bluuebunny/crossref_metadata_2025 huggingface dataset:
The Positive and Negative Appraisals of Caregiving (PANAC) scale: A new measure to examine the caregiving experience in Alzheimer’s disease and related dementias
Authors: Galvin James E
Published: December 2020

Background

Caregiving in Alzheimer’s disease and related dementias (ADRD) has long been examined as a monolithic experience describing the burdens and challenges that caregivers face. These studies typically explore one construct at a time, limiting the full understanding of the caregiver experience. In addition, there are few measures that examine the potential positive and rewarding experiences associated with caregiving. The absence of exploring these constructs may limit the exploration of how caregiver interventions may or may not succeed in meeting their primary outcomes. To address this, we developed a new scale: The Positive and Negative Appraisals of Caregiving (PANAC).

Methods

The PANAC scale was first explored in a developmental sample of 256 consecutive patient‐caregiver dyads and then validated in an independent sample of 274 consecutive patient‐caregiver dyads presenting to our center for clinical and/or research evaluations. Factor analyses using principle components with a Varimax rotation was performed revealing a two‐factor solution: Positive appraisals and Negative appraisals. Total PANAC scores, individual factors, and the ratio of positive to negative appraisals were examined for their psychometric properties and compared with patient and caregiver characteristics and caregiver reports of burden, grief, preparedness, mood, mindfulness, and care confidence.

Results

A two‐factor solution revealed a Negative Appraisal factor (Eigenvalue: 4.1; 25.8% of variance) and a Positive Appraisal factor (Eigenvalue 3.3; 20.9% of variance). Internal consistency was good with Cronbach’s alpha 0.74 for the total PANAC, 0.82 for Negative appraisals, and 0.80 for Positive appraisals (all F‐test p<0.001). Negative appraisals were highly correlated with patient cognitive performance, mood, quality of life, behavior, daily functioning, and frailty as well as with caregiver burden and depression. Positive appraisals were highly correlated with caregiver mindfulness. The ratio of Negative to Positive appraisals was derived to give an overall experience of the caregiver.

Conclusions

The PANAC scale is a useful global measure of the overall caregiver experience accounting for both negative and positive experiences associated with ADRD caregiving. The PANAC can be used to measure effectiveness of caregiver interventions and with the use of the Negative to Positive ratio, may be used to tailor programs to the individual caregiver.
Locus coeruleus signal intensity in progressive amnesia due to suspected non‐Alzheimer pathophysiology (SNAP)
Authors: Olivieri Pauline , Lagarde Julien , Lehéricy Stéphane , Valabrègue Romain , Caillé Fabien , Gervais Philippe , Bottlaender Michel , Sarazin Marie
Published: December 2020

Background

Suspected non‐Alzheimer pathophysiology (SNAP) is underlain by different pathophysiological processes, among which the recently described Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which refers to patients with cognitive/memory impairment and limbic‐predominant TDP‐43 proteinopathy, associated or not with hippocampal sclerosis (HS) characterized by severe neuronal loss and gliosis in the CA‐1 and subiculum of the hippocampal formation (Besser and al. J Neuropathol Exp Neurol. 2019), or primary age‐related tauopathy (PART). The locus coeruleus (LC) is the major noradrenergic nucleus in the brain. In AD, the early LC neuronal loss could contribute to cognitive deficits, especially mental flexibility and memory retrieval impairments (Grudzien and al. Neurobiol. Aging, 2007). The involvement of LC alteration in amnestic SNAP patients has not been studied.

Method

We included 10 SNAP subjects defined by episodic memory deficit of the hippocampal type, normal CSF biomarkers profile and negative amyloid‐PET, 26 typical AD patients defined by clinical‐biological criteria (episodic memory deficit of the hippocampal type associated with CSF biomarkers AD profile and positive amyloid PET), and 14 controls with negative amyloid‐PET. All patients had a Clinical Dementia Rating scale ≤ 1. We used the LC signal intensity (LC‐I) on 3T MRI (Neuromelanin‐sensitive T1‐weighted images) as a marker of LC atrophy (Shibata and al. Magn Reson Med Sci. 2006).

Results

SNAP patients were older than AD patients (77.9 years and 70.8 years respectively, p=0.002), with a lower proportion of APOE4 carriers. We found no difference between SNAP and AD groups in neuropsychological scores, especially for MMSE, and verbal or visual episodic memory scores, as well as for hippocampal or entorhinal cortex volumes. We found a significant decrease of the LC‐I in SNAP patients compared with controls (p<0.003) or with AD patients (p<0.009). The episodic memory score was positively correlated with the LC‐I (r=0.33, p=0.034) in SNAP patients.

Conclusion

Our results suggest a significant LC alteration in patients with amnesia not due to AD. LC involvement could not be specific of AD pathology, and could also be part of the pathophysiological process of non‐AD diseases. Amnestic SNAP patients could thus benefit from innovative therapeutic approaches targeting the noradrenergic system.
Predictors of quality of life in Chilean family caregivers of people with dementia
Authors: Miranda‐Castillo Claudia
Published: December 2020

Background

In Chile, it is estimated that about 200.000 persons have dementia and this number will triplicate by 2020. Most care is provided by family caregivers who experience a negative impact on their physical and mental health. The aim of this study was to identify which factors from family caregivers and the person with dementia (PwD) were related to caregiver’s quality of life.

