bluuebunny/crossref_metadata_2025 huggingface dataset:
Self‐reported and informant‐reported assessments of neuropsychological conditions in a Lebanese sample of community‐dwelling older adults in Lebanon
Authors: Elbejjani Martine , El Hachem Rita , Chaaya Monique
Published: December 2020

Background

Accumulated data highlight a significant role for mental health in influencing and exacerbating the risk, detection, and progression of cognitive decline and aging‐related disorders. In parallel, several findings suggest cultural and contextual differences in the manifestation and recognition of mental health problems. In Lebanon, data on mental and cognitive health and on their assessments are scarce. We examined the agreement between self‐reported and informant‐reported assessments of depressive and anxiety symptoms in a Lebanese community‐based sample of older adults.

Method

Data come from a Lebanese cohort of older adults (n=502, age=75.5 (SD=7.2); 56.2% women). Depressive and anxiety symptoms were self‐rated using the Geriatric Mental State (GMS) AGECAT and informant‐rated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q). We estimated Cohen’s Kappa and investigated factors related to mismatch in reports using logistic regression models; explanatory factors included participants’ cognitive functioning and participants’ and informants’ demographic and socioeconomic indicators. Data processing is still ongoing to include more participants.

Result

Preliminary results showed that 10.6% and 1.6% of participants self‐reported depression and anxiety symptoms and 4.6% and 2% had depression and anxiety symptoms based on informant’s reports, respectively. Cohen’s Kappa was 0.38 for depression and 0.32 for anxiety symptoms; 69.8% and 62.5% of those reporting depressive and anxious symptoms were not reported to have these symptoms by their informants and 30% and 70.4% of informant‐reported depression and anxiety were not reported by participants. Men and participants with higher educational attainment had lower odds of mismatch between self‐ and informant‐reports (OR=0.46 (95% CI=0.24, 0.88) and OR=0.54 (95% CI=0.28, 1.04)); current employment of both participants and informants was associated with lower mismatch (OR=0.19 (95% CI=0.07, 0.54) and OR=0.58 (95% CI=0.32, 1.1). Higher cognitive scores were associated with lower mismatch (OR=0.90 (95% CI=0.81, 0.99).

Conclusion

Results indicate a weak agreement between self‐reported and informant‐reported neuropsychological symptoms and that the majority of older adults with symptoms were not identified by their informants. More work is needed to improve assessments of neuropsychological symptoms and identify mechanisms underlying discrepancies in assessments in the Lebanese population to better track neurocognitive and health changes at older age.
Relationship between genetic risk for Alzheimer's, cognition and neuropsychiatric symptoms: A case study of DNA sampling and analysis through digital platform cohort studies
Authors: Creese Byron , Brooker Helen , Aarsland Dag , Corbett Anne , Ballard Clive , Ismail Zahinoor
Published: December 2020

Background

With the evolution of technologies to extract DNA and undertake analysis from saliva samples, it is now feasible to collect postal samples for genetic analysis as part of cohort studies run on digital platforms. Ethics and engagement will be discussed and Mild Behavioral Impairment (MBI) is presented as an example of where this approach has delivered a substantial and cost‐effective study.

MBI, a late‐life neuropsychiatric syndrome, is associated with faster progression to dementia and Aβ deposition even in healthy adults. MBI screening may enrich samples with individuals at risk for dementia, with benefits to clinical studies and possibly trials.

Method

25,000 participants from the PROTECT digital platform were invited to provide a saliva sample by post. Ethics approval was underpinned by an on‐line consent process, genotypes were not disclosed to participants. Polygenic scores (PRS) for Alzheimer’s disease (AD) were calculated and split by tertile (representing low, medium and high AD genetic risk). Data were analysed as a whole sample then stratified by the presence of MBI.

Result

87% of PROTECT participants agreed to provide genetic samples by post. 10,000 of these have been genotyped. 75% of the sample were women and the mean age was 62 (range: 50‐100). At the time of data freeze, genetic, MBI and cognitive data were available for 3,126. AD genetic risk was associated with a lower cognitive score (F(2,3119)=3.93, p=0.02; mean difference between low and high genetic risk: ‐15, p=0.02, Cohen’s d=0.13). In stratified analysis, genetic risk for AD was associated with worse cognition but only in the MBI group (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). There was a significant difference between the high and low genetic risk groups (mean difference: ‐0.22, p=0.005); the effect size was stronger than in the whole sample analysis (Cohen’s d increase from 0.13 to 0.19).

Conclusion

High degrees of engagement can be achieved to obtain DNA samples from participants in online cohort studies. With respect to MBI, these findings demonstrate that neuropsychiatric symptoms may modify the relationship between genetic risk for AD and cognitive impairment. MBI screening may represent a useful sample enrichment strategy for clinical studies and trials.
Quantitative mass spectrometry suggests beta‐synuclein as promising blood marker for synaptic degeneration in Alzheimer's disease
Authors: Oeckl Patrick , Halbgebauer Steffen , Straub Sarah , von Arnim Christine , Diehl‐Schmid Janine , Frölich Lutz , Grimmer Timo , Hausner Lucrezia , Denk Johannes , Jahn Holger , Weishaupt Jochen H. , Ludolph Albert , Otto Markus
Published: December 2020

Background

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read‐out for patient diagnosis and possible follow‐up in clinical trials in the mainly unsuccessful AD drug development. Several synaptic markers for AD are described in cerebrospinal fluid (CSF) but studies in blood were not successful so far.

