bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of mild behavioral impairment: A systematic review and meta‐analysis
Authors: Pan Yining , Shea Yat Fung , Li Siwen , Chen Ruijun , Mak Henry , Chiu Patrick Ka‐Chun , Chu Leung‐Wing , Song You‐Qiang
Published: December 2021

Background

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS). There has not been any systematic review or meta‐analysis on the prevalence of MBI. Main aim of the study is to calculate the pooled prevalence of MBI.

Method

A search of the literature on MBI in mild cognitive impairment (MCI), cognitively normal (CN), and subjective cognitive impairment (SCI) and cognitively normal but at risk (CN‐AR) subjects published between 1 January 2003 and 28 September 2020 was conducted. Meta‐analysis using a random effects model was performed to determine the pooled estimate of the prevalence of MBI. Meta‐regression was performed to identify factors contributing to the variance of prevalence rate. A systematic review was also performed to study the impact of MBI in cognitive outcomes and its correlation to pathology and genetics of Alzheimer’s Disease (AD).

Result

Eleven studies conducting among all 15689 subjects were subjected into meta‐analysis revealing a pooled prevalence of MBI at 33.5% (95% CI 22.6‐46.6%). Seven studies conducting among 1358 MCI subjects were subjected into meta‐analysis revealing a pooled prevalence at 45.5% (95% CI 36.1‐55.3%). Four studies conducting among 13153 CN subjects were subjected into meta‐analysis revealing a pooled prevalence at 17% (95% CI 7.2‐34.9%). Five studies conducting on 1158 SCI or CN‐AR subjects were subjected into meta‐analysis revealing a pooled prevalence at 35.8% (95% CI 21.4‐53.2%). Systematic review of 13 studies showed MBI has a significant impact on cognitive deterioration, and it is associated with pathology and genetics of AD.

Conclusion

MBI is common in MCI, CN, and SCI and CN‐AR subjects. Our finding is potentially useful in planning future clinical trials.
Alternatives to medication for the prevention of aggression by psychogeriatric patients: The challenge to adopt a new protocol
Authors: Gokkel Paul , Anderegg Arthur
Published: December 2021

Background

An increasing number of patients with dementia and a lack of personnel in nursing homes is deteriorating the quality of life and causes more aggression incidents by nursing home residents. These patients experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation. Antipsychotics are commonly prescribed off‐label to manage these symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Another fact is that this medication does not provide a hundred percent guarantee for the safety of the staff members. In many countries there is a policy to reduce fixation and isolation of aggressive patients. Therefore the nursing staff has less tools to prevent physical aggression by patients. Staff members informed us about this situation and we have designed an user friendly aggression prevention device, which limits the arm movements of the patient. In contrast to fixation the user can still perform all daily activities. This device is comfortable to wear, contrary to fixation. This device only prevents hitting movements with fully extended arms by a maximal 90 degree bending angle of the elbow. Also effective throwing with objects is inhibited. Product samples of this patented invention were made and tested for safety and effectiveness by martial art experts. After a positive result we offered this new medical device on request of a staff member, a renowned psychiatrist, to a health care organization for a medical trial. The product is registered in the European Union as a medical device Class I: NL‐CA002‐2017‐42023. This invention was considered by several medical experts as a significant improvement to the safety in health care. However the hesitance of some managers to break with old protocols and try out something new was the reason to cancel the trial. We are looking for organizations (nursing homes, psychogeriatric hospitals etc) that can test this medical device.
Association of life‐course depression with the risk of dementia in late life: A nationwide twin study
Authors: Yang Wenzhe , Li Xuerui , Pan Kuan‐Yu , Yang Rongrong , Song Ruixue , Qi Xiuying , Pedersen Nancy L , Xu Weili
Published: December 2021

Background

Depression in later life has been linked to dementia, yet whether depression is a prodromal phase or risk factor for dementia is still under debate. Thus, looking into the time window of depression occurrence may help unveil the nature of this link. We aimed to examine the association of depression with dementia from a life‐course perspective, and to explore the roles of genetic and early‐life environmental factors shared by twins, and education in this association.

Method

Within the Swedish Twin Registry, 41,727 dementia‐free twin individuals (mean age 60 years) were observed for 18 years to detect incident dementia. Life‐course depression was ascertained from the Patient Registry and divided as early‐, mid‐, late‐, early‐ to mid‐life, mid‐ to late‐life, and lifelong depression according to the age of occurrence. Dementia was ascertained based on the same registry. Generalized estimating equation (GEE) model was used for unmatched case‐control analysis and conditional logistic regression was used for co‐twin matched case‐control analysis.

Result

Of all participants, 2,832 (6.8%) had depression and 3,258 (7.8%) developed dementia. In the multi‐adjusted GEE model of unmatched analysis, the odds ratio (OR) of dementia was 1.93 [95% confidence interval (CI): 1.69–2.21] for depression at any age. In stratified analyses, the ORs (95% CIs) of dementia were 0.98 (0.51–1.90) for early‐life, 1.46 (1.09–1.95) for mid‐life, 2.16 (1.82–2.56) for late‐life, 1.62 (0.60–4.35) for early‐ to mid‐life, 2.24 (1.49–3.36) for mid‐ to late‐life, and 2.65 (1.17–5.98) for lifelong depression respectively. No statistically significant difference in ORs from the unmatched and co‐twin matched analyses was observed (P = 0.60). In joint exposure analysis, the dementia risk associated with mid‐life depression was attenuated by education ≥8 years.

