bluuebunny/crossref_metadata_2025 huggingface dataset:
Theracurmin may be a therapeutic option for elderly patients with Alzheimer’s disease: A 6‐month retrospective follow‐up study
Authors: Dost Fatma Sena , Kaya Derya , Erken Neziha , Bulut Esra Ateş , Ontan Mehmet Selman , Aydın Ali Ekrem , Isik Ahmet Turan
Published: December 2021

Background

Therapeutic options for Alzheimer’s Disease (AD) treatment are highly limited and success rate in new molecules under investigated has been disappointing so that agents with various mechanisms represent a promising therapeutic opportunity. Among these, Theracurmin, a very highly absorbable curcumin formulation, was shown to improve memory and attention in non‐demented people. We aimed to investigate the effect of Theracurmin on the disease course in elderly patients with mild cognitive impairment (MCI) and AD.

Method

This is a retrospective follow up study on 93 consecutive elderly patients with MCI or AD. All patients underwent Comprehensive geriatric assessment (CGA), including Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), clock‐drawing test, trail making, activities of daily living (ADL), at baseline and end of the sixth month. Nineteen of 52 patients with AD and 17 of 41 patients with MCI were treated with Theracurmin 180 mg/day (PO). All AD patients were also treated with an acetylcholinesterase inhibitor.

Result

During the follow up period it was observed that MMSE or MOCA and instrumental ADL (IADL) scores declined in AD patients without treating with Theracurmin (p=0.001; 0.011; 0.004, respectively), whereas these scores remained stable in those with Theracurmin. Furthermore, this stabilization in the IADL was also observed in MCI patients treated with Theracurmin, but not in those without Theracurmin. During the follow‐up, three of MCI patients who did not receive Theracurmin progressed to AD, whereas it was only one patient in those who received it. No discontinuation of Theracurmin therapy was observed.

Conclusion

Theracurmin seems to be a therapeutic option for elderly patients with AD and MCI because of providing stabilization of the disease course by preventing progressive loss in cognitive functions and ADLs. Further prospective, multicenter, community‐based studies are needed to confirm these promising findings.
CSF protein panels reflecting multiple pathophysiological mechanisms for early and specific diagnosis of Alzheimer’s disease
Authors: Campo Marta Del , Peeters Carel F.W. , Johnson Erik C.B. , Vermunt Lisa , Hok‐A‐Hin Yanaika S. , van Nee Mirrelijn , Chen‐Plotkin Alice , Hu William T. , Lah James J. , Seyfried Nicholas T. , Herradon Gonzalo , Meeter Lieke H.H. , van Swieten John C. , Levey Allan I. , Lemstra Afina W. , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M. , van der Flier Wiesje M , Teunissen Charlotte E.
Published: December 2021

Background

The development of disease‐modifying therapies against Alzheimer’s disease (AD) requires biomarker panels that reflect the diverse pathological pathways specifically involved in AD. Here we aimed to identify and validate panels of cerebrospinal fluid (CSF) proteins covering different molecular pathways for early and specific diagnosis of AD.

Method

We measured 665 proteins in 797 CSF samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n=50), AD‐dementia (n=230), non‐AD dementias (n=322; 123 DLB and 199 FTD) and cognitively‐unimpaired controls (n=195; classical AD CSF biomarkers negative) using proximity ligation‐based multiplex immunoassays. Nested and penalized linear modeling were used to identify protein differences (q<0,05) and translatable classification signatures.

Result

We detected highly dysregulated CSF proteins in MCI(Aβ+) or AD compared to controls (112 and 288 proteins respectively, lowest q:1‐15 and 1‐23), as well as between AD and non‐AD dementias (469 proteins; lowest q:1‐29). We confirmed previous findings (e.g., DDAH1, ENO2, PARK7), but we also identified novel proteins especially associated to the prodromal and/or dementia AD stages (e.g., ABL1, SCD4, ENTPD5). Proteins dysregulated in MCI(Aβ+) were primarily related to oxidative stress and energy metabolism, while those specifically dysregulated in later stages of AD dementia were related to cell remodeling, vascular function and immune system. Using penalised generalised linear modeling we identified the minimal number of markers with maximal power to discriminate clinical groups: for MCI(Aβ+) vs. controls: 10‐CSF proteins, AUC:0.99 (95%CI:0.97‐1); for AD vs. controls: 8‐CSF proteins, AUC:0.95 (95%CI:0.92‐0.99) and for AD vs. non‐AD dementias: 9‐CSF proteins, AUC:0.87 (95%CI:0.81‐0.93). The CSF panel discriminating AD from cognitively unimpaired controls was validated in an independent external cohort (n=62, AUC:0.94). Only 3 proteins overlapped across panels, suggesting that the panels with the strongest discriminative power are specific for disease stage and clinical group.

Conclusion

This unprecedented large and protein‐rich CSF study indicates that CSF proteome follows a highly dynamic trajectory with distinct CSF profiles associated to different biological processes along the AD continuum. We unveil optimal CSF biomarker panels reflecting the specific multifactorial nature of AD, which can be now translated into customised assays for widespread validation and potential use in heterogeneous diagnostic settings or clinical trials.
Complementary analyses of the AMBAR trial: Individual items of CDR and ADAS‐Cog12 in Alzheimer’s disease patients treated with plasma exchange with albumin replacement
Authors: Nicodemus‐Johnson Jessie , Hendrix Suzanne B. , Barceló Miquel , Boada Mercè , Lopez Oscar L. , Núñez Laura , Grifols Carlota , Páez Antonio
Published: December 2021

Background

AMBAR (Alzheimer’s Management By Albumin Replacement) study results demonstrated that plasma exchange and albumin replacement (PE‐A) with or without intravenous immunoglobulin slows the progression of Alzheimer’s disease (AD) as measured by cognitive (ADAS‐Cog12), functional (ADCS‐ADL), and global assessment (CDR) (Boada et al. Alzheimers Dement 2020;16:1412). In this complementary analysis, we explored the association of ADAS‐Cog12 and CDR subdomains with treatment effects overall as well as stratified by AD severity.