Method

We used quantitative mass spectrometry (IP‐MS, MRM) to measure the presynaptic protein beta‐synuclein in CSF and blood from 363 patients: AD (n=64), Creutzfeldt‐Jakob disease (CJD, n=25), behavioural variant frontotemporal dementia (bvFTD, n=16), dementia with Lewy bodies/Parkinson´s disease dementia, (DLB/PDD, n=13), Parkinson´s disease (PD, n=25), amyotrophic lateral sclerosis (ALS, n=30) and non‐neurodegenerative controls (Con, n=45). Changes in AD were validated in two independent validation cohorts from other clinical centers (AD: n=40 and n=49, Con: n=44 and n=25). Group differences were compared by non‐parametric tests and data correlated with clinical scores (MMSE, CDR).

Result

We observed increased concentrations of beta‐synuclein in CSF and blood of AD patients (CSF: median 979pg/mL, IQR: 738‐1223pg/mL vs. 659pg/mL, IQR: 521‐860pg/mL in controls; Serum: 12.9pg/mL, IQR: 10.6‐16.4pg/mL vs. 8.9pg/mL, IQR: 7.1‐10.4pg/mL in controls, p<0.01) and confirmed this finding in the two validation cohorts. Beta‐synuclein was already increased in patients with mild cognitive impairment due to AD (p<0.01). CSF and serum beta‐synuclein was also markedly increased in CJD (CSF: 19324pg/mL, IQR: 10560‐42570pg/mL; Serum: 479pg/mL, IQR: 259‐843pg/mL, p<0.001) but not bvFTD, DLB/PDD, PD or ALS. The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ³96%.

Conclusion

These findings suggest beta‐synuclein as a candidate blood marker for synaptic degeneration which might be used in clinical AD trials and patient follow‐up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.
Potential synergistic effect between Fortasyn Connect and cholinesterase inhibitors in patients with early stages (very mild and mild) of dementia due to Alzheimer disease in common medical practice: An observational, non‐interventional study
Authors: Fernandez Felix Vinuela , Crespo Angeles Barro
Published: December 2020

Background

Details implementation of an innovative care program or practice: Fortasyn connect medical food, approved for early stages of Alzheimer dementia, can have a synergistic effect with cholinesterase inhibitors drugs.

Objectives

To analyse the possible synergistic effect between Fortasyn Connect medical food and Cholinesterase Inhibitors drugs in Alzheimer disease patients in a common medical practice.

Patients and Methods

60 patients at early stages of dementia due to Alzheimer disease were followed. CDR (Clinical Dementia Rating) scale was administered at the beginning and at the end of the follow‐up period. The rate of change of CDR‐SB (sum of Blocks) was chosen as a efficacy criteria. Informed Consent was aquired. An approval of the Ethical Committee of the protocol was obtained. SSPS (v20) was used as a Statistical Software.

Results

The combination therapy with Fortasyn Connect and Cholinesterase inhibitors was well tolerated. There were no significative advers effect. The patients were distribute at the final visit in 4 groups: Those who had taken both Fortasyn Connect and Cholinesterase inhibitors (Group 1), those who had taken Fortasyn Connect and no Cholinesterase inhibitors (Group 2), those who had taken Cholinesterase inhibitors and non Fortasyn Connect (Group 3), those who had not taken neither Fortasyn Connect nor Cholinesterase inhibitors (Group 4). There was a statistical difference between the Group 1 with the Group 3 and Group 4, indicating a potential synergistic effect between both therapies.

Conclusions

The combination therapy with Fortasyn Connect medical food and Cholinesterase inhibitors was well tolerated. It seem to be a potential synergistic efect between Fortasyn Connect medical food and Cholinesterase inhibitors Drugs. An statistical difference between the Group 1 (Fortasyn Connect medical food and Cholinesterase inhibitors therapy) with the Group 3 (Cholinesterase Inhibitor alone) and Group 4 (Fortasyn Connect medical food and Cholinesterase inhibitors therapy), indicating a potential synergistic effect between both therapies. Due to the limitations of this preliminary study (non‐blinded, non randomized, small sample of patients, non placebo control), more studies are needed.
Risk and protective factors affecting the quality of life of family carers of people with dementia
Authors: Contreras Milena L , Mioshi Eneida , Kishita Naoko
Published: December 2020

Background

Contreras conducted a comprehensive meta‐analysis on predictive factors of QoL among family carers. The findings suggested that previous studies exclusively relied on generic QoL measures (e.g., feeling satisfied with own physical health) to assess wellbeing among this population. The level of generic QoL is often considered to largely depend on physical health conditions and level of independence, which could be problematic when used with older populations. To further build the evidence base, the current empirical study aimed to investigate the impact of common risk factors (i.e., care recipient’s neuropsychiatric symptoms, carer depression, anxiety and objective burden) on old age‐specific QoL (e.g., feeling valued in the community) among family carers, considering the increasing age of this population. It also aimed to explore the role of protective factors that have been proved to predict wellbeing in other populations but have not been studied yet in carers such as psychological flexibility and self‐compassion. Other potential protective factors such as carer’s knowledge about dementia and the number of hours of support they receive from other family members were also considered in the model.

Method

Eighty‐five family carers (Mean age=69.5, SD=12.9; 67.1% female) were recruited in the UK. Most of the participants were looking after a spouse (67.0%) with Alzheimer’s (43.5%) or mixed dementia (18.8%). Two separate multiple regression analyses were conducted with old age‐specific QoL as a dependent variable. First, all risk factors (i.e., neuropsychiatric symptoms, depression, anxiety and objective burden) were entered to the model as independent variables. In the second analysis, psychological flexibility, self‐compassion, knowledge about dementia and the number of hours of support carers receive from other family members were entered as independent variables to assess the impact of protective factors.

