bluuebunny/crossref_metadata_2025 huggingface dataset:
Dementia‐related psychosis symptoms and impact from the patient and care partner (caregiver) perspective: An observational, prospective study to describe the patient experience
Authors: Brandt Teresa , Frangiosa Theresa , Biggar Virginia , Taylor Angela , Keller Bill , Abler Victor
Published: December 2020

Background

This study aimed to describe the person‐centered experience of symptoms and impact of dementia‐related psychosis (DRP) from a patient and care partner (CP) perspective.

Methods

This observational, non‐interventional, prospective study collected patient experience data to understand the impact of DRP in persons with various dementia subtypes. Qualitative interviews were conducted with persons or their CP who have a clinical diagnosis of all‐cause dementia with psychotic symptoms, recruited through physician referrals. The quantitative online survey was completed by persons with self‐reported DRP or their CP recruited by advocacy groups: UsAgainstAlzheimer’s and the Lewy Body Dementia Association. CP burden was beyond the scope of this study.

Results

Sixteen individuals (1 patient, 15 CP) participated in the qualitative interview. The most commonly reported symptoms of DRP were visual hallucinations (88%), auditory hallucinations (69%), and persecutory delusions (56%). Participants described an impact of DRP on activities of daily living (75%), sleep (63%), family life (56%), and safety concerns (56%). The quantitative portion was completed by 212 participants (26 patients, 186 CP). DRP symptoms most frequently reported by patients were visual hallucinations (89%), auditory hallucinations (54%), and distortion of senses (54%); those reported by CP were paranoid delusions (76%), visual hallucinations (75%), and lack of trust for loved ones (52%). For patients with recent visual hallucinations, 61% of patients and 70% of CP reported experiencing this symptom on a weekly basis. When asked to rank the impact on the patient’s life, patients reported that visual hallucinations were the most impactful symptom (Figure 1) whereas CP reported paranoid delusions/false beliefs as most impactful, followed by visual hallucinations (Figure 2). Difficulty differentiating what is real from what is not real, increased anxiety, and effects on personal relationships were the most common types of impacts reported by both patients and CP. Most patients (>40%) were not receiving medications for DRP.

Conclusions

Persons with DRP experience hallucinations and delusions that have a substantial impact on their lives. Here, patient experience data demonstrate that there is a need for treatments to reduce the symptoms and impacts of DRP.
Characteristics of currently available informant‐based tools to obtain collateral information for diagnosis and monitoring of cognitive disorders
Authors: Choudhury Samira
Published: December 2020

Background

To systematically review literature on informant based tools for the diagnosis and monitoring of neurocognitive disorders and make evidence based recommendations to clinicians and researchers as part of the 5th Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia.

Method

A systematic search was performed in MEDLINE, PsycINFO, Cochrane, and EMBASE databases. Limits used for searches were humans, English, and age above 45. Articles that validated the tools and or described their key properties were included. The original search yielded 358 articles. After removing duplicates and reviewing titles and abstracts, 167 remained and were reviewed in full text. Eventually 92 articles that described 16 informant based tools were included for final review.

Result

Based on comprehensiveness and validity, 8 tools were found to be preferable for clinical and research use. AD8; Dementia Severity Rating Scale (DSRS); Everyday Cognition Scale (ECog); and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were selected for cognition and function and the Neuropsychiatric Inventory (NPI); Neuropsychiatric Inventory Questionnaire (NPI‐Q); Neuropsychiatric Inventory Clinician Rating scale (NPI‐C); and the Mild Behavior Impairment Checklist (MBI‐C) were selected for behaviour. Clinicians and researchers should choose a specific tool based on the need for comprehensive assessment versus desired efficiency depending on the setting.

Conclusion

There are a number of evidence based tools that are appropriate to use in clinical care and research settings to assess cognition, behavior and function. Tools can be chosen based on specific needs and available resources.
CSF proteomic profiling of mild cognitive impairment individuals with suspected non‐Alzheimer’s disease pathophysiology
Authors: Delvenne Aurore , Gobom Johan , Tijms Betty M , Bos Isabelle , Verhey Frans RJ , Ramakers Inez HGB , Scheltens Philip , Teunissen Charlotte E , Vandenberghe Rik , Gabel Silvy , Popp Julius , Peyratout Gwendoline , Martinez‐Lage Pablo , Tainta Mikel , Tsolaki Magda , Freund‐Levi Yvonne , Lovestone Simon , Streffer Johannes , Blennow Kaj , Zetterberg Henrik , Visser Pieter Jelle , Vos Stephanie JB
Published: December 2020

Background

Suspected non‐Alzheimer’s disease pathophysiology (SNAP) is a biomarker‐defined concept that encompasses individuals with Alzheimer’s disease (AD) neuronal injury but without amyloidosis. We have previously shown that 24% of mild cognitive impairment (MCI) individuals with SNAP will progress within 3 years to the AD dementia stage. Nonetheless, it remains unclear what explains the MCI‐SNAP biomarker profile and whether it reflects an early stage of AD, atypical AD or non‐AD pathology. We aimed to investigate the underlying pathophysiology of MCI‐SNAP using proteomics in cerebrospinal fluid (CSF).