Method

AD patients (N=347) were randomized (1:1:1:1) to one of the three different PE‐A treatments or placebo (sham PE‐A). We analyzed the performance of active (all 3 PE‐A‐treated groups) relative to placebo overall as well as stratified by AD severity for each of the 6 domains of CDR scale and 12 items of ADAS‐Cog12 grouped in three categories of “Memory”, “Language” and “Praxis” (Verna et al. Alzheimer Res Ther 2015;7:64). Language was also assessed through Phonetic and Semantic Verbal Fluency (PVF, SVF) tests and Neuropsychological Assessment Battery (NAB) naming test. Changes from baseline were analyzed using a mixed model for repeated measures (MMRM).

Result

PE‐A‐treated patients showed improvement by month 14 (p<0.05) in 5 of 6 CDR domains (“Memory”; “Orientation”; “Judgement & Problem solving”; “Home & Hobbies”; “Personal care”), with effect sizes from 71% (less decline) to >100% (improvement over baseline). The “Community affairs” domain had borderline significance (p=0.08). PE‐A‐treated moderate AD patients (MMSE: 18‐21) exhibited improvement over control whereas PE‐A‐treated mild AD patients (MMSE: 22‐26) were not significantly different. Among ADAS‐Cog12 items, PE‐A‐treated patients showed improvement by month 12 or 14 (p<0.05) in at least one of the categories “Language”, “Memory” or “Praxis” with effect sizes from 76 to >100%. PVF and SVF also demonstrated improvements by month 14 (all effect sizes >100%; p‐values: 0.003‐0.04). For the stratified analysis, this improvement, favoring PE‐A‐treated individuals, was only observed in the mild AD group (p= 0.0040 [PVF] and 0.02 [SVF]). Finally, NAB demonstrated improvement by 12 months only in the moderate group (p=0.04).

Conclusion

PE‐A demonstrated beneficial effects across all CDR domains and language tests, while the ADAS‐Cog12 benefit may be more prominent in specific subdomains of memory, language and praxis.
Physiotherapy with dual task improves cognition in Parkinson’s disease with postural instability and gait disorders
Authors: Leocadi Michela , Canu Elisa , Sarasso Elisabetta , Gardoni Andrea , Castelnovo Veronica , Piramide Noemi , Volonté Maria Antonietta , Filippi Massimo , Agosta Federica
Published: December 2021

Background

Previous studies suggested that action observation training (AOT) and motor imagery (MI) improve motor learning in Parkinson’s disease (PD) patients. The aim of this study was to assess cognitive changes following a 6‐week training associated with dual‐task gait/balance exercises in PD patients with postural instability and gait disorders (PD‐PIGD).

Method

25 PD‐PIGD patients were randomized into 2 groups: i) AOT‐MI+DUAL‐TASK group performed a 6‐week (W6) training consisting of AOT‐MI combined with practicing observed‐imagined gait and balance exercises; ii) DUAL‐TASK‐group performed the same exercises combined with landscape‐videos observation. At baseline, W6 and W14 patients underwent neurological, computerized cognitive and motor evaluations. A group of 23 healthy controls (HC) underwent a neuropsychological assessment at the study entry only. Cognitive changes in patients were monitored with the CANTAB (Cambridge Neuropsychological Test Automated Battery). Cognitive changes at each time point in the overall PD‐PIGD sample and between groups (AOT‐MI + DUAL‐TASK and DUAL‐TASK) were assessed.

Result

At baseline, no cognitive differences were found between the two PD‐PIGD groups. However, both PD groups performed worse than HC in several cognitive domains. Over time, both PD groups improved in terms of gait velocity and balance. Regarding cognitive changes, at W6 and at W14, all PD patients improved in terms of accuracy and reaction times in tests assessing attention switching and visuospatial localization abilities. No differences were observed between groups over time.

Conclusion

A physiotherapy approach associated with dual‐task gait/balance exercises can improve cognitive performances in PD‐PIGD patients that persist at long term. This improvement is evident in specific cognitive domains, which are usually affected in PD‐PIGD and can interfere with their motor performances.
Premorbid personality in frontotemporal dementia: Amyotrophic lateral sclerosis spectrum
Authors: Vinceti Giulia , Gallingani Chiara , Fiondella Luigi , Carbone Chiara , Salemme Simone , Tondelli Manuela , Martinelli Ilaria , Zucchi Elisabetta , Mandrioli Jessica , Chiari Annalisa , Zamboni Giovanna
Published: December 2021

Background

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered two clinical expressions of the same neurodegenerative continuum (FTD‐ALS spectrum) with common underlying pathology and genetics. Patients can present with pure behavioral/cognitive (FTD), pure motor (ALS) or mixed (FTD‐ALS) forms. The factors determining the development of one rather than the other phenotype are unknown. However, it is common observation that patients’ personality traits differ between the phenotypes: ALS patients tend to display a prosocial behavior characterized by kindness and agreeableness. On the opposite, FTD patients frequently present with disinhibition, anti‐social behaviors and lack of empathy. These traits are often described by patients’ relatives as having always characterized the patients’ personality. We therefore aimed at testing if FTD and ALS patients have different premorbid personalities, under the hypothesis that they reflect different vulnerabilities in the brain circuits related to social behavior and motor function, respectively.