Result

Anxiety was the only significant risk factor predicting old age‐specific QoL (β=‐.37) and psychological flexibility was the only significant protective factor predicting QoL (β=‐.44).

Conclusion

These findings suggested that improving carer’s anxiety and psychological flexibility may be particularly important in promoting their old age‐specific QoL Future interventions should target these key variables to achieve the desired result of improving carer QoL.
CRISPR/Cas9 genome editing of CLU to examine clusterin’s contribution to neurodegeneration and Alzheimer’s disease
Authors: Foster Evangeline M. , Ribe Elena M. , Robbins Jacqueline , Hublitz Philip , Pangalos Menelas , Buckley Noel , Lovestone Simon , Neuroscience Translational , Research Dementia
Published: December 2020

Background

Traditionally, clusterin is referred to as a secreted protein however, more recent evidence indicates clusterin may exist intracellularly where it may have a pro‐apoptotic role. Previously, our lab observed altered clusterin trafficking in rodent neurons in response to amyloid‐β suggesting it may be a key factor in neurodegeneration. We aim to use CRISPR/Cas9 in human iPSCs to explore the contribution that clusterin plays in cellular vulnerability to amyloid‐β.

Method

We aim to remove exon 2 from CLU since this exon contains the ER‐signal peptide thought to be required for secretion of clusterin protein. So far, we have generated heterozygous exon 2 knockout iPSCs (exon 2+/‐) which have been differentiated into cortical neurons and astrocytes. Clusterin gene and protein expression has been characterised in these iPSCs compared to control iPSCs. Response of control and exon 2+/‐ neurons and astrocytes to amyloid‐β treatment has also been explored.

Result

Surprisingly, exon 2+/‐ iPSCs express significantly less intracellular clusterin than control iPSCs. Secreted clusterin expression is unaltered by the edit achieved but glycosylation state is altered. We build on previous findings in rodent neurons, showing that clusterin trafficking is also altered by amyloid‐β in both control iPSC‐neurons and iPSC‐astrocytes. This response is observed in exon 2+/‐ neurons but is absent in exon 2+/‐ astrocytes. Divergence in gene expression changes of DKK1‐signature genes is observed. Here, we describe differences in both gene and protein expression changes in response to amyloid‐β treatment in control and exon 2+/‐ cells.

Conclusion

Currently, we are exploring whether differences observed in neuronal and astrocytic responses of exon 2+/‐ cells convey protection or vulnerability to amyloid‐β induced toxicity. To do so, we are using imaging techniques to quantify changes in cell death and neurite projections for both genotypes in response to treatment.
The context effect in facial emotion perception increases with age
Authors: Bartsch Kaja , Jarsch Marianne , Monsch Andreas U. , Kressig Reto W. , Sollberger Marc
Published: December 2020

Background

There is evidence that age and context (e.g. stimuli presentation) influence the way we perceive emotions (Barrett, Mesquita & Gendron, 2011; Stanley & Isaacowitz, 2015). We investigated whether there is an age‐dependent context effect on the perception of static facial emotions.

Method

In this cross‐sectional study, 240 cognitively and psychically healthy subjects (50% female), evenly distributed between 34 and 90 years old, participated. Two facial emotion intensity perception tasks (Chiu et al., 2016; Chui et al., 2018) comprising different stimuli presentations, were administered: In the congruent context, facial emotions (i.e., anger, fear, disgust, happiness and sadness) were rated on a seven point Likert scale in terms of intensity from 'not perceived' to 'very strongly perceived'. In the incongruent context each facial stimulus was shown consecutively five times and had to be rated not only on the congruent emotion, but also on the other four incongruent emotions (e.g., rating on happiness, anger, disgust, fear and sadness when a happy face was shown). Congruent scores of the two tasks were used to investigate the potential context effect on emotion perception.

We performed a linear mixed effects analysis of each emotion, entering the interaction term age x context, sex and gender of the stimulus as fixed effects; subjects were treated as random effects.

Result

With increasing age, subjects perceived happiness (t(345) = 3.04, p < 0.01), disgust (t(717) = ‐6.42, p < 0.001, sadness (t(717) = ‐2.81, p < 0.001) and fear (t(717) = ‐2.13, p< 0.05) less intensely in the incongruent compared to the congruent context. In contrast, we found no age‐dependent context effect in the perception of anger.

Conclusion

We found a significant age‐dependent context effect in the perception of happiness, disgust, sadness and fear. Older subjects were more prone to context in terms of varying stimuli presentation than younger subjects, possibly also due to a decrease of cognitive functions in older age e.g., mental flexibility (Mather, 2016). Our results contribute to a better understanding of influential factors on emotion perception, which is critical when interpreting patients’ scores on an emotion perception task.
Amygdalar nuclei and hippocampal subfields on MRI: Test‐retest reliability of automated segmentation in old and young healthy volunteers
Authors: Quattrini Giulia , Pievani Michela , Jovicich Jorge , Aiello Marco , Bargalló Nuria , Barkhof Frederik , Bartrés‐Faz David , Beltramello Alberto , Pizzini Francesca B , Blin Olivier , Bordet Régis , Caulo Massimo , Constantinides Manos , Didic Mira , Drevelegas Antonios , Ferretti Antonio , Fiedler Ute , Floridi Piero , Gros‐Dagnac Helene , Hensch Tilman , Hoffmann Karl‐Titus , Kuijer Joost , Lopes Renaud , Marra Camillo , Müller Bernhard W. , Nobili Flavio , Parnetti Lucilla , Payoux Pierre , Picco Agnese , Ranjeva Jean‐Philippe , Roccatagliata Luca , Rossini Paolo Maria , Salvatore Marco , Schonknecht Peter , Schott Björn H , Sein Julien , Soricelli Andrea , Tarducci Roberto , Tsolaki Magda , Visser Pieter Jelle , Wiltfang Jens , Richardson Jill , Frisoni Giovanni B , Marizzoni Moira , Consortium PharmaCog
Published: December 2020