Method

This was a cross‐sectional study. The sample was composed by 90 family caregivers of PwD living in the community. Caregivers were interviewed about PwD’s quality of life, cognitive function, functionality and neuropsychiatric symptoms. They were also asked about their own quality of life, dysfunctional thoughts about caregiving, frequency and satisfaction with pleasant activities, burden, anxiety, depressive symptoms and the stress generated by PwD’s neuropsychiatric symptoms.

Result

None of the PwD’s factors were directly associated with caregivers’ quality of life. However, caregivers with higher levels of stress generated by PwD’s neuropsychiatric symptoms showed significant lower quality of life (r=‐0.22; p<.01). In addition, caregivers with higher levels of anxiety (r=‐0.45; p<.01), depression (r=‐0.45; p<.01) and burden (r=‐0.41; p<.01) plus lower frequency (r=0.31; p<.01) and satisfaction (r=0.41; p<.01) with pleasant activities had significantly worse quality of life. Finally, anxiety and depressive symptoms explained 25% of the variability in caregivers’ quality of life (F=14.1; p<.01).

Conclusion

In order to improve family caregivers’ quality of life it is essential that dementia public policies address their needs. Interventions focused on improving their mental health should consider not only pharmacological approaches but also psychosocial and psychotherapeutic ones which could help with both, the management of PwD’s neuropsychiatric symptoms and the reduction of depressive and anxiety symptoms.
Development of a robust and stable mass based spectrometry method for analysis of Alzheimer’s disease biomarkers in human cerebrospinal fluid
Authors: Leslie Shannon N. , Wilson Rashaun , Trombetta Bianca A. , Kivisäkk Pia , Arnold Steven E. , Nairn Angus C. , Carlyle Becky C.
Published: December 2020

Background

Current diagnostic tests for Alzheimer’s Disease (AD) rely predominantly on amyloid‐beta and tau measurements. However, these markers are insufficient to predict onset of disease, response to treatment, and do not capture the full spectrum of disease progression. Thus, a more expansive approach to diagnostic markers is required. Given the low abundance of putative proteins of interest in biofluids and the impact of relatively small changes in protein levels on the function of central nervous system, a highly sensitive but broad approach to protein monitoring is essential to identifying more comprehensive biomarkers. Data‐independent acquisition (DIA) mass spectrometry is an important tool for achieving this goal given both breadth and depth of protein analysis it enables. Thus, we developed a DIA method that allows for technically reproducible monitoring of thousands of peptides in human cerebrospinal fluid (CSF) to better characterize effective candidate peptides for the development of future targeted biomarker assays.

Method

Human CSF was analyzed via liquid‐chromatography tandem mass spectrometry (LC‐MS) with a data‐independent acquisition (DIA) technique. Stable isotopic peptides, enriched for putative proteins of interest to AD diagnostics, were used to create a heavy peptide standard mix. We characterized the stability and linearity of these peptides for use as a normalization tool. Utilizing this well characterized standard mix, we analyzed 30 samples from 15 patients collected at 2 different sites using DIA LC‐MS. Samples included a variety of disease states as well as longitudinal samples to assess both technical and biotemporal stability of peptides.

Result

Our novel heavy peptide standard mix showed strong technical reproducibility and linear coherence with concentration. We were able to minimize and control for technical variation utilizing this standard mix; thus, enabling better cross‐sample comparisons of peptides. We characterized the technical reproducibility and stability of our methodology for thousands of peptides across a variety of technical and biological conditions. Overall, this methodology enables stable characterization of peptides across longitudinal samples and between disease conditions.

Conclusion

We have developed a robust approach for stable monitoring of hundreds of proteins in human CSF, an important step toward utilization of novel biomarkers in AD diagnostics.
Sex differences in red blood cell α ‐synuclein protein and its heteroaggregates with amyloid‐β and tau in early Alzheimer’s disease
Authors: Prete Eleonora Del , Daniele Simona , Giampietri Linda , Galgani Alessandro , Piccarducci Rebecca , Gerfo Annalisa Lo , Petrozzi Lucia , Cavallini Chiara , Pietrobono Deborah , Trincavelli Maria Letizia , Frosini Daniela , Siciliano Gabriele , Bonuccelli Ubaldo , Ceravolo Roberto , Tognoni Gloria , Martini Claudia , Baldacci Filippo
Published: December 2020

Background

A growing interest is recently focused on sex‐related differences in Alzheimer’s Disease (AD) pathology to optimize patients stratification and to personalize treatment. Among markers that are expression of this neurodegenerative disease, red blood cells (RBCs) levels of α‐synuclein (α‐syn) and its heterocomplexes with amyloid‐β (Aβ) and tau have been proposed as peripheral biomarker of AD. The aim of our study was to explore sex differences in RBC levels of α‐syn and its heterocomplexes in a group of AD/ mild cognitive impairment due to AD (MCI‐AD) patients and of Healthy Controls (HC).

Method

Differences between male and female sex matched for age were investigated in RBC regarding homo‐ and heteroaggregates of α‐syn, Aβ and tau [total tau (t‐tau) , Aβ42 ,total α‐syn (t‐ α‐syn), oligomeric α‐syn (o‐α‐syn), α‐syn/Aβ and α‐syn/tau] in a cohort of AD/MCI‐AD patients in early stages of disease and in HC.