Method

We prospectively recruited the patients presenting to our Memory and Motor Neuron Disease Clinics between December 2018‐December 2020. Patients’ personality was assessed through the NEO Personality Inventory 3 (NEO‐PI‐3), which analyses the five main personality factors (Neuroticism, Extraversion, Openness, Agreeableness, Conscientiousness). NEO‐PI‐3 was administered to patients’ caregivers with reference to the patient’s personality at two timepoints: at diagnosis and 15 years prior to symptoms onset. Differences in personality factors between groups at each timepoint were tested with ANOVA.

Result

46 consecutive patients (30 FTD, 13 ALS, and 3 FTD‐ALS assigned to the FTD or ALS group, based on their first symptom) were recruited. A significant difference in premorbid personality emerged in the Openness domain, showing that ALS patients (mean value 153±15) had been more open to new experience, ideas and emotions than FTD patients (132±21 ‐ p=0.049), even many years before symptoms onset. Such difference in Openness was decreased at the current moment but persisted (147±16 vs 123±24, p= 0.06).

Conclusion

we found that premorbid personality profile differed in FTD and ALS patients in at least one personality domain (Openness), supporting the hypothesis that premorbid personality may represent a vulnerability marker to the development of behavioral or motor disturbances. Our finding needs to be further explored with imaging.
Patient attitudes towards remote memory clinic assessment
Authors: Blane Jasmine , ClareO'Donoghue M , Craig Emma , Clarke Laura , Raymont Vanessa , Mackay Clare , Martos Lola
Published: December 2021

Background

Due to demand on UK memory clinic services, most patients have limited consultant interaction before diagnosis/discharge. Technology offers an opportunity for remote assessment, from telephone/video‐based consultations to fully digitised cognitive assessments with potential to track disease progression. Whilst many acute services utilise remote assessment, there are perceived barriers in memory clinic populations. However, COVID‐19 and related national restrictions may have altered patients’ attitudes towards and experience with remote assessment tools. We aimed to investigate attitudes including confidence and perceived challenges towards remote assessment as well as access and experience with technology amongst Oxfordshire memory clinic patients.

Method

Between June and September 2020, all patients awaiting initial memory clinic assessment were asked to participate in a standardised semi‐quantitative survey as part of an Oxford Health NHS Foundation Trust service evaluation. Designed with service‐user input, questions aimed to capture availability, experience and confidence using technology and patients’ comfort with assessment, diagnosis and future care discussions being conducted remotely, as well as any concerns or comments.

Result

Amongst 73 respondents (average age=79.1 years), access to technology was high; 82% reported telephone access and 58% to a laptop, tablet, smartphone or combination of the three. 17% reported previous use of web‐based video conferencing tools, and although confidence using these tools was 7%, this increased with written instruction or relative assistance. Similarly, whilst under half of the respondents felt comfortable with assessments, diagnosis or future care discussions occurring remotely, this increased to approximately two thirds with relative presence (67%, 69% and 66%, respectively). Qualitative analysis of patient’s comments regarding remote assessment also revealed concerns over wait times/urgent need for assessment. However, 62% preferred to wait for an in‐person visit, rather than an immediate remote appointment.

Conclusion

This survey demonstrates availability of technology in this population but a disparity in willingness to engage in remote assessment. Consequently, there is a need to diverge from one‐size‐fits‐all models to a tiered approach that helps facilitate individual choice based on the availability/confidence with technology and level of relative support. The Oxford Brain Health Centre, an integrated clinical‐research service, provides an opportunity to research this tiered approach in clinical practice.
Assessing and disclosing test results for MCI: The perspective of UK old age psychiatrists
Authors: Saunders Stina , Ritchie Craig W. , Russ Tom C , Muñiz‐Terrera Graciela , Milne Richard
Published: December 2021

Background

Mild cognitive impairment (MCI) is a state between normal healthy ageing and dementia with an uncertain prognosis. This uncertainty creates a complex dynamic between the clinicians’ conception of MCI, what is communicated to the individual about their condition, and how the individual perceives the information conveyed to them. The aim of this study was to explore clinicians’ views around the assessment and communication of MCI in memory clinics.

Method

As part of a larger longitudinal study looking at patients’ adjustment to being told they have MCI, we interviewed Old Age Psychiatrists at the five participating sites across South‐East Scotland. The study obtained ethics approvals and the interviews (carried out between Nov 2020–Jan 2021) followed a semi‐structured schedule focusing on [1] how likely clinicians are to use the term MCI with patients; [2] what tests clinicians rely on and how much utility they see in them; and [3] how clinicians communicate risk of conversion to dementia. The interviews were voice recorded and will be analysed using reflective thematic analysis (Clarke and Braun, 2019).

Result

Initial results show that most clinicians interviewed (Total N=19) felt MCI had significant limitations as a diagnostic label. Nevertheless, more clinicians reported using the term MCI (n=15) with patients than not (n=4). Clinical history was commonly described as the primary aid in the diagnostic process and also to rule out functional impairment (which was sometimes corroborated by Occupational Therapy assessment). All clinicians reported using the Addenbrooke's Cognitive Examination‐Revised as a primary assessment tool; neuroimaging (e.g., CT) was frequently found to have minimal usefulness due to the reports being non‐specific.