Background

The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behaviour but their small size hampers their manual segmentation in multicenter datasets. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors. We applied a new high‐resolution atlas in two independent cohorts of older and younger healthy adults.

Method

Sixty‐four older (PharmaCog study; age range: 50‐78 years) and 67 younger subjects (CoRR consortium; age range: 18‐43 years) underwent repeated 3D‐T1 MRI at two different time points between 1 and 90 days. Amygdala and hippocampus segmentation was performed using FreeSurfer v6.0. Reliability of functional parcellations was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. Nuclei/subfields were considered as single structures and grouped into relevant subregions (for the amygdala, basolateral and the centromedial complexes; for the hippocampus, head, body, and tail subdivisions).

Result

Differences in MRI site/vendor had a significant impact (p<.05) for the ε of few subfields/nuclei, while extensively impacted DICE of most structures. The effect on DICE was limited by the functional parcellation only in the younger cohort. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (|rs|>.43, p<.001). In line, nuclei larger than 200 mm3 and subfields larger than 300 mm3 (except for molecular layer) had the best test‐retest reproducibility (ε<5% and DICE>0.80).

Conclusion

Our results support the use of volumetric measures derived automatically from larger amygdalar nuclei and hippocampal subfields as reliable measures in multisite longitudinal MRI studies. These measures could be useful for studies evaluating disease progression and treatment response.
Acute vascular dementia with bi‐thalamic infarction due to the artery of Percheron occlusion
Authors: Suen Mengfan , Zhang Qian , Chen Qidong , Xu Jun
Published: December 2020

Background

Previous studies reported the altered mental status and behavioral amnesic impairment were the dominated clinical findings in patients with bi‐thalamic paramedian infarction only due to the occlusion of the artery of Percheron(AOP). However, the clinical features of multidomain cognitive impairment because of bi‐thalamic paramedian infarction need to be clarified.

Method

We report a 72 year old male with a history of hypertension who presented an acute vascular dementia with a multidomain cognitive impairment including memory, attention, orientation. Laboratory test results were not remarkable. Brain magnetic resonance imaging (MRI) revealed a bi‐thalamic symmetrical paramedian infarction. Large arterial computed tomography angiography (CTA) showed the thinner right vertebrobasilar artery and atherosclerotic plaques in the beginning of both internal carotid arteries and the right subclavain artery. Transthoratic echocardiograp‐ ‐hy revealed left ventricular diaslolic dysfunction with ejection fraction of 60%. 24‐hour dynamic eletrocardiogram(Holter) revealed paroxymol atrial tachycardia. However, there was no evidence of cardioembolism.

Result

The diagnosis of cerebral infarction that causes vascular dementia with a presumed occlusion of the artery of Percheron resulting from atherosclerosis was made and the treatment of antiplatelate and improving cognition was provided.

Conclusion

This case illustrates vascular dementia resulting from bi‐thalamic paramedian infarction deserves clinical attention.
A double‐blind, placebo‐controlled study of the effect of a TNFα inhibitor, Etanercept, on microglial activation in amyloid PET‐positive patients with mild cognitive impairment due to AD‐intermediate likelihood
Authors: Gerhard Alexander , Jacobs Andreas H. , Goerttler Tsepo , Sharples Richard , Beardmore Rebecca C. , McDonald Katy R. , Visi Eszter , Hinz Rainer , Turkheimer Federico , Herholz Karl , Holmes Clive
Published: December 2020

Background

Previous studies have shown that systemic TNFα is associated with increased disease progression in AD and that this may be modulated by the anti‐TNFα agent Etanercept. The effect of Etanercept on microglial activation in patients with MCI due to AD is unknown.

Method

A total of 13 patients (from a planned 46 patients) with a clinical diagnosis of MCI due to AD were randomised to receive either placebo or 50 mg of Etanercept (weekly s.c injection) over one year. Aß deposition was established by AmyvidTM ([18F]Florbetapir‐PET) scan. Clinical assessments, [11C]‐(R)‐PK‐11195 PET (a marker of microglial activation) and [18F]Florbetapir‐PET were performed at baseline and after 1 year.

Result

10 out 13 enrolled participants completed the whole study. 6 on Etanercept and 4 on placebo. The region of interest analysis of the [11C]‐(R)‐PK‐11195 binding potential (BP) at baseline showed a widespread increase in MCI patients as compared to age‐matched controls with the cingulate gyrus being targeted. When comparing the change of regional and global PK11195 BP for these 10 patients between baseline and follow‐up after one year, there were no significant differences in the placebo or in the active drug group. Likewise, we found no major changes in measurement of memory function or other cognitive tasks in those subjects taking Etanercept compared with placebo. However, study power was severely compromised.

