coefficient of 0.839.

Conclusion

Use of the CODEx database enables to derive relationships between popular cognitive clinical scales. This would help historical clinical trials in perspective using ADAS‐Cog with more recent studies where CDR‐SOB is used as the primary outcome.
Prevalence of sporadic cerebral amyloid angiopathy: A systematic review and meta‐analysis
Authors: de Kort Anna M. , Jäkel Lieke , Klijn Catharina J.M. , Schreuder Floris H.B.M. , Verbeek Marcel M.
Published: December 2021

Background

There is large variation in estimates of the prevalence of cerebral amyloid angiopathy (CAA). CAA is associated with an increased risk of cognitive dysfunction and intracerebral hemorrhages, and it is tightly linked to immunotherapy‐related side‐effects in Alzheimer’s disease (AD). Thus, accurate estimates of the prevalence of CAA are important. CAA can be diagnosed neuropathologically (‘definite CAA’), or during life (‘probable CAA’) using the (modified) Boston criteria based on MRI markers.

Method

We performed a systematic literature search in PubMed and EMBASE for studies on CAA prevalence in cohorts of patients with AD, population‐based individuals, healthy elderly, patients with intracerebral hemorrhage (ICH), and patients with lobar ICH. Study inclusion criteria were: 1) a study population of at least 10 subjects, 2) a mean age of ≥ 55 years, 3) diagnostic criteria included use of neuropathology or MRI (T2* or SWI), 4) outcome measures included CAA prevalence according to neuropathological assessment or the (modified) Boston criteria, or the prevalence of the MRI markers used in the Boston criteria: strictly lobar microbleeds or cortical superficial siderosis.

Result

We included 170 studies including over 73,000 subjects. We found that in patients with AD, the estimated prevalence of CAA based on pathology (48%) is twice the prevalence based on the presence of strictly lobar microbleeds (22%). In the general population, this difference is threefold (23% vs 7%). However, both methods yield the same estimated prevalence of CAA in healthy elderly (5‐7%), in patients with ICH (19‐24%), and in patients with lobar ICH (50‐57%). In addition, we observed large heterogeneity in both neuropathology and MRI study protocols.

Conclusion

CAA is a very prevalent condition in AD and in the population. Since CAA is associated with the development of amyloid‐related imaging abnormalities in anti‐amyloid β immunotherapy, a faster decline of cognitive function in AD, and a growing spectrum of clinical symptoms, awareness of the high prevalence of CAA is important. In addition, we found that MRI markers seriously underestimate the prevalence of CAA in AD patients and population‐based individuals. Lastly, our results emphasize the need for standardized assessment and reporting of CAA in neuropathology and MRI studies.
Plasma biomarker profiles and the association with cognitive function across the clinical spectrum of Alzheimer's disease
Authors: Xiao Zhenxu , Wu Xue , Wu Wanqing , Liang Xiaoniu , Luo Jianfeng , Ding Saineng , Zheng Li , Zhao Qianhua , Xu Hong , Ding Ding
Published: December 2021

Background

The plasma biomarkers showed a promising value in the disease management of Alzheimer’s disease (AD). However, the profiles of the plasma biomarkers and the association with cognitive domains along the spectrum of AD have seldom been reported.

Method

A total of 451 participants were recruited from a memory clinic cohort and a cohort with community‐dwellings. The global and domain‐specific neuropsychological tests were administrated in all participants. The Clinical Dementia Rating (CDR) was used to assess the severity of cognitive impairment. The diagnosis of mild cognitive impairment (MCI) and dementia were based on the Petersen’s criteria and DSM‐IV criteria. The AD was diagnosed according to the NINCDS‐ADRDA criteria. We described the continuum of AD based on the combination of CDR and the cognitive diagnosis: NC (CDR = 0), aMCI‐s (CDR = 0.5), aMCI‐m (CDR = 0.5), AD (CDR = 1), AD (CDR = 2), and AD (CDR = 3). The plasma Aβ 40, Aβ 42, Aβ 42/Aβ 40, t‐Tau, neurofilament protein light chain, and p‐Tau 181 were quantified using the Single molecule array platform. One‐way Analysis of Variance and Welch test were used for comparison among plasma markers. The association between domain z scores and log‐transformed plasma biomarker indexes were examined using partial Pearson correlation analysis with the adjustment for confounding variables.