Conclusion

Our study revealed a mixture of approaches to assessing and disclosing test results for MCI. Some clinicians consider the condition as a separate entity among neurodegenerative disorders whereas others find the term unhelpful due to its poor prognosis. Clinicians report a lack of specific and sensitive assessment methods for identifying MCI in clinical practice. Our study demonstrates a broad range of views and therefore variability in MCI risk disclosure in memory assessment services which may impact on the management of individuals with MCI.
Patients with amnesic mild cognitive impairment due to Alzheimer's disease and with epileptiform‐like signatures showed abnormal cortical sources of resting state delta EEG rhythms: An EEG study
Authors: Tucci Federico , Babiloni Claudio , Noce Giuseppe , Di Bonaventura Carlo , Lizio Roberta , Lorenzo Ivan , Soricelli Andrea , Ferri Raffaele , Nobili Flavio , Famà Francesco , Arnaldi Dario , Palma Eleonora , Cifelli Pierangelo , Marizzoni Moira , Stocchi Fabrizio , Frisoni Giovanni , Percio Claudio Del
Published: December 2021

Background

Cortical sources of resting state eyes‐closed electroencephalographic (rsEEG) rhythms are abnormal in patients with amnesic mild cognitive impairment due to Alzheimer’s disease (ADMCI). In the present exploratory and retrospective study, we tested whether those abnormalities may be stronger in ADMCI with (ADMCI‐EEA) than without (ADMCI‐noEEA) epileptiform‐like EEG signatures.

Method

Clinical, neurophysiological, and rsEEG data in 56 ADMCI patients and 35 normal elderly (Nold) subjects were available in a national archive. The eLORETA freeware estimated rsEEG cortical sources. Area under receiver operating characteristic (AUROC) curves indexed the accuracy of eLORETA solutions in the classification between ADMCI‐EEA and ADMCI‐noEEA individuals.

Result

As compared to ADMCI‐noEEA patients, ADMCI‐EEA (N=25%) patients showed worse executive functions (Trail making Test B‐A) and more abnormalities in widespread delta (about 2‐4 Hz) and temporal theta (about 4‐6 Hz) source activities. Furthermore, those sources were able to classify with moderate/good accuracies (AUROC =0.75‐0.85) the ADMCI‐EEA vs. ADMCI‐noEEA individuals.

Conclusion

These results suggest higher abnormalities in low‐frequency (i.e. delta and theta) rsEEG cortical activities in ADMCI‐EEA than ADMCI‐noEEA patients at both group and individual levels.
The association of the ANU‐ADRI Alzheimer risk index score with cognition in the FINGER study
Authors: Hall Anette , Barbera Mariagnese , Stephen Ruth , Lehtisalo Jenni , Ngandu Tiia , Anstey Kaarin J , Kivipelto Miia , Solomon Alina
Published: December 2021

Background

The ANU‐ADRI is a validated risk index for Alzheimer’s disease comprised of lifestyle, medical and demographic factors, with higher scores indicating more risk. We investigated the association of the ANU‐ADRI score with cognition over the 2‐year FINGER multidomain prevention trial.

Method

The ANU‐ADRI score was calculated for the participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), at baseline (N=1174) and 24‐months (N=1023). Cholesterol and BMI were excluded due to age and pesticide exposure was not available. Age and sex were excluded from changes in ANU‐ADRI score, to focus on change in modifiable factors only.

Result

At baseline, ANU‐ADRI score was strongly associated (p<0.001) with the total cognitive score as well as all the cognitive subdomains of memory, executive function and processing speed. Baseline ANU‐ADRI was also associated (p<0.001) with changes in all domains of cognition over the trial period, with lower ANU‐ADRI scores indicating better cognition. Additionally, the decline in the ANU‐ADRI score was associated with improvement in cognition (p<0.01) in all domains. Preliminary results indicated no significant modifying effect of the FINGER intervention on cognition by baseline ANU‐ADRI score. Overall, the ANU‐ADRI score was lowered 1.0 [0.8‐1.3] points during the 2‐year trial, but no significant difference was found between the intervention arms.

Conclusion

Within the FINGER intervention, the ANU‐ADRI score and its change correlated negatively with cognition, with lower scores indicating better cognitive ability. However, the FINGER intervention, despite improving cognition, did not significantly modify the ANU‐ADRI score compared to the control group.
When verbal fluency inverts: Temporality of semantic impairment in preclinical Alzheimer’s disease
Authors: Vonk Jet MJ , Rentería Miguel Arce , Geerlings Mirjam I. , Avila Justina F , Mayeux Richard , Manly Jennifer J
Published: December 2021

Background

Worse semantic than letter fluency performance is a clinical marker of Alzheimer’s disease (AD), but the longitudinal course of performance on these tasks in pre‐dementia stages remains undefined. This study investigated how many years before clinical AD the performance on the two verbal fluency tasks starts to diverge, and if this process develops similarly across race/ethnicity groups.

Method

To estimate the trajectories and inflection point of verbal fluency performance in years prior to AD diagnosis, we performed piece‐wise linear mixed effects models in a diverse sample of 569 individuals (mean age = 78.5) from a community‐based cohort who were cognitively normal at baseline but developed dementia across 10 years of follow‐up (up to 5 visits). Performance was standardized on 569 age, sex/gender, education, and race/ethnicity matched controls who remained cognitively healthy during follow‐up (i.e., robust norms approach). Models were adjusted for recruitment wave and demographic factors.

Result

AIC model comparison of spline‐fit revealed that prior to AD diagnosis, performance on both fluency tasks started to decline more rapidly 3.6 years before diagnosis (slope within later timeframe: semantic: B=‐1.34 [‐1.52, ‐1.16], p<.001; letter: B=‐.56 [‐.70, ‐.42], p<.001). Point‐in‐time performance on semantic fluency became worse than letter fluency as of approximately 2.8 years before AD diagnosis due to the disproportionally fast decline of semantic fluency. Stratified models showed that the inflection point for Whites was earlier than for Blacks and Hispanics, but that the rate of decline and flip in performance between the two tasks was similar across race/ethnicity.