Conclusion

MCI patients show increased microglial activation as compared to healthy controls. In our relatively small treatment group Etanercept does not seem to modify microglial activation as measured with [11C]‐(R)‐PK‐11195 PET.
Plasma amyloid‐beta42/40 ratio as biomarker of cerebral amyloidosis in cognitively unimpaired APOE‐e4 homozygotes, heterozygotes and non‐carriers
Authors: Jansen Willemijn J. , Ghisays Valentina , DeMarco Kathryn L. , Boker Connie A. , Chen Kewei , Chen Yinghua , Luo Ji , Protas Hillary D. , West Tim , Meyer Matthew , Kirmess Kris , Verghese Philip B. , Hu Helen , Yarasheski Kevin E. , Su Yi , Reiman Eric M.
Published: December 2020

Background

Plasma amyloid‐β (Aβ) blood tests have great promise in research and care. C2N Diagnostics has developed a mass spectrometry‐based plasma Aβ42/40 assay (APTUSTM‐ pAβ42/40), which has previously demonstrated approximately 88% accuracy (81% sensitivity and 83% specificity; CTAD 2019) to distinguish between individuals with Aβ‐positive and negative (A+ and A‐) PET scans. We sought to characterize the assay’s ability to discriminate cognitively unimpaired APOE4 homozygotes, heterozygotes, and non‐carriers from the Arizona APOE Cohort.

Methods

Plasma Aβ42/40 concentration ratios and APOE4 gene dose (0, 1, 2 alleles) were characterized blindly using 0.5 cc plasma aliquots from 121 cognitively unimpaired 66±8 (47‐85) year‐old participants, including 21 APOE4 homozygotes, 37 heterozygotes and 63 non‐carriers whose blood samples and PiB or florbetapir PET scans were acquired at the same visit. Neuropathologically validated PiB 1.47 and florbetapir 1.17 SUVR cut‐offs were used to determine A+ and A‐ PET scans. Receiver operating characteristic (ROC) analyses were performed calculating the areas‐under‐the curve (AUCs) before and after adjustment for APOE4 gene status or dose, age and sex. The optimal Aβ42/40 cut‐off, sensitivity and specificity were retrospectively characterized.

Results

Plasma Aβ42/40 ratios discriminated between individuals with A+ and A‐ PET scans with 0.87 and 0.89 AUCs, respectively, before and after adjustment for APOE4 status. Further adjustment for APOE4 gene dose, age and sex did not significantly influence these results. In the APOE4 status‐adjusted ROC, a plasma Aβ42/40 0.096 cutoff, with 91% sensitivity and 82% specificity had the maximum Youden Index. We observed trends of a greater percentage of A‐ PET APOE4 homozygotes than heterozygotes or non‐carriers being plasma A+ (29%, vs. 11%; p=0.08, and vs. 11%; p=0.05, respectively). Further, individuals with an A+ plasma test but an A‐ PET scan at baseline were at 9‐fold increased risk of conversion to A+ PET compared to individuals with an A‐ plasma test.

Conclusion

APOE4‐adjusted plasma β42/40 assays have great promise in AD research, prevention trials and clinical care, with demonstrated high accuracy for cognitively unimpaired persons with two, one or no copies of the APOE4 allele. This study suggests that an A+ plasma test result predicts progression from an A‐ to an A+ PET scan in the near future.
Screening characteristics of PSEN1 E280A mutation carriers and non‐carriers in the API Autosomal Dominant Alzheimer’s Disease Colombia Trial
Authors: Rios‐Romenets Silvia , Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Tobon Carlos , Ramos P Claudia , Lopez Hugo , Aguirre‐Acevedo Daniel C. , Muñoz Claudia , Bocanegra Yamile , Henao Eliana , Tirado Victoria , Ospina Paula , Sink Kaycee M. , Hu Nan , Langbaum Jessica B. , Reiman Eric M. , Tariot Pierre N. , Lopera Francisco
Published: December 2020

Background

The Colombia Alzheimer’s Prevention Initiative (API) Registry was a resource for enrollment into the API Colombia clinical trial. Potentially eligible candidates from the Colombia API Registry went through a prescreening and then in‐person screening process with the goal of enrolling them in the API ADAD Colombia Trial. Analysis of screening data might provide additional information to consider for other AD prevention trials. We present descriptive screening data from the API ADAD Colombia trial in Presenilin 1 (PSEN1) E280A mutation carriers vs non‐carriers.

Method

Consent was obtained from 319 potentially eligible participants after prescreening. Screening data from 315, including 210 mutation carriers, were used to compare demographics, medical comorbidities, toxic and reproductive antecedents, selected clinical, functional, and anthropometric measurements, vital signs, and brain MRI and laboratory results in the mutation carrier and non‐carrier groups. Descriptive statistics comparing mutation carriers and non‐carriers were performed using generalized linear regression models using link function according to whether the outcome was categorical or numerical. Results were adjusted for age, sex, level of education, depression or body mass index (BMI) depending upon which measurements were compared.

Result

Results of the above characteristics at screening for carriers and non‐carriers will be presented. Briefly, compared to mutation non‐carriers in screening, carriers were younger (mean 40 vs 48 years), had similar educational attainment (mean 8.3 vs 7.5 years), and showed generally lower cognitive performance, especially in memory (e.g., mean (sd) CERAD world list scores were 20.30 (3.82) vs 19.46 (3.68), respectively). There were no differences in other demographic characteristics, medical comorbidities, toxic and reproductive antecedents, anthropometric measurements, vital signs, MRI findings or laboratory results. Mutation non‐carriers compared to carriers showed a non‐significant trend towards more vascular risks according to medical comorbidities (hypertension, dyslipidemia), borderline higher level of triglycerides and cholesterol, microvascular changes in the brain and higher BMI. The higher prevalence of vascular risk factors among non‐carriers may be explained by an 8‐year age difference between non‐carriers vs carriers.