Conclusion

Not only late‐life depression, but also depression beginning from midlife is associated with dementia. Genetic and early‐life environmental factors seem not to account for the association. Higher education might buffer the impact of mid‐life depression on dementia.
Masupirdine (SUVN‐502): A promising clinical candidate for the management of agitation in Alzheimer’s dementia
Authors: Nirogi Ramakrishna , Jayarajan Pradeep , Tadiparthi Jayaprakash , Shinde Anil K , Rasheed Mohammed Abdul , Goyal Vinod Kumar , Bhyrapuneni Gopinadh , Benade Vijay , Palacharla Veera Raghava Chowdary , Ravula Jyothsna , Jetta Satish
Published: December 2021

Background

Masupirdine is a potent and selective 5‐HT6 receptor antagonist and has completed Phase‐2 clinical proof of concept studies in patients with Alzheimer’s type dementia. 5‐HT6 receptors are G‐protein coupled receptors mainly localized in the brain regions primarily involved in cognition and behavior i.e., cortex, dorsal hippocampus and striatum. Evidence from the studies in animal models suggests that 5‐HT6 receptor antagonists may have a potential role in controlling neuropsychiatric behavior such as agitation.

Method

Masupirdine has been evaluated in a phase‐2a proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel groups in United States under active US IND. Sub group analyses has been carried out to evaluate the effects of masupirdine on domains related to agitation/ aggression using Neuropsychiatric Inventory (NPI‐12) scale.

Masupirdine was also tested in resident intruder task to evaluate its effects on animal model relevant to aggression. Additionally, masupirdine has been evaluated using microdialysis technique to assess its effect on the modulation of monoaminergic neurotransmitters.

Result

In Phase‐2 clinical study subgroup analyses, masupirdine showed robust efficacy in agitation/aggression scores in subjects who had baseline symptoms of agitation/aggression. The effect observed was greater than the minimum difference observed to be clinically important. Similar beneficial effects were observed on extended composite NPI‐12 score related to agitation/ aggression (agitation/ aggression + aberrant motor behavior + sleep and nighttime behavior disorder). Masupirdine was found to be safe and well tolerated in this study. In preclinical animal models, masupirdine reduced the aggressive behaviour in resident intruder task and increased neurotransmitters with role in modulation of agitation and aggression.

Conclusion

Masupirdine showed clinically meaningful improvement in the neuropsychiatric symptoms associated with agitation/aggression in patients with AD and reduced aggression in animal models. Masupirdine could be a differentiated novel therapeutic option for the management of agitation/ aggression in Alzheimer’s patients.
Idiopathic normal pressure hydrocephalus with synucleinopathy: Diagnosis and treatment
Authors: Han Sang‐Won , Park Young Ho , Ryoo Nayoung , Kim Kitae , Pyun Jung Min , Kim Sangyun
Published: December 2021

Background

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic triad of gait disturbance, urinary incontinence, and cognitive impairment in the presence of ventriculomegaly, which is ameliorated by the removal of CSF, and is diagnosed by excluding known risk factors for communicating hydrocephalus including meningitis, traumatic brain injury, subarachnoid hemorrhage, and brain irradiation. Shunt surgery is indicated for iNPH patients who respond to the removal of CSF.

Method

A 70‐year‐old man presented with a 2‐year history of progressive disturbances of gait, balance, control of urination, and cognition. His family reported that he exhibited dream enactment behavior. Brain MRI showed enlarged lateral ventricles and disproportionately enlarged subarachnoid space hydrocephalus. Although our iNPH patient whose gait disturbance was improved by lumbar puncture with CSF removal, FP‐CIT PET showed reduced DAT binding bilaterally throughout the striatum, including the caudate nucleus and the putamen.

Result

It is known that patients with iNPH present with normal presynaptic DAT binding in the striatum. However, although our iNPH patient’s gait disturbance was improved by LP with CSF removal, FP‐CIT PET showed reduced DAT binding throughout the striatum. Given that 25% of iNPH patients who underwent shunt surgery were revealed to have a diagnosis other than iNPH, we supposed our patient might have a concomitant neurodegenerative disorder affecting presynaptic nigrostriatal neurons. His dream enactment behavior suggests underlying synucleinopathy. Recently, Broggi et al. reported that the striatal dopaminergic deficit on DAT scan was common (46.7%) in patients with iNPH. And the long‐term outcome of shunt surgery of patients with abnormal DAT scan was not favorable.

Furthermore, it is also known that the improvement of gait after the removal of CSF rarely persists for more than a few days in patients with iNPH. However, the response after CSF removal sometimes could be sustained, as in our patient, for a few months, which might be attributed to the elasticity of the ventricular wall.

Conclusion

For iNPH patients with clinical features suggesting synucleinopathy such as REM sleep behavior disorder, DAT scan could be considered to identify concurrent synucleinopathy before shunt surgery, even in cases with initial response to high‐volume lumbar puncture.
Development of educational system for paramedics specializing to dementia elderlies analyzed by artificial intelligence and its learning effects
Authors: Honda Miwako , Une Saki , Gineste Yves , Nakazawa Atsushi
Published: December 2021

Background

While the number of emergency transfer of dementia elderlies to acute care hospitals has being increasing, paramedics are facing challenges to perform their duties promptly due to difficult communication with patients.

Objectives

To develop the standardized educational system for paramedics specializing to dementia elderlies with the use of artificial intelligence.