Result

In our study 147 subjects were enrolled, 47 AD, 40 MCI‐AD and 60 HC. In AD/MCI‐AD cohort we identified significant differences in t‐tau levels between sex (p=0.010), with higher value in men than women (6.1±5.9ng/mg vs 4.0±6.8ng/mg), no significant differences Aβ42 , t‐α‐syn, o‐α‐syn, α‐syn/Aβ and RBC‐α‐syn/tau. In HC group we reported significant differences in Aβ42 (p=0.014) and α‐syn/tau (p=0.030). In particular, women presented higher Aβ42 and α‐syn/tau compared to men (18.22±12.19 ng/mg vs 13.31±13.86 ng/mg and 2.93±1.67 ng/mg vs 1.95±1.75 ng/mg, respectively). Mean age for the group AD/MCI‐AD was 72.5±6.61yy for women and 71.9±6.43 yy for men, while mean age was 62.38±8.48 yy for women and 66.20 yy for men in HC group. Comparison in biomarkers between AD/MCI‐AD and HC was not performed due to significant differences between age p<0.001 in women and p=0.003 in man.

Conclusion

Sex differences in RBC biomarkers for AD were identified in AD/MCI‐AD patients and in HC. Women reported higher levels of RBC Aβ42 and RBC α‐syn/tau than men in HC, while RBC t‐tau concentrations were higher in men than in women in AD/MCI‐AD cohort. Although additional investigations in larger samples are needed to confirm our data, a different distribution of neurodegenerative biomarkers in men and women is likely.
The validity and reliability of the digital Ruff Figural Fluency Test (RFFT) in the general adult population
Authors: Vrijsen Joyce , van Erpecum Carel‐Peter , Niebuur Jacobien , Smidt Nynke
Published: December 2020

Background

The Ruff Figural Fluency Test (RFFT) is a valid pencil‐and‐paper test for evaluating cognitive functioning in the general population. The assessment of the pencil‐and‐paper‐RFFT is time‐consuming and requires training of raters. We developed a digital‐RFFT which can be filled in by people independently on an Ipad, after which RFFT patterns are automatically processed and stored. We aimed to investigate the validity and reliability of the digital‐RFFT in the general population.

Method

Stratified randomization (based on age, gender, and education) was used to allocate participants either to the digital‐RFFT or the pencil‐and‐paper‐RFFT. After the first test, the other test was repeated (cross‐over). The number of unique designs and perseverative errors of the pencil‐and‐paper‐RFFT and digital‐RFFT were assessed by an computerized algorithm (automatic) and by two independent trained human raters (criterion standard). For the statistical analysis, we used Intraclass correlation coefficients(ICC), sensitivity, specificity, %agreement, weighted Kappa, and Bland Altman plots, including limits‐of‐agreement(LoA).

Results

The study population comprised 96 participants (58% women; mean(SD) age 40(15)years). The mean(SD) number of unique designs was 84.2 (26.0) (automatic assessment) and 85.3 (26.2) (human assessment) for the digital‐RFFT and 91.3 (22.7) for the pencil‐and‐paper‐RFFT. The median number(IQR) of perseverative errors was 4(2‐7) (automatic assessment) and 4.5(2‐8) (human assessment) for the digital‐RFFT and 4.5(2‐7.5) for the pencil‐and‐paper‐RFFT. The percentage agreement (kappa) between the two human raters for the digital‐RFFT and pencil‐and‐paper‐RFFT was 0.94(0.90) and 0.94(0.81), respectively. ICC between human assessment and automatic assessment of the digital‐RFFT (unique designs) was 0.988(95%CI:0.981‐0.992); sensitivity and specificity was 0.98 and 0.96 respectively; mean difference(95%CI):‐1.12(‐1.92,‐0.33); 95%Limits‐of‐Agreement ‐8.75,6.51). The ICC between digital‐RFFT and pencil‐and‐paper‐RFFT was 0.53(95%CI 0.37,0.67). When starting with the paper‐and‐pencil‐RFFT, this ICC was 0.73 (95%CI:0.34,0.87). The mean difference (unique designs) between the digital‐RFFT and pencil‐and‐paper‐RFFT was ‐7.09 (95%CI ‐11.8 to ‐2.38 (95%limits‐of‐agreement: ‐52.12, 37.94). This was due to unclear instructions (i.e. complex examples) that were given on the Ipad (digital‐RFFT) and learning effect.

Conclusions

Although small and systematic differences between human assessment and automatic assessment of the digital‐RFFT were found, we conclude that the digital‐RFFT is a valid test to assess cognitive functioning among the general population if instructions of the digital‐RFFT are improved.
Effects of bibliotherapy on improving caregiving appraisal and coping among informal caregivers of people with dementia: A pilot randomized controlled trial
Authors: Wang Shanshan , Cheung Daphne Sze Ki , Leung Angela
Published: December 2020

Background

The number of people with dementia is increasing worldwide, and the majority are cared for by informal caregivers in home settings. Both positive and negative caregiving outcomes have been found among informal caregivers, the essential determinant was caregiving appraisal. Improving their caregiving appraisal is important for both the caregiver and care‐recipient’s health. However, as professional support for informal caregivers are limited, self‐help approaches are needed. Bibliotherapy, a self‐help intervention requiring minimal professional support, has been proved to be effective on improving caregiving appraisal in other populations, the effect on dementia caregivers is yet to be explored. Objectives: To explore the efficacy of bibliotherapy on improving caregiving appraisal and coping among informal caregivers of people with dementia.