Conclusion

The API ADAD Colombia Trial screening data provide insights into demographics as well as clinical, cognitive and non‐cognitive characteristics, and medical comorbidities of a (PSEN1) E280A population.
Identifying early markers of synaptic dysfunction in a mouse model of tauopathy
Authors: Meftah Soraya , Witton Jonathan , Cavallini Annalisa , Murray Tracey K. , Jankowski Lukasz , Bose Suchira , Ashby Michael , Brown Jonathan T.
Published: December 2020

Background

Synaptic degeneration is currently the best correlate of cognitive decline in Alzheimer’s Disease. Tau pathology, one of the hallmarks of the disease, correlates well with synaptic degeneration and has been shown to abnormally mislocate to synapses in the disease. This process is thought to induce changes in the activity, number and structure of synapses leading to widespread synaptic dysfunction prior to neurodegeneration. However, the precise mechanistic and functional changes are unclear. Therefore, identifying early markers of synaptic dysfunction will provide novel insights into mechanistic changes that precede neurodegeneration and underlie symptomatic onset in tauopathy.

Method

To investigate this, we used a multi‐faceted approach to characterise synaptic changes in the somatosensory cortex of the rTg4510 model of tauopathy, just prior (5.5 months) and post (7.5 months) neurodegeneration. Synaptic, neuronal and network function was assessed using in vitro and in vivo whole‐cell patch clamp electrophysiology, which allows for post‐hoc complementary analysis of morphology in recorded neurons. Protein expression of glutamatergic receptors, synaptic markers and tau were also quantified in crude synaptosomes by western blot.

Result

Prior to neurodegeneration, glutamatergic synaptic function was altered (decreased NMDA:AMPA ratio) and dendritic structure was altered (increased branching proximal to soma). Protein expression of synaptic markers and AMPA receptors were significantly decreased in the somatosensory cortex. Post neurodegeneration, a reduction in AMPA mediated synaptic communication was observed (sEPSC frequency), matched with a progressive decrease in AMPA receptor expression and the synaptic marker, PSD95.

Conclusion

Our results suggest that glutamatergic signalling is altered differently at the regional and single cell level just prior to neurodegeneration. For example, whilst regional AMPA receptor expression decreases pre‐neurodegeneration in the brain, it appears to be partially compensated for functionally within single neurons and the larger network. We predict that there may be a degree of compensation within the network, which when past a threshold leads to widescale network alterations and symptomatic changes. Deconstructing how functional compensation occurs in the brain in neurodegenerative diseases will shed light on how to delay symptomatic onset in tauopathies.
EVOO polyphenols can relieve autophagy dysregulation in Alzheimer's disease
Authors: Leri Manuela , Stefani Massimo , Bucciantini Monica
Published: December 2020

Background

Autophagy, a key process involved in cell proteostasis, regulates lipid metabolism and organelle turnover and contributes to clear materials of endogenous or exogenous origin. Abnormalities in the autophagic flux may contribute to several pathophysiological conditions, associated with ageing and neurodegeneration. Alterations of the autophagy machinery are involved in the onset of Alzheimer’s disease (AD), the most common form of dementia in the elderly increasingly occurring in developed countries. Indeed, several studies have revealed that the maturation of autophagolysosomes and the inhibition of their retrograde transport creates favourable conditions for accumulation of the Ab peptide whose aggregation into extracellular plaques is considered a main responsible for neuronal damage in AD. Recent data have shown that oleuropein aglycone (OleA), a polyphenol found in olive oil (EVOO), stimulates cell defences against plaque‐induced neurodegeneration and triggers autophagy. After ingestion, about 30% OleA is metabolized to hydroxytyrosol (HT), the most powerful antioxidant compound in the olive tree.

Method

Accordingly, we investigated the molecular mechanism involved in autophagy activation by a mixture of OleA and HT. To this purpose, we performed a set of in vitro experiments on SH‐SY5Y cell model such as confocal microscopy;MTT assay; western‐blotting and ROS production evaluation, to extend and to deepen the knowledge on the molecular determinants of the beneficial properties of olive polyphenols.

Result

Our results show that a mix of OleA/HT is able to activate the autophagy pathway more than the same amounts (in molar terms) of OleA or HT. Moreover, a reduction of ROS production with a significant recovery of cell viability was observed in cells exposed to toxic Ab1‐42 oligomers.

Conclusion

These studies confirm and extend previous data and provide the rationale for consideration of these molecules as promising candidates for prevention and long‐term nutraceutical treatment of neurodegeneration or as molecular scaffolds for further pharmacological development.
The visual ventral network is disconnected in Lewy body dementia with visual hallucinations
Authors: Mehraram Ramtin , Taylor John‐Paul , Murphy Nicholas , Rodriguez Luis Peraza , Cromarty Ruth , Graziadio Sara , O'Brien John T , Killen Alison , Colloby Sean J , Kaiser Marcus
Published: December 2020

Background

Visual hallucinations (VH) are a common symptom in Lewy body dementias (LBD), which comprise dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Previous studies investigated functional brain network alteration associated with VH in different diseases. However, there is a lack of studies on VH in LBD, and a clear picture of the affected pathways is still missing. In this study, we used electroencephalography (EEG) to detect the weakened cortical connections and the functionally disconnected cortical regions in LBD with VH.