Conclusion

These results show how the conventional clinical index of worse semantic than letter fluency develops over time in the years before AD diagnosis. This study highlights the importance of serial neuropsychological assessments in detecting high‐risk individuals by showing that the differential rate of decline in semantic versus letter fluency is a sensitive preclinical AD‐marker, equivalent across race/ethnicity.
Serum albumin and indoxyl sulfate were predictive of cognitive impairment via amyloid beta and tauopathy, respectively, in end‐stage renal disease patients
Authors: Hou Yi‐Chou , Lu Kuo‐Cheng , Huang Chuen‐Lin , Lin Yuh‐Feng , Chen Ruei‐Ming
Published: December 2021

Background

Patients with ESRD tend to have more risk factors for cognitive impairment than members of the general population, including hypertension, malnutrition, and accumulation of uremic toxin. Blood‐based assays with immunomagentic reduction manner have the advantages of being less invasive and more cost‐effective for diagnosing patients with cognitive impairment. However, the clinical application for cognitive impairment in patients with ESRD is still lacking.

Method

In total, 76 participants aged >45 years were enrolled. The definition of ESRD was receiving maintenance hemodialysis for >3 months. Cognitive impairment was defined as a Mini‐Mental State Examination score of ≤24. The participants were divided into groups for health control (n=12), ESRD with (n=23)and without cognitive impairment (n=41). The blood‐based biomarkers (tau protein, Aβ1/40, Aβ1/42 ) were analyzed through immunomagnetic reduction assay. Other biochemical and hematologic data were obtained simultaneously.

Result

The study enrolled 76 patients with health control, ESRD who did not have cognitive impairment and ESRD who had cognitive impairment (Mini‐Mental State Examination [MMSE]: 30.00± 0.00, 27.60 ± 1.80 vs 18.00 ± 5.09, p < 0.05). The serum albumin was lower in the ESRD with cognitive impairment group (3.70 ± 0.24g/dL, vs 3.89±0.30 g/dL in ESRD without cognitive impairment and 4.40± 0.27g/dL in health control, p<0.05). The indoxyl sulfate concentration was lower in the health control rather than other group (5212 ±14621 ng/mL vs 44783 ±23799ng/mL in ESRD with cognitive impairment and 52148±23453 ng/mL in ESRD without cognitive impairment, p<0.05). Tau protein, and amyloid beta 1/42 and amyloid beta 1/40 were similar between groups. The area under the curve of albumin and indoxyl sulfate was 0.759 (95% confidence interval: 0.560–0.955, p = 0.037) and 0.748 (95% confidence interval: 0.542–0.954, p = 0.046) respectively for predicting cognitive impairment in the ESRD group. The concentration of albumin was negative correlated with tau (r=‐0.306, p=0.011). The indoxyl sulfate was positively correlated with amyloid beta 1/42 (r=0.283, p=0.013)

Conclusion

Serum albumin and indoxyl sulfate were predictive to the severity of cognitive impariment in patients with ESRD. The albumin was negatively associated with tau protein concentration. Indoxyl sulfate was positively correlated with amyloid beta 1/42.
Upper extremity dual‐task in autosomal dominant Alzheimer disease, PSEN1 E280A
Authors: Sarasti Luis , Alvarez Kevin Caicedo , Aguillon David , Garcia‐Cifuentes Elkin , Ochoa John F , Lopera Francisco
Published: December 2021

Background

Alzheimer’s disease and identification of non‐cognitive preclinical biomarkers is one of the key aspects in research worldwide, in Latin‐American is even more important because the lack of biomarkers in clinical practice. Dual‐task cost have been proposed previously as biomarker in Alzheimer disease. This study aims to create a low‐cost technology using smart phones camera to identify dual‐task in with Early‐onset Autosomal Dominant Alzheimer’s‐Disease carrying PSEN1 – E280A.

Method

Pilot study creating a low‐cost technology. Procedure: The execution of the motor‐task is recorded with the integrated camera of a smart‐phone and the verbal fluency‐task with the microphone integrated in the headset or an external lavalier type microphone. To determine the angle of elbow‐flexion in the dominant arm, anatomical markers are placed in the acromion (shoulderjoint), lateral epicondyle(elbow) and the ulnar/radial styloid(wrist). After segmenting the markers in the video, the elbow flexion‐angle and the dynamics of the arm movement (angular velocity, range of motion, limb elevation time and number flexions); from the audio recording, the words and quantity named in the task execution and the changes of these with respect to the task execution during the dual task are extracted. The flexion angle was validated with commercial biomechanical‐analysis software and goniometer, also the arm movement dynamics curves were validated with OpenPose.

Result

21 controls. The value of the dual‐task cost in verbal fluency in animal category was ‐11.35 % and for arithmetic calculation tasks ‐1, ‐3 was ‐19.09 % and ‐3.13 % respectively. negative values indicating no impairment. 2 Cases with the disease were also evaluated, the results of the dual‐task cost were 28.77 % for the verbal fluency task in animal category and 14.44 % and 38.34 % for the arithmetic calculation (‐1 and ‐3) the latter being the one with the highest load.