Design

Single arm, pre‐post study. Participants are paramedics in a metropolitan area of Japan.

Exposure

The two sessions of standardized multimodal communication training program which contains lecture and workshop were provided twice, 1 month apart. The training consists three parts. 1: Mechanism and clinical manifestations of dementia, 2: Communication skills: face‐to‐face interaction; mutual gaze, geometric characteristics and duration of eye contact, verbal communication with phonetic elements, and touch interactions. 3: Interaction strategies with dementia elderlies in emergency situation. All participants performed the rescue simulation training before the training and 1 month after the completion of the training, which were video‐recorded and analyzed by artificial intelligence (AI). The video was taken by wearable camera with eye‐trackers (1st person camera) and fixed camera (3rd person camera). The satisfaction survey of effectiveness on their work and the Jefferson Scale of Empathy for healthcare professionals were also taken.

Main Outcomes

The primary outcome is the change of communication skills in physical position, distance, eye contact with patients, phonetic elements and touch. The system to analyze face‐to‐face communication; mutual gaze, geometric characteristics and duration of eye contact by AI was developed by our team. Other elements of communications were evaluated manually. Secondary outcome were satisfaction and the empathy to patients.

Result

31 paramedics enrolled the study. Prior to the training, 88% had experienced any difficult condition taking care of dementia patients. The video analysis showed significant change of the interactive communication in the direction of approach, eye contacts and duration of mutual gaze. 96.7% considered the training was effective for their daily work and 97.5% of participants recommended this training to a colleague. The score of empathy scale showed no significant change.

Conclusion

The educational system for paramedics specializing to dementia with the use of artificial intelligence is effective for their work.
Upregulation of microRNA‐451a in the blood of the patients with Alzheimer’s disease (AD)
Authors: Kulczynska‐Przybik Agnieszka , Dulewicz Maciej , Borawska Renata , Doroszkiewicz Julia , Kaczynska Aleksandra , Litman‐Zawadzka Ala , Slowik Agnieszka , Mroczko Barbara
Published: December 2021

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disease, that characterize a long preclinical phase. Therefore, improving the early diagnosis of the disease is crucial. Biological and cognitive markers that will help improve the accurate diagnosis of the disease, understanding the underlying etiology of the clinical syndrome and that can be useful in clinical trial recruitment are constantly sought. It has been suggested that changes in miRNAs expression may predict the onset of cognitive decline. Measuring miRNA in the blood could be a promising approach for the early detection of AD. The literature data have indicated that circulating miRNAs could reflect the early neurodegenerative changes and predict the MCI/AD onset during the pre‐symptomatic stage. This study aims to evaluate the concentration of the miRNA‐451a in patients with AD and compare it with classical biomarkers for the disease.

Method

A total of 30 individuals, including 15 patients with AD and 15 non‐demented controls, were enrolled in the study. miRNA was isolated from serum samples, and it was hybridized with the biotin‐labeled specific DNA oligonucleotide. The RNA hybrids were then transferred onto a stationary solid phase coated with a monoclonal antibody specific to matched RNA‐biotin hybrids. The absorbance of the complex was proportional to the concentration of miRNA‐451a present in the serum sample. The classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau, and pTau181, were assessed in the cerebrospinal fluid (CSF) by immunoenzyme assays.

Result

The significantly higher concentrations of miRNA451a in AD patients in comparison to non‐demented controls were revelded. Moreover, the elevated level of miRNA451a correlated significantly with Aβ‐42/Aβ‐40 ratio and tau protein in the whole study group.

Conclusion

Presented results indicate that miRNA451a deregulation may be important in the initiation of AD‐related neurodegeneration, but these investigations need to be further clarified using a larger study group.

Acknowledgement

The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Comparison of automated CLEIA and manual ELISA immunoassays for CSF AD biomarkers: The Fundació ACE Biomarker Research Program (FACEBREP)
Authors: Orellana Adelina , Valero Sergi , Abdelnour Carla , Montrreal Laura , de Rojas Itziar , Rosende‐Roca Maitee , Mauleon Ana , Vargas Liliana , Tartari Juan Pablo , Esteban‐De Antonio Ester , García‐González Pablo , Alarcón‐Martín Emilio , Alegret Montserrat , Alcolea Daniel , Lleó Alberto , Hernandez Isabel , Tarraga Lluis , Marquié Marta , Boada Mercè
Published: December 2021

Background

Clinical diagnosis of Alzheimer’s disease (AD) increasingly incorporate CSF biomarkers. However due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, it is recommended to establish in‐house cutoffs defining the positivity/negativity of CSF biomarkers.

Method

We quantified CSF Aβ1‐42, t‐Tau, p181Tau and Aβ1‐40 with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme‐immunoassay (CLEIA) performed on automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with Alzheimer Disease (AD, n=37) and amyloid‐negative Subjective Cognitive Decline subjects (SCD, n=45), cognitively stable during 3‐years and with no evidence of brain amyloidosis in 18F‐Florbetaben‐labeled positron emission tomography (FBB‐PET). To compare both methods, a subset of samples for Aβ1‐42 (n=519), t‐Tau (n=399), p181Tau (n=77) and Aβ1‐40 (n=44) were analyzed. Kappa agreement of single biomarkers and Aβ1‐42/Aβ1‐40 was performed in an independent group of mild cognitive impairment (MCI) and dementia patients (n=68).

Result

Cutoffs values of Aβ1‐42 and t‐Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aβ1‐40 and 0.96 for p181TAU. Passing‐Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aβ1‐40. Bland‐Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers were good but lower for Aβ1‐42/Aβ1‐40.