Method

A two arm randomized controlled trial was conducted in Zhengzhou, China. Participants were randomized to either the intervention group, receiving 8 weekly bibliotherapy sessions at home without withdrawing from usual care; or the control group, receiving usual care from the community health centers. Assessors were blinded to group allocation. Generalized estimating equation was used for data analysis.

Results

Sixty participants were recruited, and 24 out of 30 participants in the intervention group finished the intervention. Bibliotherapy had significant group (Wald χ2=4.98, p=0.026), time (Wald χ
2=15.27, p<0.001) and group‐by‐time interaction effects (Wald χ2=16.51, p<0.001) on the total score of caregiving appraisal. In terms of the subscales, there were significant time effects on subjective burden (Wald χ2=8.81, p=0.003), caregiving impact (Wald χ
2=11.31, p=0.001) and caregiving mastery (Wald χ
2=11.74, p=0.001), and significant group effects on caregiving satisfaction (Wald χ
2=7.39, p=0.007). The group‐by‐time interaction was significant on all the subscales (Wald χ2=5.38‐10.89, p=0.001‐0.020). Bibliotherapy also had significant group (Wald χ2=10.93‐15.24, p<0.001), time (Wald χ
2=10.99‐33.02, p<0.001) and group‐by‐time interaction (Wald χ
2=8.91‐17.80, p=0.001‐0.003) effects on the total score of coping and the positive coping subscale. However, the effects on negative coping were not significant (Wald χ
2=0.53‐3.17, p=0.075‐0.467). No adverse events were found.

Conclusion

Bibliotherapy had significant preliminary effects on improving caregiving appraisal and positive coping. The effect on negative coping is still limited. Future randomized controlled trials with larger sample sizes and long‐term follow‐ups are encouraged.
Dual‐task gait and cognitive performance in midlife type 2 diabetes mellitus (T2DM): Baseline data from ENBIND
Authors: Dyer Adam H , McKenna Louise , Gamage Githmi , Killane Isabelle , Woods Conor , O'Neill Desmond , Gibney James , Bourke Nollaig , Reilly Richard , Kennelly Sean
Published: December 2020

Background

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of dementia in later life. Despite this, few studies have examined the utility of midlife biomarkers to predict later cognitive decline in T2DM. We evaluated the association between dual‐task gait speed and cognitive performance in midlife T2DM as part of ENBIND Study.

Method

Participants with midlife T2DM and matched healthy controls were recruited. Participants with T2DM only included if they had no micro/macrovascular complications of T2DM. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and computerised neuropsychological assessment battery (CANTAB®). Gait was assessed using both stopwatch and accelerometry across four tasks: (i) self‐selected (usual) gait speed, (ii) maximal gait speed and (iii) dual‐task gait speed (reciting alternate letters of the alphabet). Appropriate univariate statistics in addition to Poisson and linear models were used to analyse results.

Results

102 cognitively‐intact middle‐aged (52 ± 7.9 years) adults with (N = 71) and without (N = 31) T2DM were recruited. T2DM was associated with a greater likelihood of error on the MoCA (IRR = 2.36, 1.53‐3.64, p<0.001) which persisted after covariate adjustment. T2DM was associated with poorer performance on reaction/movement time, executive function, attention and visuospatial memory tasks, however results were attenuated by covariate adjustment. T2DM was associated with slower gait speed on all three tasks (all p<0.001). Overall, self‐selected, maximal and dual‐task speed were associated with greater likelihood of error on the MoCA (all p<0.001). However, after robust adjustment for covariates, only the association for Dual Task Cost (DTC) persisted (p = 0.021). A DTC*T2DM interaction was not significant.

Conclusions

The current analysis showed diminished cognitive and gait performance in midlife T2DM vs. healthy controls. We observed significant associations between gait performance on the addition of a dual task and general cognitive function. This association, whilst greater in T2DM, was not T2DM specific and adds further evidence for the association between dual task‐gait and cognitive performance in midlife. Our findings support the ongoing exploration and use of gait as a physiological biomarker of overall cognitive function and warrants longitudinal investigation in this high risk group.
Reduction of anticholinergic cognitive burden (ACB) in primary care using a clinical decision‐support software (CDSS) platform
Authors: Zelek Mark C , Walker John Q , Sabbagh Marwan N
Published: December 2020

Background

Many oral medications can induce a level of “brain fog,” known as Anticholinergic Cognitive Burden. This cognitive burden can be quantified; a consensus on the scoring, from 0 (best) to 3 (worst), has been developed. Drugs with non‐zero scores span pharmacological classes, including antidepressants, antipsychotics, and urological treatments. Higher ACB scores have been correlated with lower performance in cognitive assessments; every 3 points of ACB score may reduce MMSE results by one. This burden confounds cognitive status (i.e., are medications causing observed cognitive impairment?). Recently, some ACB drugs have also been correlated with future dementia incidence.

Methods

uMETHOD Health has developed a CDSS platform to address dementia, MCI, and mild AD through the creation of personalized, multidomain treatment plans. The software sums the ACB score across all the medications in someone’s active medication list, showing their impact visually in the generated treatment plan. Drawing from multiple published sources, the platform evaluates 314 generic ACB drugs (including combination drugs). The treatment plans recommend alternatives for each drug with an ACB score of 2 or 3 (called definite anticholinergics). 2,566 individuals aged 65 to 102 comprise the population analyzed here.