Conclusion

This evaluation method is widely applicable, low cost and time, does not require patient preparation and accessible, since it does not require large space availability or costly and complex instruments in comparison to its analogue, the dual‐task gait. It has great potential to be a non‐cognitive biomarker.
Construct validity of the Clinical Dementia Rating Scale to assess the level of cognitive decline by informants
Authors: Ferretti‐Rebustini Renata Eloah de Lucena , Rebustini Flávio , Suemoto Claudia K. , Grinberg Lea T. , Leite Renata Elaine P. , Rodriguez Roberta Diehl , Ferrioli Eduardo , Pasquallucci Carlos Augusto , Nitrini Ricardo , Jacob‐Filho Wilson
Published: December 2021

Background

Clinical Dementia Rating Scale (CDR) is one of the most used assessment scales in the care of dementia but it still lacks a detailed analysis of construct validity. We aimed to analyze evidences of construct validity of the CDR to assess the level of cognitive decline by informants.

Method

We analyzed 650 records of elderly subjects belonging to the Brazilian Biobank for Aging Studies. A trained nurse fulfilled the CDR during the clinical interview with a knowledgeable next‐of‐kin, after informed consent. We considered each domain of the CDR as one item. Exploratory (EFA) and Confirmatory factor analysis (CFA) were performed. We used Robust Unweighted Least Squares with promax rotation, with a bootstrapping of 1.000 cases, and Parallel Analysis. Sample adequacy was tested by the Kaiser‐Meyer‐Olkin and Bartlett sphericity tests. UniCo, ECV and Mireal tested the dimensionality. Factor loading ≥ 0.50 and communalities ≥ 0.40 were indicators of good factor solution. In CFA we tested: Goodness of Fit Index (GFI), Adjusted Goodness of Fit Index (AGFI), Non‐Normed Fit Index (NNFI), Comparative Fit Index (CFI ), and Weighted Root Mean Square Residual (WRMR). Reliability was tested by standardized Chronbach’s Alpha, Ordinal McDonald’s Ômega and GLB. For the analysis, we used Factor 10.10.3.

Result

Sample was composed by 55.5% of females, the mean age of the sample was 68.7±11.3 years and 78.8% of the participants were cognitively normal (CDR = 0). KMO was 0.86 and Bartlett was <0.001. Total explained variance was 84.6%. Parallel analysis showed only one dimension and values of UniCo (0.994); ECV (0.919) and MIREAL (0.279) confirmed the unidimensionality of the structure. Factor loadings ranged from 0.846 to 0.945 and communalities from 0.716 to 0.894. Memory was the item with the higher factor loading and communality. All the goodness of fit indexes confirmed the structure of CDR. Indicators of reliability were also very good (Table 1).

Conclusion

CDR is a unidimensional instrument composed by six items that together explain 84.6% of the ‘level of cognitive decline’. Results indicated that the CDR has very good evidence of construct validity and reliability and can be used to assess the level of cognitive decline by informants.
Do polygenic scores of cerebral small vessel disease MRI markers predict white matter lesions?
Authors: de Silva Eric , Sudre Carole H , Barnes Jo , Scelsi Marzia Antonella , Altmann Andre
Published: December 2021

Background

Evidence of cerebral small vessel disease (CSVD) is commonly found in those with a diagnosis of Alzheimer’s disease (AD) and is associated with T2‐weighted MRI‐visible white matter hyperintensities (WMHs). Here we investigate whether macrostructural and microstructural polygenic risk scores (PRS) predict WMH volumes.

Method

We used Genome Wide Association Studies (GWAS), based on UK Biobank (UKB) MRI markers of WMH, Fractional Anisotropy (FA) and Mean Diffusivity (MD) from (Persyn et al., 2020, https://doi.org/10.1038/s41467‐020‐15932‐3) to compute PRS for n=730 participants (following strict quality control) from the AD Neuroimaging Initiative (ADNI) using PRSice. We calculated WMH volumes for ADNI subjects using a Bayesian Model Selection method BaMoS (Sudre et al., https://doi.org/10.1109/TMI.2015.2419072). Linear regression models (with confounds for age, gender, education, APOE4 status, total intracranial volume and five principal components of population structure) were used to test for association (including multiple testing correction) between WMH, FA and MD PRS (based on p‐value thresholds at p=1.0e‐05 and p=0.5) and WMH volumes in each of three diagnostic groups: Healthy Controls (HC; n=218), Mild Cognitive Impairment (MCI; n=390) and AD (n=122).

Result

WMH and FA PRS did not predict WMH volume in the ADNIGO and ADNI2 cohort (Table 1) despite high correlation between BaMoS‐derived and BIANCA‐derived WMH volumes (r=0.84 on 19,070 UKB subjects). However, MD PRS at the p=0.5 threshold in the MCI group was positively correlated with WMH volume (Table 1) with t=3.4 (FDR‐corrected P=0.0008; Figure 1).

Conclusion

Despite a high heritability of WMH (h2=0.76; Sachdev et al.. 2016, https://doi.org/10.1161/STROKEAHA.116.012532), unexpectedly, WMH PRS did not predict WMH volume in ADNI in any of the diagnostic groups. The correlation between total WMH estimated with both tools was very high and thus is unlikely the source of this lack of association,however, this may be due to different inclusion criteria for ADNI. The statistically significant relationship in the ADNI MCI group between MD PRS and WMH volume may reflect the early white matter tract damage that is visible before AD manifests and these structural insults become overwhelming. This is reflected in many of the other PRS‐WMH corelations in the MCI group which are borderline statistical significance.
Development and dissemination of an ethical guidance and person‐centred isolation care planning tool to support the care of people with dementia during the COVID‐19 pandemic
Authors: Iaboni Andrea , Grigorovich Alisa , Barned Claudia , Rodrigues Kevin , Pia Kontos , Chu Charlene H , Astell Arlene J. , Flint Alastair , Bingham Kathleen , Maxwell Colleen J , Kirkham Julia , McMurray Josephine , Quirt Hannah , Tsokas Mario
Published: December 2021