Conclusion

We established internal cutoffs to discriminate AD patients from amyloid‐negative SCD individuals. Results obtained by both methods are not interchangeable but showed good agreement. We propose automated CLEIA as a good alternative to manual ELISA together with Aβ1‐42/Aβ1‐40 to classify amyloidosis.
Reduction of behavioural inhibition disorders in behavioural variant frontotemporal dementia patients observed under semi‐ecological conditions
Authors: Tanguy Delphine , Batrancourt Bénédicte , Bouzigues Arabella , Godefroy Valérie , Bendetowicz David , Rametti‐Lacroux Armelle , Bombois Stéphanie , Cognat Emmanuel , Le Ber Isabelle , Morandi Xavier , Jannin Pierre , Levy Richard , Migliaccio Raffaella
Published: December 2021

Background

Behavioural variant frontotemporal dementia (bvFTD) is characterised by a progressive deterioration of personality, social conduct and cognition. Especially, inhibition troubles are reported, impairing the daily lives of patients and caregivers. However, assessment and characterisation of disinhibition are still poorly known, leading to a limited management of these disorders. We aim to identify activities related to an increase or a decrease of behavioural disinhibition, in order to better apprehend these disorders and set up non‐pharmacological approaches to limit these troubles.

Method

We assess behavioural disinhibition in a semi‐ecological setting, noting occurrences of 16 behaviours – derived from clinical criteria of bvFTD – related to compulsivity, impulsivity or social disinhibition, in a population of 25 bvFTD and 25 healthy controls (HC). Subjects are placed in a waiting room during 45 minutes, instructions are to get comfortable and enjoy the room. During the scenario, they are firstly free to explore the room (Free Phase) and are then guided by a questionnaire to be filled in (Guided Phase). Duration of activity related behaviours and motor patterns are also collected to look for correlations with behavioural disinhibition scores.

Result

To date, we included 22 bvFTD and 24 HC. We found out that disinhibition behaviours are not constant during the scenario. BvFTD patients are less impulsive during the guided phase compared to the free phase (p=0.014, Wilcoxon test), and show more social disinhibition than HC during the free phase and at the end of the guided phase (p=0.014 and p=0.026 respectively, Mann‐Whitney U tests), but not during the guided phase. Compulsive behaviours remain unchanged. Moreover, looking for correlations between behavioural disinhibition and activity related behaviours or motor patterns, we found out that: 1) social disinhibition would be less present during activity (eg, reading), 2) there would be less compulsivity when patients are dealing with the questionnaire, and 3) impulsivity would increase during exploration of the room (eg, books).

Conclusion

This study relying on a semi‐ecological setting highlights interesting areas for non‐pharmacological treatments of behavioural disturbances in bvFTD, consistent with previous studies encouraging concentration on a given task, hobbies or a tidy environment to reduce undesired behavioural symptoms in dementia.
SUVN‐I6107: Efficacy and safety assessments of a true muscarinic M1‐positive allosteric modulator for the treatment of dementia
Authors: Abraham Renny , Subramanian Ramkumar , Grandhi Venkata Ramalingayya , Muddana NageswaraRao , Kamuju Venkatesh , Badange Rajesh Kumar , Reballi Veena , Nirogi Ramakrishna
Published: December 2021

Background

M1 muscarinic agonist has failed in time past in clinical trials to treat dementia observed in the elderly on account of its side effect profile. In the current investigation, we evaluated efficacy and safety of SUVN‐I6107 an M1‐positive allosteric modulator (PAM) in various animal models and compared it with earlier M1‐PAMs.

Method

In‐vitro characterization of SUVN‐I6107 was done using the reporter gene assay and radio‐ligand binding assay at muscarinic receptors. SUVN‐I6107 was evaluated for efficacy and compared with earlier M1‐PAMs. An extensive characterization of SUVN‐I6107 was carried out to understand the margin of safety in various animal models. Earlier M1‐PAMs were also assessed as a comparator.

Result

Based on the reporter gene assay and radio‐ligand binding studies, SUVN‐I6107 was characterized as a M1‐PAM with no agonist like activity. No notable effects were observed at other muscarinic receptors subtypes (M2, M3, M4 and M5). SUVN‐I6107 was found to reverse time, and scopolamine induced memory deficits in various animal models of cognition. SUVN‐I6107 did not show any spike potentiation effect in agonist mode of testing (slice electrophysiology), which indicates that it has no M1 agonist like effect. Cholinergic signs were not observed at doses which were efficacious in the cognition studies. Cholinergic signs were observed several folds higher than the efficacious doses. SUVN‐I6107 was found to be safer than the earlier M1‐PAMs sans several of the characteristic side effect profile.

Conclusion

Doses of SUVN‐I6107 which exhibited procognitive activity were several folds lower than the doses where cholinergic signs were seen in animals. Earlier M1‐PAMs did not have a wide margin of safety in comparison to the efficacious dose.
Optimal parametric imaging methods for dual‐time‐window [18F]flutemetamol and [18F]florbetaben PET studies
Authors: Heeman Fiona , Yaqub Maqsood , Hendriks Janine , Bader Ilona , Barkhof Frederik , Gispert Juan Domingo , Van Berckel Bart N.M. , Alves Isadora Lopes , Lammertsma Adriaan A. ,   AMYPAD Consortium
Published: December 2021

Background

Accurate quantitative measures of amyloid beta (Aβ) plaques are needed to identify individuals with subthreshold Aβ levels or for measuring small changes over time. To this end, dynamic or dual‐time‐window scanning protocols are required. Optimal pharmacokinetic models for quantifying Aβ burden using both [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans have previously been identified at a region of interest (ROI) level. This study aimed to determine optimal parametric methods for analyses of [18F]flutemetamol and [18F]florbetaben dual‐time‐window scans.