Method

We included 206 individuals from the European EMIF‐AD MBD study and Maastricht BB‐ACL study. Based on CSF Aβ1‐42 (A) and p‐tau (T), individuals were classified as cognitively normal with normal A and T (CN, n=100), MCI with normal A and abnormal T (MCI‐SNAP, n=32), and MCI with abnormal A and T (MCI‐AD, n=74). We centrally generated CSF proteomic data for 1761 proteins using tandem tag mass spectrometry. We compared protein concentrations between groups using ANOVA adjusted for age and sex (1/3 observations per group minimum). We performed Gene Ontology enrichment analyses with false discovery rate to uncover the biological pathways of MCI‐SNAP. We investigated the expression profile of proteins in fetal/mature astrocytes, neurons, oligodendrocytes, microglia and endothelial cells.

Result

Sample characteristics are presented in Table 1. In MCI‐SNAP, we found 83 decreased and 28 increased proteins compared to CN and 177 decreased and 21 increased proteins compared to MCI‐AD. In MCI‐AD, we found 13 decreased and 193 increased proteins compared to CN. Proteins with decreased levels in MCI‐SNAP compared to both CN and MCI‐AD (n=55) were enriched for extracellular matrix, hemostasis, immune system, proteolysis and lysosome (Figure 1). A high percentage of these decreased proteins in MCI‐SNAP are expressed by mature astrocytes (51%) and endothelial cells (49%). Proteins increased in MCI‐SNAP and MCI‐AD compared to CN (n=17) were related to cytoskeleton organization and mainly expressed by neurons (88%).

Conclusion

Our results show that the pathophysiology of SNAP is distinct from that of AD. Further studies are needed to clarify the role of extracellular matrix, hemostasis, immune system, proteolysis and lysosome processes in SNAP.
AR1001 ameliorates Alzheimer’s disease pathology and symptoms by multi‐mechanisms
Authors: Kang Byung Woo , Kim Fred , Choi Yoon Pyo , Lee Younje , Kwak Da Eun , Shin Jisu , Kim YoungSoo , Choung Jai Jun , Rhee Jinseol
Published: December 2020

Background

The accumulation of amyloid‐b (Ab) in the brain is the primary pathological hallmark of Alzheimer’s disease (AD). Aggregated Ab is associated with cytotoxicity by a variety of mechanisms leading to neuronal apoptosis and synaptic impairments. Here, we present experimental evidence showing that AR1001, a highly selective and potent phosphodiesterase 5 (PDE5) inhibitor, acts as a polypharmacological agent for the treatment of AD by promoting neuronal cell survival and inhibiting Ab accumulation.

Method

The in vitro toxic effects of Ab were examined using the human neuroblastoma derived SH‐SY5Y cell line and mouse hippocampal neuronal HT‐22 cell line. Cell‐free Thioflavin T (ThT) fluorescence assay and SDS‐PAGE with PICUP (Photo‐Induced Cross‐Linking of Unmodified Proteins) of Ab plaques were employed to test inhibition of Ab aggregate formation and reduction of preformed oligomers and fibrils. To identify transcription factors responsible for inhibitory effects of AR1001 on Amyloid Precursor Protein (APP) / b‐site APP cleaving enzyme 1 (BACE1) expression, the Transcription Factor Profiling Plate Array was used to monitor the activation/inhibition of various transcription factors. 5XFAD transgenic mice were used to evaluate Ab42 induced neurodegeneration and amyloid plaque formation. NSE/APP‐C105 transgenic mice were used to test spatial and learning memory in the Morris water maze test and the passive avoidance test.

Result

AR1001 markedly increased cGMP levels and activated cGMP/cGMP‐dependent protein kinase/cAMP responsive element‐binding protein (CREB) cascade in Ab‐treated SH‐SY5Y cells, promoting neuronal cell survival. In Ab‐treated HT‐22 cells, downregulation of Glucocorticoid Receptor (GR) transcriptional activity by AR1001 was responsible for reduced expression of APP, BACE1 and Dickkopf‐1 (Dkk1). In addition, AR1001 disrupted pre‐formed Ab42 fibrils in vitro. Interestingly, AR1001 reduced deposition of Aβ plaques in 5XFAD transgenic mouse brain by activating the autophagic process. Finally, AR1001 significantly improved memory functions in NSE/APP‐C105 mice.