Background

Long‐term care (LTC) residents have been disproportionately impacted by the COVID‐19 pandemic, both from the virus itself and the restrictions in effect for infection prevention and control. Many barriers exist in LTC to prevent the effective isolation of suspect or confirmed COVID‐19 cases. Furthermore, these measures have a severe impact on the well‐being of LTC residents. Our aim was to develop a guide for long‐term care to address the ethical challenges associated with isolating dementia patients during the pandemic. The Dementia Isolation Toolkit (DIT) was developed by members of the research team in partnership with LTC stakeholders to address: 1) the practical challenges of isolating or quarantining people with dementia in a compassionate, safe, and effective manner; and 2) the need for ethical guidance to support decision‐making regarding isolation and infection control in LTC, to prevent indecision and moral distress. To develop the DIT the team reviewed and synthesized the literature on pandemic ethics in a plain‐language document, which was then reviewed by our partners and stakeholders. The final ethical guidance tool includes a discussion of the ethics around infection control measures in a pandemic, an ethical decision‐making tool, and a person‐centred isolation care planning tool. The ethical guidance tool has been downloaded more than 6500 times since it was published (bit.ly/dementiatoolkit), and has been disseminated internationally. The worksheets are being used during outbreaks to support care and decision‐making, as well as proactively, to prepare for outbreaks by developing isolation care plans. There is a need for support for ethical decision‐making in the context of a pandemic, particularly in settings such as LTC. Future studies will evaluate the implementation of the tool and its impact in addressing moral distress in health care providers in long‐term care.
The PRagmatic EValuation of evENTs And Benefits of Lipid‐lowering in oldEr adults (PREVENTABLE) trial: Study design and procedures for cognitive assessment and adjudication
Authors: Sachs Bonnie C. , Rapp Stephen R. , Kistler Christine E , Musi Nicolas , Supiano Mark A. , Pajewski Nicholas M. , Callahan Kathryn E. , Alexander Karen P. , Shah Raj C , Snyder Heather M. , Carrillo Maria C. , Espinoza Sara , Williamson Jeff D.
Published: December 2021

Background

No existing therapies for Alzheimer’s disease and related dementias fundamentally alter the trajectory of the disease. While observational data suggests statins may reduce cognitive and functional decline in older adults, randomized evidence is lacking.

Method

The PRagmatic EValuation of evENTs And Benefits of Lipid‐lowering in oldEr adults (PREVENTABLE) trial is funded by the National Institute on Aging, National Heart, Lung, and Blood Institute, and supported by the Alzheimer’s Association. The trial will test the primary hypothesis that randomization to atorvastatin 40 mg versus placebo results in superior survival free of incident dementia or persistent physical disability over 5 years. The development of mild cognitive impairment (MCI) is a secondary endpoint. The target sample size is 20,000 participants ≥75 years without dementia recruited from 90 sites across the US from the National Patient‐Centered Clinical Research Network and the Veterans Affairs system. The trial will use a pragmatic, standardized telephone‐based cognitive battery, centrally administered annually, which includes a cognitive screener, the Telephone Interview for Cognitive Status‐modified (TICSm). Based on TICSm scoring, an extended phone cognitive battery will be performed that includes measures of attention/executive function, verbal memory, language, and mood. In addition, the Functional Activities Questionnaire will be administered to a trusted contact. A telephone assessment of physical and functional status will also be administered annually. Cognitive and functional data will be adjudicated by a panel of experts, blinded to treatment assignment, to determine the occurrence of MCI (and subtype) or probable dementia.

Result

PREVENTABLE will utilize pragmatic data sources (electronic health records and administrative claims) to obtain relevant medical data; however, these mechanisms are unreliable at identifying incident dementia and MCI. The pandemic required modification of cognitive testing, embracing a purely telephonic approach at baseline, which will nonetheless permit cognitive adjudication of participants. Recruitment will be ongoing through April 2023 with results available in 2026.

Conclusion

PREVENTABLE represents the largest randomized pragmatic trial examining cognitive outcomes associated with statin use in older adults. Launching during the pandemic required adaptation to remote assessment, which will facilitate progress towards efficient and novel methods for pragmatic clinical trials aimed at preventing dementia.
Quantitative R1 in the locus coeruleus in Alzheimer’s disease dementia
Authors: Bhalla Deepali M. , Kohli Akshay , Betts Matthew , Pasquesi Mary‐Elizabeth , Nair Veena A. , Düzel Emrah , Kecskemeti Steven R. , Alexander Andrew L. , Johnson Sterling C. , Prabhakaran Vivek , Bendlin Barbara B.
Published: December 2021

Background

Prior studies employing neuromelanin‐sensitive MRI have linked neurodegeneration in the locus coeruleus (LC) to Alzheimer’s disease (AD) pathology. MPnRAGE (Keckskemeti et al., 2016), a novel MRI technique developed at UW‐Madison, generates multiple inversion recovery contrasts and quantitative T1 relaxometry. Quantitative R1 (= 1/T1), the longitudinal relaxation rate, is sensitive to brain myelin, lipid, and iron content according to post‐mortem studies. As prior studies suggest altered quantitative R1 (QR1) among individuals with AD pathology, this imaging marker may be sensitive to AD‐associated pathology in the LC, one of the first regions in the brain to show signs of AD pathology (Braak et al., 2011). Here we performed preliminary assessments to test for differences in QR1 among individuals with and without clinical mild cognitive impairment (MCI‐AD), or AD dementia. We hypothesized that R1 would be lower among individuals with AD and MCI compared to unimpaired controls.