Method

Forty‐six participants were scanned on a PET/MR scanner using a dual‐time‐window protocol and either [18F]flutemetamol or [18F]florbetaben. The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two‐step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90‐110 min post injection interval. All parametric images were assessed visually for possible image artefacts and regional cortical outcome measures were compared with DVR derived using regional RLogan, based on AUC values for differentiating between Aβ‐positive and Aβ‐negative scans, Bland‐Altman plots and linear regression analyses.

Result

Visually, RPM and SRTM2 performed best across tracers and, in addition to SUVR, provided the highest AUC values for differentiating between Aβ‐positive and Aβ‐negative scans ([18F]flutemetamol: range AUC=0.96‐0.97, [18F]florbetaben: range AUC=0.83‐0.85). Outcome parameters of most methods were highly correlated with those of the reference method (R2≥0.87), with lowest correlations observed for MRTM2 (R2=0.71‐0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. On the other hand, bias in SUVR was high for [18F]flutemetamol (mean bias>10%), but low for [18F]florbetaben (mean bias=1%) and strongly proportional with underlying Aβ burden for both tracers.

Conclusion

The best overall compromise was provided by MRTM0, followed closely by SRTM2. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression. “This work has received support from the EU‐EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (grant No 115952).”
Associations of objective and subjective sleep quality with MRI markers of brain ageing and Alzheimer’s disease
Authors: Weihs Antoine , Frenzel Stefan , Katharina Wittfeld , Obst Anne , Stubbe Beate , Berger Klaus , Fietze Ingo , Penzel Thomas , Bülow Robin , Voelzke Henry , Grabe Hans J.
Published: December 2021

Background

Sleep is increasingly recognised as a major risk‐factor for cognitive ageing and neurodegenerative disorders such as late‐onset Alzheimer’s Disease (LOAD). Poor sleep quality has been linked to impaired cerebral clearance of amyloid‐beta, neurofibrillary tangles and reduced cognitive function. Recent studies have also highlighted a relationship between disturbed sleep and age‐related changes in brain structure.

Method

We used ordinary least‐squared regression adjusted for age, gender, BMI, intracranial volume and APOE4‐status to investigate the associations of MRI‐based markers of brain ageing and LOAD‐related brain atrophy patterns (Frenzel et al. 2019; Janowitz et al. 2016 and Weihs et al. 2020) as well as cognitive performance in terms of the immediate and delayed wordlist recollection from the Nuremberg‐Age‐Inventory (NAI) with questionnaire and polysomnography (PSG) based measures of sleep quality in 717 subjects from the large‐scale population‐based Study of Health in Pomerania (SHIP‐Trend). We analysed the percentage of total sleep time (TST) spent in slow‐wave and rapid eye movement (REM) sleep, sleep duration, sleep efficiency and sleep latency as objective sleep quality measures and the Pittsburgh sleep quality index (PSQI) as subjective sleep quality measure.

Result

We have identified inverse associations of the percentage of TST spent in slow‐wave and REM sleep with brain atrophy related to ageing and LOAD, which was mainly driven by slow‐wave sleep, with both percentages of TST and duration showing significant inverse associations. Furthermore, there was a non‐linear u‐shaped association between sleep duration and age‐related atrophy patterns. Similar associations were found for the NAI sum score and the NAI delayed recollection sub‐score, but neither were significant after correcting for multiple testing. No associations with the PSQI score were found.

Conclusion

We identified associations between PSG based sleep quality markers, but not subjective sleep quality, and brain atrophy related to ageing and LOAD. With no treatment being yet available, improving objective sleep quality, especially slow‐wave sleep, could prove a viable target to slow‐down the process of cognitive decline and reduce the risk of neurodegenerative disorders such as LOAD.
Amyloid and APOE4 status interact with age on different medial temporal lobe subregions in cognitively unimpaired elderly
Authors: de Flores Robin , Demeilliez‐Servouin Solène , Kuhn Elizabeth , Chauveau Lea , Landeau Brigitte , Delcroix Nicolas , Gonneaud Julie , Chetelat Gaël
Published: December 2021

Background

Medial temporal lobe (MTL) subregions, more specifically the CA1 subfield of the hippocampus and the entorhinal cortex (ERC), are particularly affected in Alzheimer’s disease (AD). However, the specific impact of amyloid (Aβ) pathology and APOE ε4 on MTL subregional atrophy remains relatively unknown. Our aim was to uncover these effects to further our understanding of the mechanisms underlying MTL atrophy in the context of AD.

Method

We used baseline data from 132 unimpaired older adults (mean age: 68.9 ± 3.8 years) from the Age‐Well randomized controlled trial for whom high‐resolution structural MRI (T2‐weighted; 0.4x0.4x2.5mm3), amyloid‐PET (Florbetapir) and APOE genotype were available. Participants were dichotomized into amyloid positive (Aβ+, n=27) and negative (Aβ‐, n=105), and APOE ε4 carrier (ε4+, n=36) and non‐carriers (ε4‐, n=96). Hippocampal subfield (CA1, CA2, CA3, dentate gyrus, subiculum) and extra‐hippocampal region (entorhinal cortex [ERC], Brodmann area [BA] 35 and 36, and parahippocampal cortex [PHC]) volumes were estimated using ASHS and normalized by total intracranial volume. For each subregion, group comparisons were performed (Aβ+ vs Aβ‐ and ε4+ vs ε4‐) using ANCOVAs, including age, sex and education as covariates. Interactions with age (i.e., Aβ status * age and APOE ε4 status * age) were also investigated for each subregion.