Result

The concentration of plasma p‐Tau 181 basically increased along the clinical cognitive status, from normal cognition (CDR = 0) to AD (CDR = 3). There are varying degrees of correlation between six plasma biomarkers and different cognitive domains. Plasma p‐Tau 181 had the strongest correlation with MMSE (r = ‐0.494, P< 0.001), Memory (r = ‐0.417, P< 0.001), Attention (r = ‐0.388, P< 0.001), Visuospatial function (r = ‐0.328, P< 0.001), and Language (r = ‐0.123, P= 0.014). There was significant negative correlation between plasma p‐Tau 181 and four subgroups of cognitive domains, including MMSE in CDR >=1 group, Memory in CDR = 0.5 group & CDR >=1 group, and Attention in CDR >= 1 group.

Conclusion

Plasma p‐Tau 181 increased along the clinical continuum of AD, and had the strongest correlation with cognitive domains among all plasma biomarkers.
Cannabinoid agonist WIN 55,212‐2 improves memory consolidation in a rat model of basal forebrain cholinergic lesion
Authors: de Tena Iker Bengoetxea , Martínez‐Gardeazabal Jonatan , Moreno‐Rodríguez Marta , Pereira‐Castelo Gorka , Manuel Iván , Rodríguez‐Puertas Rafael
Published: December 2021

Background

Alzheimer’s disease (AD) is associated with a selective vulnerability of basal forebrain cholinergic neurons (BFCN). The endocannabinoid (eCB) system modulates those BFCN pathways in AD. However, the effect of cannabinoid compounds on memory and learning remains controversial. Therefore, we evaluate the effect of cannabinoid agonists in recognition learning and memory in rats with a specific lesion of BFCN.

Method

Sprague‐Dawley male rats were infused bilaterally in the BFCN with 192IgG‐saporin toxin, (SAP group, n=10). Another group of SAP rats was treated with CB1 receptor agonist WIN 55,212‐2 for 5 days (SAP+WIN, n=10). Memory and learning were evaluated by Novel Object Recognition Task (NORT). The ability to identify new objects in the short term (3h after learning) and the long term (24h after learning), and other exploratory parameters, were measured.

Result

In the short term, control group and SAP group spent significantly more time exploring the new object than the old one (CON: 68.37% ± 4.05, p>0.01 and SAP: 60.72% ± 2.86, p>0.01), while SAP+WIN group did not (50.42% ± 5.73). In the long term, control group spent significantly more time exploring the new object than the old one (70.81% ± 2.42, p>0.001), but SAP group failed to do so (54.85% ± 3.93). Interestingly, SAP+WIN rats also spent more time exploring the new object than the old one (60.37% ± 6.36, p>0.05). Moreover, SAP group showed an increased exploratory behavior compared to control group, measured by the total exploration time in the long term (SAP: 49.76s ± 5.36 vs CON: 26.51s ± 4.45, p>0.05) and the number of rearings performed (SAP: 30.5 ± 2.4 vs CON: 21.3 ± 2.3, p>0.05). WIN 55,212‐2 treatment did not modify these latter parameters.

Conclusion

These results suggest that degeneration of BFCN pathways does not impair learning in NORT test, but impairs memory consolidation. A sub‐chronic treatment with WIN 55,212‐2 was able to restore memory in rats with a BFCN lesion, even if it induces attention deficits at the short term. Thus, we suggest that cannabinoid agonists might be a plausible treatment for the typical contextual recognition problems derived from BFCN impairment in AD patients.