Method

Participants were enrolled in the Alzheimer’s Disease Connectome Project (ADCP) at UW‐Madison. 103 older adults diagnosed as cognitively unimpaired (N=53), MCI‐AD, and AD‐Dementia (Table 1) underwent MPnRAGE at a 1mm3 resolution. MPnRAGE‐derived QR1 maps were registered to MNI space using SPM12. LC masks (from Betts et al., 2017) were transformed to subject space to extract mean R1 in the bilateral LC using the Marsbar toolbox. Multiple linear regression was run within Rstudio to investigate the relationships between age, R1, and diagnosis. The main effects of interest included age and diagnosis, as well as their interaction. Sex was included as a covariate.

Result

No significant associations were found between QR1 and age, diagnostic status, and their interaction. The main effect of age on R1 trended toward significance (p=0.059). Age trends are shown in Figure 1. Sex was not a significant covariate.

Conclusion

While QR1 was not significantly associated with age or clinical diagnosis within the LC, further research will evaluate the extent to which QR1 is altered among other regions affected by AD pathology. Further, R1 could be tested between groups stratified by AD biomarker status. Finally, the LC is a small structure, thus future work could also test R1 estimated at higher resolution.
Cardiovascular risk moderates aerobic exercise efficacy on executive function in subcortical ischemic vascular cognitive impairment
Authors: Liu‐Ambrose Teresa , Barha Cindy K , Dao Elizabeth , Hsiung Ging‐Yuek Robin , Marcotte Lauren , Tam Roger
Published: December 2021

Background

Aerobic exercise can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, one’s cardiovascular health may attenuate the benefits of aerobic exercise on cognitive outcomes in SIVCI. We examined whether baseline Framingham Cardiovascular Risk Profile Score (FCRP) moderates the effect of a 6‐month progressive aerobic exercise program on executive function in adults with SIVCI.

Method

A secondary analysis of a proof‐of‐concept randomized controlled trial in 71 adults, who were randomized to either: 1) 3x/week progressive aerobic exercise program (AT); or 2) education program (CON). Three executive processes were measured: 1) response inhibition by Stroop Colour Word Test; 2) working memory by digits backward test, and 3) set shifting by the Trail Making Test (B‐A). Baseline cardiovascular risk was calculated using the FCRP, and participants were classified as either low risk (<20% FCRP score; LCVR) or high risk (>20% FCRP score; HCVR). A complete case analysis (n=57) was conducted using an analysis of covariance (ANCOVA) to evaluate between‐group differences in the three executive processes. Age, baseline Montreal Cognitive Assessment score, education, and baseline score for the outcome variable were entered as covariates in all models.

Result

A significant interaction was found between FCRP and group (AT or CON) for the digit span backward (F(1,49)=4.67, p=0.03) and the Trail Making Test (F(1,50)=4.09, p=0.04). On the digit span backward test, AT improved performance compared to CON (3.74±.33 vs. 2.75±.46) in those with LCVR, while in those with HCVR, AT did not improve performance compared to CON (2.97±.45 vs. 3.76±.41). Similarly, for the Trail Making Test (B‐A), AT improved performance compared to CON (52.66±13.27 vs. 80.12±17.82) in those with LCVR, while AT was not beneficial compared to CON in those with HCVR (98.80±18.06 vs. 59.92±17.09).

Conclusion

Baseline cardiovascular risk significantly moderates the efficacy of aerobic exercise on working memory and set shifting in adults with SIVCI. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise.
CSF and blood biomarkers: How strongly do they reflect Alzheimer's pathophysiology and are they dynamic?
Authors: Zetterberg Henrik , Karikari Thomas K.
Published: December 2021

Background

The past few years have seen a rapid development of biofluid‐based biomarkers for Alzheimer’s disease (AD) pathophysiological processes. The goal of this presentation is to critically review how well the currently available biofluid‐based biomarkers for AD reflect brain pathological changes. This has important implications for the interpretability of biomarkers in clinical trials and practice, and for how fluid‐based biomarkers could be most effectively used together with imaging in different contexts.

Method

An overview of the biofluid‐based biomarker landscape with emphasis on amyloid accumulation, tau aggregation, neurodegeneration, synaptic dysfunction, glial activation, and inflammation will be given. Available data on biomarker concentrations and dynamics in relation to tissue changes will be scrutinized, and the lack of anatomic information discussed.

Result

Originally, CSF and plasma total tau (T‐tau) and phosphorylated tau (P‐tau) concentrations were thought to reflect neurodegeneration and tangle pathology, respectively. However, animal and human experimental studies now suggest that CSF and plasma T‐tau and P‐tau reflect amyloid β (Aβ)‐induced neuronal tau phosphorylation and secretion, which in turn may be predictive of future neurodegeneration and tangle pathology. CSF Aβ42/Aβ40 ratio is the fluid biomarker with the firmest correlation with brain pathology; the ratio reliably reflects Aβ accumulation in the brain. Similar results have recently been obtained using plasma. But why does this biomarker show such an intriguing bimodal distribution? How rapid is the change from a normal to abnormal ratio? Regarding neurodegeneration, the best‐established biomarker is neurofilament light (NfL). It can be measured in CSF and blood, but can the two sample types be used interchangeably? And how can we be certain that a change in NfL reflects a change in AD‐related neurodegeneration and not something else, e.g., cerebrovascular disease? Biomarkers for synaptic dysfunction, glial activation, and inflammation will be discussed in similar ways.

Conclusion

CSF and plasma Aβ42/Aβ40 ratio is a relatively direct marker of brain Aβ pathology, whilst the other biomarkers seem to reflect tissue reactions to Aβ, which likely eventually translates into manifest neuropathological changes. More research using imaging and neuropathological measures is needed to validate and examine this further.