Result

No significant differences were observed between Aβ+ and Aβ‐, nor between ε4+ and ε4‐. However, significant Aβ status * age interactions were observed for CA1 and PHC (p<0.05), where volumes were negatively associated with age in the Aβ+ group only (figure 1). In addition, a significant APOE ε4 status * age interaction was found for ERC (p<0.05), where volume was negatively associated with age in the ε4+ group only (figure 2).

Conclusion

Overall, our analyses showed that Aβ and APOE ε4 status differentially interact with age on MTL subregions (CA1/PHC and ERC, respectively) in cognitively unimpaired elderly. These observations suggest that the atrophy of MTL regions that are specifically altered in AD relies on distinct mechanisms involving amyloid pathology and APOE ε4. These results are particularly important to develop MRI‐based biomarkers to detect early AD and further our understanding of MTL atrophy in normal and pathological ageing.
Association between late‐life neighborhood built environment and cognitive impairment in older adults
Authors: Chen Ting‐An , Chen Jen‐Hau , Yu Hwa‐Lung , Chen Ta‐Fu , Yeh Su‐Ling , Chen Yen‐Ching
Published: December 2021

Background

Elders’ mobility and social activities are closely related to their living environments and cognitive function. Built environments and social activities tend to vary across populations and geographic regions. Therefore, this study aims to explore the association between late‐life neighborhood built environment and cognitive function in community‐dwelling older adults.

Methods

This prospective cohort study recruited 605 participants aged 65 or older from senior health checkup program at a tertiary medical center at baseline (2011‐2013) with three biennial follow‐ups. After excluding participants with suspected dementia, stroke, brain tumor, incomplete or changing residential address between 2005 and 2011, 465 participants remained for analyses. Global and domain‐specific cognition (memory, attention, executive function, and language) were assessed at baseline and each follow‐up. Built environment data was obtained from 2005 land use survey in Taiwan. Two buffer zones (500 m and 1000 m) centering at each participant’s residential address were created to assess built environment by the following indices: (1) the percentage of public open space, (2) the number of cultural resources, and (3) sports venue. Generalized linear mixed models were used to explore the association between built environment and global or domain‐specific cognitive function adjusting for age, sex, socioeconomic status, apolipoprotein E e4 status, physical activity, physical function and chronic conditions.

Results

Over six years, more public open space was associated with better logical memory delaying theme recall (within a 1000‐m buffer: β=2.17), more cultural resources were associated with poor executive function (Trail Making Test A, within a 500‐m buffer: β=‐0.078). For every 1 year increment, more public open space was associated with poor executive function (Trail Making Test B, within a 1000‐m buffer: β=‐0.52), more cultural resources was associated with better executive function (within a 1000‐m buffer: β=0.006) and poor logical memory delayed theme recall (within a 500‐m buffer: β=‐0.019). No significant association was found for sports venues in relation to cognition.

Conclusion

We found that different neighborhood built environment was associated with the performance of specific cognitive domains. Findings from this study indicate that choosing proper neighborhood environment may prevent cognitive impairment in the preclinical stage of dementia.
Dynamic functional connectivity patterns associated with Alzheimer’s disease risk and protective factors
Authors: Dautricourt Sophie
Published: December 2021

Background

Regions of high functional connectivity (hubs) are particularly sensitive to Alzheimer’s disease (AD). Dynamic functional connectivity (DFC) recently emerged as a powerful technique to reflect changes in functional connectivity over a short time. In this study, we used resting‐state DFC to investigate whether transient connectivity configurations are associated with AD risk and protective factors.

Method

We collected resting state fMRI data in 127 healthy older adults from the Age‐Well cohort. We estimated DFC using a sliding window approach to identify the transient connection between the default mode network (DMN), the salience network (SN) and the executive control network (CEN) and identify different states using k‐mean clustering. Stepwise regression analyses were used to assess the relationship between the time spent in each state, the number of transitions between states and AD risk factors and biomarkers, including cardiovascular factors, depression, lifestyle (Lifetime of Experiences Questionnaire (LEQ), Cognitive Activity Questionnaire (CAQ)), cognition (Preclinical Alzheimer’s Cognitive Composite 5 (PACC5)), neuroimaging biomarkers (amyloid burden, glucose metabolism and hippocampal volume) and APOE4 status.

Result

We identified four states (Figure 1). Longer time spent in a configuration characterized by strong connections between all networks (State 1), was associated with higher scores in the CAQ (β=0.27, P=0.001) and PACC5 (β=0.25, P=0.011). More time spent in State 2, where the DMN is disconnected from the other networks, was associated with higher scores in the LEQ (β=0.21, P=0.015) and absence of hypertension or cholesterol. The time spent in a configuration where all networks are weakly connected (State 3), was associated with lower scores in the CAQ (β=‐0.23, P=0.001) and LEQ (β=‐0.22, P=0.007). The time spent in State 4, where the SN is disconnected from the other networks, was associated with lower hippocampal volume (β=‐0.19, P=0.040). Finally, higher number of transitions between states was associated with higher amyloid burden (β=0.21, P=0.025).