Method

Resting state eyes closed EEG signals (128 channels) were recorded from 45 LBD participants: 18 without VH (eight DLB) and 27 with VH (13 DLB). EEG time series were filtered (bandpass: 8‐13 Hz), and cleaned from artefacts. Magnetic resonance imaging (MRI) recordings were individually obtained with magnetisation prepared rapid gradient echo (MPRAGE) sequence, and source estimation was performed with sLORETA technique (Destrieux atlas). Connectivity was measured with weighted phase lag index (WPLI), and assessed with Network Based Statistics (NBS), including the MMSE score as covariate. Node strengths of the subnetworks detected with NBS was computed. The visual hallucination score was collected through the NPI questionnaire.

Result

The NBS revealed two subnetworks affected in VH, both comprising regions belonging to the visual ventral pathway (p<0.05, t>3.8). The first one (Figure 1) comprised connections between the right temporal lobe and the prefrontal cortex, which showed reduced strength. In the second one (Figure 2), contra‐lateral connectivity between occipital and right infra‐temporal lobe was significantly weakened.

Conclusion

We propose a topography of the subnetworks affected in LBD with VH. The first and second subnetworks comprise regions involved respectively in the top‐down and bottom‐up visual perception streams. Our results resonate with the literature related to the pathology of LBD and VH. We found indeed that both affected subnetworks comprise the right inferior temporal lobe, which has been previously found to show a great burden of Lewy bodies in patients with VH. Our results support EEG as a suitable biomarker for assessing the severity of the pathology, and providing useful insights into the disease.
Promoting sustainable dementia education in African American communities
Authors: Lucas John A , Robinson Maisha T , Bergeron Caroline D , Willis Floyd B , Parfitt Francine C , Graff‐Radford Neil R
Published: December 2020

Background

African Americans are at higher risk of developing Alzheimer’s disease (AD) and AD‐related dementia. They are also more likely to live in communities with fewer dementia resources. The 2011 National Alzheimer’s Project Act calls for special attention to dementia‐related health disparities in high risk groups. Ensuring access to dementia‐specific information is one tactic for addressing disparities; however, the method by which information is delivered may play a role in how effectively that information is understood and retained over time.

Method

We delivered the same dementia education presentation to two comparable, predominantly African American neighborhoods in Jacksonville, FL. In one (intervention) community, the presentation was followed by an hour‐long focus group on what makes a community “dementia friendly”, using modified materials from the Dementia Friendly America (DFA) toolbox. In the other (control) community, the presentation was followed by a social hour allowing participants to interact with presenters and ask questions informally. Our primary objective was to assess the impact of the different conditions on AD knowledge.

Results

A 7‐item scale assessing AD knowledge was administered to immediately before and after the educational presentation (pre‐test, immediate post), and again two months later (Intervention group n=40; Control n=37). Additional, one‐year follow‐up was completed on the intervention community (n=21). Groups did not differ in AD knowledge at pre‐test (M=4.5 vs. 4.2, p=NS). At immediate post‐test, both groups improved their scores, but there was again no difference between groups (M=5.8 vs. 5.4, p=NS). At two‐month post‐testing, both groups declined in their knowledge score, but the control group declined more precipitously, yielding a significant group mean difference (M= 5.4 vs. 4.7, p=0.02). At one year follow‐up, a subsample of the intervention group (n=21) was re‐examined and demonstrated no significant decline in knowledge scores as compared to 2‐month follow‐up (M=5.7 vs. 5.4, p=0.36).

Conclusion

Results suggest that focus group discussion following dementia education as per the DFA model may contribute to greater retention of information and exert a sustainable impact on AD knowledge over time in an African American community setting.
Ultra‐performance liquid chromatography‐tandem mass spectrometry method for analysis of tau in human cerebrospinal fluid without the need of immunocapture
Authors: Korecka Magdalena , Leinenbach Andreas , Gobom Johan , Delatour Vincent , Becher Francois , Blennow Kaj , Zetterberg Henrik , Pannee Josef , Hofving Katarina , Shaw Leslie M.
Published: December 2020

Background

Reliable tau protein measurement in CSF is required for detection of Alzheimer’s disease pathology when combined with Aβ42/40 measurement. Tau is present at a very low concentration in CSF, has 6 different isoforms and many forms with post‐translational modification including methylation, glycosylation and phosphorylation. Immunoassays are sensitive enough to measure low tau concentration however poor linearity and lack of specificity in regards to tau’s isoforms have been reported. Thus, mass spectrometry is a candidate alternative technology. Additionally, the possibility of avoiding immunocapture would be important for a protein with multiple isoforms.

Method

Here we describe our efforts to develop an LC‐MS/MS (triple quadrupole) assay for quantification of tau in CSF. Sample preparation includes selective protein precipitation, neutralization and on‐filter digestion with trypsin without the need of immunocapture. Following trypsinization the peptide mixture is washed/centrifuged through the filters, injected onto the analytical column and eluted with water/ acetonitrile/0.1% formic acid gradient. For quantification we use the tryptic peptide ‐ GAAPPGQK [(156‐163, m/z‐ 363.26/526.28 (quantifier ion)], which is present in all tau isoforms and does not contain a phosphorylation site, and whose quantity is directly proportional to tau concentration. The same peptide labelled with 15N is used as the internal standard (IS) (m/z‐ 368.19/267.14 and 368.19/533.28, quantifier ions).