Results

Individuals were an average of 9.5 medications (stdev: 6.5). 75.1% were on anticholinergic medications (mean: 3.4, stdev: 2.7). Had the 350 patients with an ACB score of 5 or more followed the platform recommendations, their average ACB score may have been reduced from 6.94 to 3.3, potentially improving their cognitive assessment performance. Females were taking more anticholinergic drugs than males (2.7 vs. 2.2) and had a higher average ACB score (3.7 vs. 2.7).

Conclusions

ACB drugs are confounders of cognitive decline, and some are contributors to it. Managing medications is a complex task, the complexity of which increases when dealing with an older population who are not only on more medications, but also have existing comorbidities. The CDSS platform identifies many polypharmacy problems; taking the recommended alternative medications to treat the same comorbidities could lower their ACB score significantly. Clinical professionals should consider ACB analysis part of every visit with their older patients, especially those evincing cognitive decline.
Feasibility and efficacy of the indoor cognitive training combined physical activity (ICT‐PA) program using wearable sensor and mobile device in subjects with mild cognitive impairment
Authors: Han Ji Won , Kim Grace Eun , Moon Woori , Han Ji Hyun , Shin Jeonga , Suh Seung Wan , Shin Jeong Hun , Jeong Won Kyo , Kim Ki Woong
Published: December 2020

Background

We developed the Indoor Cognitive Training combined Physical Activity (ICT‐PA) program using wearable sensor for location information. ICT‐PA consists of 1) memory registration of some specific indoor locations using a tablet device, 2) navigating those locations in order and recognition by Bluetooth Low Energy (BLE) tags installed at each of the above words, and 3) recall images placed together at each of the above recognition tags. ICT‐PA aimed to enhance 1) cognitive function by combining verbal/visual memory training and visuospatial navigation training and 2) indoor physical activities by walking during this sequential training. The objective of this study was to evaluate the feasibility and efficacy of ICT‐PA in elderly subjects with mild cognitive impairment (MCI).

Method

Forty‐three participants aged over 60 years old and diagnosed with MCI participated in the intervention program of 6 weeks. Feasibility was evaluated by checking the satisfaction of the participants with a 5‐point Likert scale. The efficacy of the program on cognitive functions was evaluated by the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery total score (CERAD‐TS) and Mini‐Mental State Examination (MMSE) before and after ICT‐PA. (ClinicalTrials.gov ID: NCT03928613)

Result

Thirty‐six participants completed both pre‐ and post‐ICT‐PA assessment. The overall satisfaction score was 7.7±1.6 out of 10. The mean CERAD‐TS scores significantly increased after ICT‐PA training (pre, 57.3 ± 11.3; post, 60.3 ± 13.1; p=0.006, paired t‐test), but MMSE did not. Subgroup analysis by compliance (equal to greater than 360 minutes of total use of the ICT‐PA) showed that the compliance group (N=26) improved the CERAD‐TS score (pre, 58.5 ± 11.7; post, 62.7 ± 12.9; p=0.002, paired t‐test), but non‐compliance group did not.

Conclusion

ICT‐PA was effective in improving cognition and was well tolerated by most participants with MCI. Further studies with large numbers of participants and randomized controlled trial are necessary, and the use of at least 60 minutes per week might be suggested. (This work was supported by Institute for Information & communications Technology Promotion (IITP) grant funded by the Korea government (MSIP) (No.2017‐0‐00662, Development of Smart Care system for Dementia Patients based on ICT)).
The burden of dementia and dementia due to Down syndrome, Parkinson’s disease, stroke, TBI, and HIV: An analysis for the Global Burden of Disease study 2019
Authors: Nichols Emma , Vos Theo
Published: December 2020

Background

In light of the increasing trends in the global number of individuals affected by dementia and the lack of any available disease‐modifying therapies, it is necessary to fully understand and quantify the global burden of dementia. Previous efforts to quantify the relationships between dementia and stroke, Parkinson’s disease, Down syndrome, traumatic brain injury and HIV, but these analyses have remained isolated and results have not been summarized across disease topics. We estimated the proportion of dementia due to Down syndrome, Parkinson’s disease, clinical stroke, TBI and HIV using consistent and comparable methods, in order to better understand their contribution to the prevalence of dementia.

Method

Through systematic review, we obtained data on the relative risk of dementia with each condition and found sufficient evidence to estimate relative risks for all clinical conditions except HIV. We then estimated relative risks by age using a Bayesian meta‐regression tool and calculated population attributable fractions (PAFs) using the estimates of relative risk and prevalence estimates for each condition from the Global Burden of Disease Study 2019. Finally, we multiplied these estimates by dementia prevalence to calculate the number of dementia cases attributable to each condition.

Result

The relative risk of dementia for all four conditions decreased with age. Relative risks were highest for Down syndrome, followed by Parkinson’s disease, stroke and TBI. However, due to the high prevalence of stroke, the PAF for dementia due to stroke was highest. Overall, Down syndrome, Parkinson’s disease, stroke and TBI explained 9.9% (5.9 to 16.4) of the global prevalence of dementia.