Conclusion

Distinct DFC patterns are differentially associated with AD risk. We were able to identify two DFC states associated with increased AD risk and two states associated with AD protective factors. These findings shed new lights on the dynamic neural mechanisms underlying reserve and vulnerability in healthy older adults.
Medial temporal lobe subregional atrophy in ageing and Alzheimer’s disease: A longitudinal study
Authors: Chauveau Lea , Kuhn Elizabeth , De la Sayette Vincent , Chetelat Gaël , de Flores Robin
Published: December 2021

Background

Medial temporal lobe (MTL) subregions are sensitive to Alzheimer’s disease (AD) but also to normal ageing. To enhance the clinical utility of this biomarker, we need to improve our understanding of the differential effects of age versus AD by i) encompassing the full clinical range from cognitively unimpaired (CU) to dementia, ii) including all MTL‐subregions with up‐to‐date approaches and iii) using longitudinal designs to assess atrophy more sensitively. This study aimed to fill these gaps.

Method

Longitudinal T1‐weighted MRI of 209 CU participants aged from 19 to 85 were used to estimate age‐related trajectories using polynomial best‐fit from model selection. AD‐related changes were compared i) across the Alzheimer’s continuum in 121 participants divided into amyloid‐β negative (Aβ‐, controls) and Aβ+ CU elderly, Aβ+ mild cognitive impairment (MCI) and AD demented patients; and ii) between 19 MCI‐to‐AD dementia converters and 34 non‐converters. All participants were followed up to 47 months. MTL‐subregions (hippocampus [HPC] ‐anterior[a] and posterior[p]‐, entorhinal cortex [ERC], Brodmann area [Ba] 35 and 36 ‐as perirhinal cortex [PRC] components‐, and parahippocampal cortex [PHC]) were segmented using a new longitudinal pipeline (LASHiS) and manually corrected when necessary. Statistical analyses were performed using mixed models.

Result

Adult lifespan models highlighted both linear (PRC, Ba35, Ba36, PHC) and non‐linear (HPC, aHPC, pHPC, ERC) trajectories (Figure 1). Aβ+ MCI and AD patients showed steeper volume decline over time in most subregions compared to controls. No significant differences between controls and Aβ+ CU or between Aβ+ MCI and AD patients were observed (Figure 2). MCI‐to‐AD dementia converters showed significant greater volume decline only in hippocampal subregions compared to non‐converters (Figure 3).

Conclusion

Our results emphasized the benefits of studying MTL‐subregions to distinguish age‐related changes from AD. MTL‐subregions were unequally vulnerable to the detrimental effects of ageing, and subregions displaying a late‐onset decline were particularly involved in AD from the MCI‐stage. However, none of these biomarkers detected changes at the preclinical stage (Aβ+ CU). Finally, our results suggested that hippocampal volumes could constitute reliable predictors of MCI‐to‐AD dementia conversion. Together, these findings provide a better understanding of MTL alterations, which is crucial for the definition of AD‐specific biomarkers.
Sildenafil reduces the incidence of Alzheimer’s disease
Authors: Cheng Feixiong , Fang Jiansong , Zhang Pengyue , Zhou Yadi , Chiang Chien‐Wei , Pieper Andrew A. , Cummings Jeffrey L.
Published: December 2021

Background

There is an urgent need for effective therapeutic treatments for patients with Alzheimer’s disease (AD).

Method

To address this need, we developed an endophenotype molecular network‐based methodology for AD drug repurposing and then validated network‐based predictions using state of‐the‐art pharmacoepidemiologic analysis of 7.23 million U.S. commercially insured individuals. We conducted five comparison analyses: (i) sildenafil (n = 116,412) vs. a matched control (n = 460,356), (ii) sildenafil vs. diltiazem, (iii) sildenafil vs. losartan, n = 664,265), (iv) sildenafil vs. glimepiride, and (v) sildenafil vs. metformin, n = 723,082). We estimated the un‐stratified Kaplan‐Meier curves and conducted propensity score stratified log‐rank tests and the Cox regression model.

Result

We found that sildenafil usage was significantly associated with a 69% reduced risk of AD, compared with matched non‐sildenafil users (hazard ratio [HR] =0.31, 95% confidence interval [CI] 0.25‐0.39, P < 1 × 10‐8) after 6 years of follow‐up. Propensity score‐stratified cohort studies reveal that sildenafil usage is significantly associated with a 65% reduced risk of AD compared to diltiazem (HR 0.35, 95% CI 0.29‐0.44, P < 1 × 10‐8), a 55% reduced risk compared to losartan (HR 0.45, 95% CI 0.35‐0.55, P <1 × 10‐8), a 64% reduced risk compared to glimepiride (HR 0.36, 95% CI 0.28‐0.45, P <1 × 10‐8), and a 63% reduced risk compared to metformin (HR 0.37, 95% CI 0.30‐0.45, P <1 × 10‐8). Sildenafil usage was significantly associated with reduced likelihood of AD across all five drug cohorts in individuals (Figure 1) with coronary artery disease (CAD), hypertension (HT), and type 2 diabetes (T2D), and in individuals after excluding CAD, HT, and T2D. Age‐specific subgroup analyses showed that sildenafil was significantly associated with reduced likelihood of AD across all five drug cohorts in both mid‐older (65‐74 years) and older individuals (75‐100 years). In vitro experiments show that sildenafil downregulates GSK3β and CDK5 in human microglia cells, supporting a possible mechanism for its beneficial effect in AD.