Result

The method is still under development however several parameters have been established: surrogate matrix (0.5% serum in water), amount of IS added at the beginning of sample preparation (4ng/mL), lower (350pg/mL) and upper (30000pg/mL) limit of measuring interval, analytical recovery of human peptide from the filters (67‐83%), duplicates precision (5.0 3.9%). No background peaks found at the retention time of the analyte/IS from a matrix‐matched double blank sample confirms good assay specificity. Collection of a full set of imprecision/accuracy data using surrogate matrix and human CSF are underway.

Conclusion

The assay will be assessed for tau quantification in human CSF by evaluating each parameter of the full validation process. This newly developed and validated assay will be important for direct measurement of tau in CSF samples, and may be applied as a candidate reference measurement procedure for CSF tau in standardization projects on this biomarker.
Evaluation of the effects of a systematized music stimulation program on cognition and mood aspects of the elderly: The possibility of cognitive rehabilitation based on art in the Brazilian Amazon
Authors: Silva Vanessa Feitoza , da Silva Laís Rafaelly Rodrigues Justino , Pinheiro Livian Maria da Silva , de Almeida Maria Emília Pirovano , Bozi Brenno Silva , de Lima Lucas Aguiar , da Silva Lucia Cristina Cavalcante , Shigaeff Nadia
Published: December 2020

Background

In Brazil, the elderly population has the highest growth rate. The estimated number of aged is 32 million for the year 2020. The city of Maraba, in the state of Para, located in and Brazil's Amazon region presents a very low Urban Development Index for Longevity. Previous studies have shown that music can enhance the willingness of the elderly to participate in other social activities, contributing to social interaction and, consequently, to prevention of depression. In addition to an important resource to stimulate memory and attention.

Method

The study was developed with 13 elderly from two public long term care institutions who completed all the stages of this study. They were evaluated through a neuropsychological assessment tool. It was composed of 9 objective tests about memory, executive function, attention, praxis and information processing speed. The instruments was applied in two moments: before and after the musical stimulation intervention which consisted of 12 weekly sessions lasting one and a half hours.

Result

92.3% were man, 69.2% aged 60‐70 years and 73% with a low level of formal education (Table 1). All had the diagnosis of mild to moderate dementia. There was significant improvement in cognitive performance of sustained attention and immediate recall short‐term memory between the baseline application and the post‐intervention (‐3.8 ± 2.0 vs. ‐2.2 ± 1.8, p = 0.07 and 3.6 ± 1.1 vs. 4.8 ± 2.0, p = 0.02, Table 2 and Figures 1 and 2). Significant improvement in mood symptoms was also observed (5.5 ± 2.0 vs. 4.5 ± 1.8, p = 0.04, Table 2 and Figure 3).

Conclusion

The results corroborate with other studies, demonstrating the effectiveness of musical stimulation as a way to slow the progression of cognitive impairment, also contributing to euthymic mood. Thus, this would be an accessible and low cost technique for performing cognitive stimulation/rehabilitation in elderly with dementia and possibly delaying the onset or progression of mood and/or cognitive symptoms. Even to elderly people living in long‐term care institutions who show a faster progression of cognitive decline compared to community‐dwelling elderly also benefit from this intervention strategy.
Combined caloric restriction and exercise provides the best benefit in obese brain
Authors: Pratchayasakul Wasana , Mantor Duangkamol , Suparan Kanokphong , Sangtragul Teepaka , Keawtep Puntarik , Chunchai Titikorn , Kerdphoo Sasiwan , Jaiwongkam Thidarat , Palee Siripong , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: December 2020

Background

Lifestyle modification, including dietary intervention or exercise training, has beneficial effects on the improvement of metabolic and brain function in cases of metabolic syndrome, diabetes and Alzheimer’s disease. However, the comparative effects of calorie restriction, exercise training, and a combination of calorie restriction and exercise training on brain and cognitive function in the obese condition have not been thoroughly investigated. Our hypothesis is that both calorie restriction and exercise training improve brain and cognitive function in an obese condition, but a combination of these two therapies has a greater efficacy in the restoration of brain functions and cognition than either single therapy.

Method

Twenty‐five female rats were fed with either a normal diet (ND; n=5) or a high‐fat diet (HFD; n=20) for 27 weeks. At week 20, the ND‐fed rats were assigned to a sedentary lifestyle (NDS; n=5), and HFD‐fed rats were assigned to either a sedentary lifestyle (HFS; n=5), calorie restriction (HFCR; n=5), exercise (HFEX; n=5) or a combination of calorie restriction and exercise (HFCB; n=5) for 7 weeks. After that, metabolic parameters, brain parameters and cognition were determined.

Result

HFD‐fed rats developed insulin resistance and cognitive decline via increased oxidative stress, inflammation, apoptosis, and synaptic dysfunction in the hippocampus. Calorie restriction decreased metabolic disturbance, decreased inflammation and oxidative stress in the hippocampus, but failed to improve cognition in HFD‐fed rats. Exercise attenuated metabolic disorders, oxidative stress, inflammation, apoptosis, and synaptic dysfunction, resulting in improved cognition in HFD‐fed rats, while the combined therapy had the greatest beneficial effect on this improvement (p<0.05, Figure 1).

Conclusion

A combination of calorie restriction and exercise may be the best therapeutic approach for the restoration of brain and cognitive function in the obese condition.