Conclusion

Less than 10% of dementia prevalence could be explained by Down syndrome, Parkinson’s disease, stroke and TBI. This result emphasizes the large fraction of dementia prevalence unexplained by the four diseases examined in this analysis, and highlights the need for additional epidemiologic research exploring lifestyle risk factors and further research in the basic sciences focused on elucidating intervention approaches to prevent or delay the neuropathological changes that characterize dementia.
Time to invest in nonpharmacological interventions for behaviours and psychological symptoms associated with dementia
Authors: Burley Claire V , Livingston Gill , Knapp Martin Richard John , Wimo Anders , Norman Richard , Brodaty Henry
Published: December 2020

Background

Behaviours and psychological symptoms associated with dementia (BPSD) affect up to 90% of people living with dementia and strongly correlate with functional and cognitive impairment (Cerejeira et al. 2012). BPSD cause high levels of distress for people living with dementia, families, carer partners and staff, and impose significant service‐related and other costs. Nonpharmacological person‐centred interventions can reduce agitation and other BPSD though uptake is limited. This is possibly due to concerns about cost and staff time, driven by insufficient awareness of studies that have focused specifically on economic analysis and demonstrated potential savings that can be made. We aimed to evaluate the cost‐effectiveness of non‐pharmacological interventions to reduce BPSD.

Method

We reviewed studies that calculated overall cost of BPSD symptoms, costs of individual BPSD (e.g. agitation), and costs of nonpharmacological interventions for reducing BPSD (i.e. cost per unit reduction on the Neuro‐Psychiatric Inventory (NPI) or Cohen‐Mansfield Agitation Inventory (CMAI)). Papers included cross‐sectional, prospective and longitudinal studies, intervention studies and one systematic review.

Result

Approximately 30% of total annual cost of a community‐dwelling person living with dementia is invested in the direct management of BPSD (Beeri et al. 2002). Agitation was reported to increase dementia costs by 17% per month in family care costs in a community home care setting (Costa et al. 2018) and 44% in total annual costs in a residential care home setting (Sköldunger et al. 2019). Linear regression approaches show several nonpharmacological interventions were effective in reducing agitation where the incremental cost per unit reduction in CMAI score ranged from £3 to £62 for person‐centred care training, £4 for music therapy, £24 to £143 for sensory interventions and £162 to £3480 for activities (Chenoweth et al. 2008; Livingston et al. 2014). Cost‐effectiveness was also demonstrated for physical activity reducing BPSD (D'Amico et al. 2016).

Conclusion

Potential savings and cost‐effectiveness gains can be made by investing in treatments for BPSD that are symptom‐targeted and person‐centred, providing strong incentives for service providers to adopt such interventions. Effective partnerships between care providers, researchers and government bodies, and targeted investments are required to support the initiation of these changes.
Global cognitive performance is not influenced by diurnal rhythm
Authors: De Jager Celine H , Burns Eleanna , Stern Yaakov
Published: December 2020

Background

There are conflicting reports on the extent to which cognitive performance varies over the course of the day and whether such effects change with advancing age.

Method

We used data collected in two longitudinal studies of cognitive reserve: Cognitive Reserve & Reference Ability Neural Network. We reviewed study documents and extracted the time of the day during which an individual’s cognitive battery. Of 543 subjects with available cross‐sectional data, 281 were tested in the AM and 242 in the PM. Mean age was 55 yo. 178 subjects were <50 yo. Multivariate models were used to evaluate the data.

Result

We found expected effects of age on cognitive performance, but we found no evidence supporting a difference in either global cognitive performance or of performance in one of the four tested domains in relation to time of day. Further, we saw no evidence for an interaction by age: age did not influence performance differences relative to time of day.

Conclusion

We have analyzed a large dataset of prospectively collected data in which we see no evidence that time of day influences results of cognitive testing. This analysis settles an important issue that could have implications on study design when subjects select study visits that are convenient for their schedule.
Discovery and development of multi‐target potential of flavonoids as potent acetylcholinesterase inhibitors and anti‐amnestic agents
Authors: Singh Manjinder , Arora Sandeep , Silakari Om
Published: December 2020

Background

Multi‐target compounds comprise a novel class of therapeutic agents for the treatment of multi‐factorial diseases like Alzheimer’s disease (AD). Following this approach, a new series of flavones were designed, synthesized and biologically evaluated against acetylcholinesterase (AChE), advanced glycation end products formation (AGEs) with additional free radical scavenging activity.

Method

On the basis of proposed hypothesis, 33 flavone derivatives were designed and subsequently synthesized and were primarily evaluated for in vitro AChE inhibitory, AGEs inhibitory and anti‐oxidative activity and prominent compounds further evaluated by in vivo anti‐amnestic activity. After that, molecular docking and Molecular dynamic simulations (MD) were carried out for the most potent compounds to study protein‐ligand interactions.

Result

The in vitro studies showed that the majority of synthesized derivatives inhibited acetylcholinesterase (AChE) with IC50 values in the nanomolar range. Additionally, these compounds also exhibited greater ability to inhibit advanced glycation end products formation in micromolar range with additional radical scavenging property in nanomolar range. The most active compounds were also ameliorated scopolamine‐induced amnesia in mice in terms of restoration of time spent in target quadrant (TSTQ) and escape latency time (ELT). Moreover, the molecular docking study displayed that most potent compounds simultaneously bind to catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.