Conclusion

This study supports a proof‐of‐concept of endophenotype‐based drug discovery and identifies that sildenafil is a promising drug candidate for prevention and treatment of AD.
Results of the first‐in‐human, randomized, double‐blind, placebo‐controlled phase 1b study of lumbar intrathecal bolus administrations of antisense oligonucleotide (ISIS 814907; BIIB080) targeting tau mRNA in patients with mild Alzheimer’s disease
Authors: Mummery Catherine J , Junge Candice , Kordasiewicz Holly B , Mignon Laurence , Moore Katrina M , Yun Chris , Baumann Tiffany L , Li Dan , Norris Daniel A , Crean Rebecca , Graham Danielle , Huang Ellen , Ratti Elena , Lane Roger M
Published: December 2021

Background

ISIS 814907 (BIIB080) is an antisense oligonucleotide (ASO) that hybridizes to a complementary nucleotide sequence of mRNA of the human microtubule‐associated protein tau (MAPT) gene, preventing production of tau protein. Accumulation of hyperphosphorylated tau is associated with cognitive decline and brain atrophy in Alzheimer’s Disease (AD). The placebo controlled period of the Phase 1b multiple ascending dose (MAD) study of ISIS 814907 in patients with mild AD is complete and the open‐label long term extension (LTE) is ongoing in the UK, Canada, Germany, Sweden, Netherlands and Finland (EudraCT: 2016‐002713‐22; NCT03186989).

Methods

The study is divided into 2 parts. Part 1 is the MAD study, comprising a 3‐month Treatment Evaluation (TE) Period and a 6‐month Post‐Treatment (PT) Period. Part 2 is the open‐label LTE, comprising a 12‐month TE Period and a 4‐ or 6‐month PT Period. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal (IT) bolus administrations of ISIS 814907 or placebo. Male or female patients aged 50‐74 years with mild AD and confirmed amyloid positivity (via CSF) at Screening were considered eligible. The primary objective was to assess safety and tolerability of multiple IT bolus administrations of ISIS 814907. The secondary objective was to evaluate CSF pharmacokinetics (PK). Exploratory objectives include assessment of plasma PK, target engagement and disease biomarkers, genotype and clinical endpoints relevant to AD.

Results

All subjects (N=46) completed the MAD TE Period and 43 subjects completed the PT Period. All AEs were mild/moderate in severity. No serious AEs occurred in subjects receiving ISIS 814907. Dose‐dependent mean reduction from baseline in CSF total tau and phospho‐tau was observed in the TE period and continued in the PT period. CSF total tau and phospho‐tau reductions were comparable.

Conclusions

IT bolus administration of multiple ascending doses of ISIS 814907 over 3 months was well‐tolerated in patients with mild AD. The robust lowering of CSF total tau and phospho‐tau warrants further investigation for the treatment of AD.
Trajectories of gait and cognitive decline in aging, and as a function of parental longevity and the motoric cognitive risk syndrome
Authors: Jayakody Shanika Oshadi , Ayers Emmeline , Verghese Joe , Barzilai Nir , Milman Sofiya , Weiss Erica , Blumen Helena M.
Published: December 2021

Background

Accelerated gait decline in aging often precedes mild cognitive impairment, Alzheimer’s disease, and related dementias. The relative trajectories of gait and cognitive decline are poorly understood, particularly, in older adults who are a) more resilient to cognitive impairment because they are offspring of parents with exceptional longevity (OPEL) and, b) at increased risk for cognitive impairment and dementia because of the Motoric Cognitive Risk (MCR) syndrome. MCR is a pre‐dementia syndrome, characterized by slow gait and subjective cognitive complaints. We examined trajectories of gait and cognitive decline in older adults overall, and as a function of parental longevity and MCR.

Method

LonGenity study participants (n=1,095; M Age=75.4±6.7 years) were followed for up to 12 years (M =6.6±3.4 years). Participants were of Ashkenazi Jewish descent and free of dementia at baseline. 53% were OPEL and 9% had MCR. Gait speed was measured on an instrumental walkway. Standardized performance on 13 different cognitive tests were examined separately, and as a composite global cognition score. Linear mixed‐effects models adjusted for baseline age, sex, education, cognitive impairment, and parental longevity were used to examine trajectories of gait and cognition over time – and as modified by parental longevity and MCR.

Result

Gait speed and performance on all cognitive tests (except phonemic fluency and digit span) declined with time. Gait speed (β= ‐0.076; 95% CI= ‐0.083‐0.070) declined faster than cognitive tests, including figure copy (β= ‐0.041; 95% CI= ‐0.050‐0.031), digit symbol substitution (DSST; β= ‐0.036; 95%CI= ‐0.041‐0.031), and trail‐making test interference (β= ‐0.032; 95%CI= ‐0.024‐0.040). Global cognition, DSST, and logical memory declined at a slower rate in OPEL. Figure copy performance declined at a faster rate in MCR.

Conclusion

These findings suggest that 1) gait declines faster than most cognitive functions in aging, 2) OPEL are more resilient to cognitive decline in general, and processing speed/attention and memory in particular, and 3) individuals with MCR are more susceptible to visuo‐spatial and executive function decline. This study adds important knowledge of trajectories of gait and cognitive decline in aging, and identifies a protective factor and a risk factor of age‐related cognitive decline.