Conclusion

In conclusions, the results support the proposed hypothesis that newly designed multi‐target flavones have the ability to act on different targets or exhibit multiple pharmacological activities related to Alzheimer’s disease. Thus, flavones might be the promising lead compound as potential multi‐target anti‐Alzheimer’s agents.
Development of a fast and versatile method for genome‐wide association studies of longitudinal data
Authors: Kleineidam Luca , Andrade Victor , Wagner Michael , Lambert Jean‐Charles , Ruiz Agustín , Ramirez Alfredo
Published: December 2020

Background

Apolipoprotein E ε4 shows a strong effect on the risk for developing Alzheimer’s disease (AD) but does not modulate the speed of cognitive decline after dementia onset. Accordingly, the influence of other genetic determinants might also change during the disease course of AD. To identify those determinants, methods are needed allowing for genome‐wide analysis of genetic effects using longitudinal data. Since the disease progression of AD, measured e.g as cognitive decline, may show a non‐linear trajectory over time, we developed a fast and flexible method for conducting genome‐wide association studies (GWAS).

Method

We extended the previously developed generalized least square approximation of linear mixed models (Rönnegard et al., 2016) to account for potential non‐linear trajectories. As GWAS studies usually combine results from different cohorts, this approach was combined with a partial derivative‐based meta‐analysis (Roshchupkin et al., 2016) that yields identical statistical power as pooled analysis but without the need of sharing individual participant data. To ensure suitability of our method, we conducted a Monte Carlo Simulation study generating data on 8000 participants with a non‐linear decline over 6 years of follow‐up and a 70% drop‐out rate. In each condition of the simulation study, we varied the number of cohorts providing the final sample size (1/5/40 studies), the minor allele frequency (MAF; 0.33/0.03) and the effect size of the genetic predictors on the longitudinal data. Thousand replications per condition were generated. Performance was compared to standard methods (i.e., full linear mixed models and invers‐variance‐weighted meta‐analysis).

Result

Compared to a standard linear mixed model, our method was able to reduce, from several seconds to milliseconds, the computation time needed to calculate the association of one genetic variant with the longitudinal change. Our method producing unbiased effect estimates across all conditions. In case of less frequent variants (MAF = 0.03) and 40 studies, the standard invers‐variant weighted meta‐analysis showed higher type‐I‐error, but lower statistical power compared to the partial derivative‐based approach implemented in our method.

Conclusion

We developed a fast and versatile method for longitudinal GWAS that maximizes power to detect genetic determinants of a wide range of different phenotypes in research on neurodegenerative diseases.
Clinical implications of white matter hyperintensities in patients with Alzheimer’s disease
Authors: Yang Hyun‐ju , Park Joon Hyuk
Published: December 2020

Background

White matter hyperintensities (WMHs) are commonly found on the fluid‐attenuated inversion recovery (FLAIR) or T2‐weighted magnetic resonance imaging (MRI) in elderly people. Most recent studies have shown that increased volume of WMHs has been linked to both late life depression and functional impairment such as impaired mobility, gait and motor disturbance, and poor balance in elderly. In this analysis, we examined the relationship among depressive symptoms, physical disability, quality of life and WMH severity in Alzheimer`s disease (AD).

Method

The volume of WMHs were quantified using Lesion Segmentation Toolbox (LST). After then, the volume of WMHs were adjusted by the estimated intracranial volume, and we used a logarithmic transformation to produce normally distributed data. Because WMH distribution concerns three areas (juxtaventricular, periventricular, deep area), regression analyses were also used to identify the relationship between each WMH area and clinical symptoms in AD. All subjects underwent standardized clinical interviews and neurological and physical examinations to assess their cognitive (CERAD‐K), physical function (muscle mass index, grip strength, gait speed and timed up and go test), depressive symptoms (sGDS‐15) and quality of life (SF‐36).

Result

In 112 AD, the mean age was 80.5±7.1. WMH volume was associated with s‐GDS‐K score (P=0.005). After adjusting for sGDS‐K, MMSE‐KC‐Z score and Charlson Comorbidity Index, the degree of WMH volume were significantly associated with the muscle mass index (p=0.003), gait speed (p <0.001), and Korea frail index (p =0.016). Furthermore, social function (p=0.029), physical functioning (p<0.001), bodily pain (p=0.007), role physical (0.010), mental component score (0.028) and physical component score (p=0.001) were associated with the degree of WMHs.

Conclusion

Given the greater volume of WMH among AD, and considering that loss of the personal and social life of older people, these results might be relevant to the main functional problems related to aging in AD.
Cognitive evolution of patients with mild Alzheimer’s disease can be predicted by circulatory microRNA expression profile
Authors: Dakterzada Faride , Piñol Gerard , Carnes Anna , Targa Adriano , Moncusi Anna , Benitez Ivan David , Huerto Raquel , Barbe Ferran
Published: December 2020

Background

To evaluate whether the expression profile of plasma microRNAs is able to predict the cognitive evolution of patients with early‐phase Alzheimer’s disease (AD).

Method

Through the Mini‐Mental State Examination (MMSE), we evaluated the cognitive level of 19 AD patients at the baseline and after two years of follow‐up. The patients were grouped according to the rate of decline in the MMSE score along the two years: those who lost less than 4 points (N = 8) and those who lost four or more points (N = 11). To assess the expression profile of circulating microRNAs, blood samples were collected at baseline and plasma was used for total RNA extraction. The extracted RNA was subjected to two 384‐well TaqMan® array cards.

Result

We found a profile of 17 microRNAs that were differentially expressed between the two groups. From those, 11 microRNAs had an increased expression in patients with higher cognitive decline while 6 microRNAs had a decreased expression in these patients compared with those with a mild cognitive decline (Image). Furthermore, we observed that a subset of three microRNAs provided a tool with AUC of 0.90 for predicting the severity of the cognitive decline.

Conclusion

These preliminary results are indicating that the profile of circulating microRNAs could be a useful tool for predicting the cognitive evolution in patients with early‐stage AD. The results of this study need to be validated in an independent cohort.
FKBP51‐Hsp90 complex as a novel therapeutic target for Alzheimer’s disease
Authors: Wang Lisha , Pavlov Pavel F. , Kumar Rajnish , Winblad Bengt
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common form of dementia without effective treatments. FK506‐binding protein 51 (FKBP51) recently emerged as a possible therapeutic target for resolving both tau aggregation and insulin resistance in AD. FKBP51 in complex with its partner, molecular chaperone Hsp90, increases tau stability, thereby promoting tau aggregation [1, 2]. FKBP51 also regulates insulin resistance and altered glucose metabolism which represent early events that precede or accompany the development of AD [3, 4]. Our study aims to investigate the potential roles of FKBP51‐Hsp90 interaction inhibitors in AD.

Methods

A large dataset of available compounds were investigated using AlphaScreen™ and in silico virtual screening techniques to evaluate their inhibition on FKBP51‐Hsp90 interactions. Two of the selected specific inhibitors, E8 and C674, were then applied to SH‐SY5Y cells to test their effects on neurite outgrowth, overexpressed tau levels and glucose uptake. Furthermore, insulin signaling pathways were compared between vehicle‐treated vs inhibitor‐treated AD specimens.

Results

Compounds E8 and C674 inhibit FKBP51‐Hsp90 interactions at sub‐micromolar concentrations. E8 and C674 enhance neurite elongation, reduce overexpressed tau levels, stimulate glucose uptake and regulate insulin resistance.

Conclusion

We showed that inhibiting specific FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets for AD. References: 1. Jinwal, UK, et al., J Neurosci, 2010. 30(2): p. 591‐9. 2. Blair, LJ, et al., J Clin Invest, 2013. 123(10): p. 4158‐69. 3. Pereira, MJ, et al., Metabolism, 2014. 63(9): p. 1198‐208. 4. Balsevich, G, et al., Nature Communications, 2017. 8(1): p. 1725.
MRI morphometric data as predictor of PET amyloid positivity: New insights using brain connectivity metrics and machine learning
Authors: Pereira Helena Rico , Ferreira Hugo Alexandre
Published: December 2020

Background

The presence of brain amyloid‐beta plaques is relevant for the diagnosis of Alzheimer’s Disease (AD) [1‐3]. However, positron emission tomography (PET), used to assess amyloid loading, is expensive and not widely available as other imaging modalities [2]. Therefore, the aim of this study was to assess if magnetic resonance imaging (MRI) morphometric data (volumes, areas and thicknesses) and derived brain connectivity metrics would predict PET amyloid positivity.

Method

MRI and 18F‐florbetapir PET images, age, gender, Mini‐Mental State Examination (MMSE) scores, and corresponding diagnosis were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database at baseline (90 AD: 77 amyloid positive; 177 Mild Cognitive Impairment ‐ MCI: 130 amyloid positive; 122 Control: 72 amyloid positive). PET images were processed using PETSurfer to compute the relative Standardized Uptake Value (rSUV) values [5] to be used as labels to divide subjects into amyloid positive (rSUV > 1.1) and amyloid negative (rSUV < 1.1) regardless of diagnosis. Volumetric T1‐weighted MRI images were segmented and parcellated using FreeSurfer to obtain morphometric data of cortical and subcortical structures. These data were also used to derive graph theory connectivity (GTC) metrics, which translate relations between the morphometry of different brain regions. Then, all these data were used as features to obtain models for predicting amyloid positivity using various machine learning algorithms. A 10‐fold cross‐validation approach with a data split of 70% for training and 30% for testing was used.

Result

The combination of morphometric data and GTC metrics, demographic and MMSE score data was the model with the highest accuracy: 77.8%, AUC‐ROC=0.719 (CI95%=[0.633; 0.804]), NPV=76.9%, PPV=77.9% using a support vector machine algorithm. Using the morphometric data and GTC metrics only the model achieved an accuracy of 77.3%, AUC‐ROC=0.713 (CI95%=[0.627; 0.799]), NPV=66.7%, PPV=79.6%, whilst using morphometric data alone achieved an accuracy of 75.6%, AUC‐ROC=0.671 (CI95%=[0.583; 0.760]), NPV=64.7%, PPV=77.4%. .

Conclusion

While the relationship between brain atrophy and amyloid deposition has been reported previously [6], the results described here suggest that GTC increases the sensitivity in depicting the atrophy‐amyloid correlation. Additionally, results also suggest that volumetric T1‐weighted may provide additional information for predicting amyloid positivity and loading. References: See https://drive.google.com/file/d/11fIvB9QM2R61WXPrXqHlyXjlbP87_V4H/view.