Conclusion

Our findings strongly support that AR1001 has benefits against the accumulation of Ab and cognitive deficits in AD mouse models. We have demonstrated that AR1001 serves as a polypharmacological agent to inhibit PDE5 activity, promoting cell survival, and downregulate GR activity, reducing APP/BACE1 expression.
Longitudinal increase in depressive symptoms in relation to neurodegeneration in clinically normal older adults: Findings from the Harvard Aging Brain Study
Authors: Premnath Pranitha , Marshall Gad A. , Buckley Rachel F. , Donovan Nancy , Jacobs Heidi I.L. , Amariglio Rebecca , Vannini Patrizia , Chou Hsiang‐Chin Lori , Properzi Michael J. , Quiroz Yakeel T. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Hanseeuw Bernard , Gatchel Jennifer R.
Published: December 2020

Background

Evidence suggests that depressive symptoms may be early behavioral changes preceding the development of Alzheimer’s Disease (AD). However, the neurobiological trajectory of depressive symptoms in reference to neurodegeneration of the hippocampus—a structure implicated in both mood and memory regulation—remains poorly understood in preclinical AD. In the current study, we examined the impact of baseline hippocampal volume (HV) both independently, and interactively with amyloid‐ß, on longitudinal change in depressive symptoms in clinically normal (CN) older adults.

Method

270 Harvard Aging Brain Study participants (age:73.5 ±6.1; 58% females) completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=4.28 annual visits). All participants were cognitively unimpaired without clinically significant depression at study entry (mean GDS=3.09±2.86; range: (0‐12)). All underwent structural MRI scans and amyloid‐ß (11C‐Pittsburgh Compound B) PET at study year 1. In the primary linear mixed model, the association between dependent variable GDS (for each annual study visit) and HV was examined, with a random intercept and slope for each participant, covariates: age, sex, and education; and the interaction of predictors with time. In a secondary model, HV X cortical amyloid, X time was additionally included as a predictor.

Result

In the primary model, lower baseline HV (ß=‐0.0006; t=‐1.909; 95 % CI (‐1.2 x 10‐3, 1.7 x10‐5); p=0.057), but not its interaction with time (HV X time:(ß =‐0.000; t=‐1.12; 95% CI (‐7x10‐5, 6x10‐5); p=0.903) was marginally associated with higher GDS. In the secondary model, baseline HV and cortical amyloid were not interactive predictors of longitudinal GDS (HV X cortical amyloid X time: (ß =‐0.0001; t=‐0.90; 95% CI (‐4x10‐4, 0.0002); p=0.364).

Conclusion

Lower baseline hippocampal volume is marginally associated with greater depressive symptoms; however, it did not independently, or in synergy with cortical amyloid, predict worsening depressive symptoms over time. These preliminary findings suggest that hippocampal atrophy may not be a predominant indicator of accelerating depression in CN older adults. Of note, our sample was non‐depressed at baseline. Future work in samples with non‐restricted behavioral symptoms and incorporating longitudinal AD biomarkers is needed to better understand neurobiological trajectory and identify targets for treatment at the earliest stages of AD.
Blood‐based detection of early‐stage Alzheimer using multiomics and machine learning
Authors: Souchet Benoit , Michaïl Alkéos , Billoir Baptiste , Mouton‐Liger Francois , Fortea Juan , Lleó Alberto , Paquet Claire , Braudeau Jerome
Published: December 2020

Background

The diagnosis of AD is based on cognitive symptoms, CSF assays and PET imaging. A blood test capable of detecting patients suffering from AD, at a prodromal or even pre‐symptomatic stage, will reduce the invasive and costly diagnostic tools currently used and, would allow an earlier clinical intervention. Here we assess the performance of a multiomics blood test using Machine Learning to combine metabolomic and proteomic biomarkers, pre‐identified in a brand‐new rat model.

Method

By sampling the plasma of a non‐transgenic animal model successfully reproducing the continuum of Alzheimer's disease progression at the brain level (Audrain et al., 2017), we identified the 105 most informative biomarkers using Artificial Intelligence. Then we analyzed the behavior of these biomarkers in 232 human plasma samples collected up to 15 years before the dementia. Three independent cohorts were used: two with the sporadic form of AD and one with Down Syndrome individuals. For each sample the 105 pre‐identified biomarkers (proteins, metabolites) were analyzed by global mass spectrometry. Using Artificial Intelligence, we identified the 25 best‐in‐class biomarkers in humans. Then we developed a neural network based on these 25 biomarkers to detect AD patients from the pre‐symptomatic phase.

Result

Among the 25 biomarkers, 13 are proteins and 12 are metabolites. None of these biomarkers are produced by the brain. They are produced or regulated by peripheral organs. The neural network identify Alzheimer’s patients (including pre‐symptomatic, prodromal and demented patients) from Non Alzheimer Individuals (Healthy controls and patients suffering from a neurodegenerative disease excluding Alzheimer) with 100% sensitivity and 99% specificity on a 5‐folds cross validation. Based on non‐linear and non‐monotonic biomarker progression, the neural network can identify undemented AD patients, including pre‐symptomatic and prodromal patients, against demented patient, with 99% overall accuracy.

Conclusion

In our retrospective, multi‐center study, we achieved high accuracy (>99%) for Alzheimer’s from pre‐symptomatic phase. Proteic and metabolomic signals are required for an effective early detection. These results strongly suggest that the use of non‐brain‐produced biomarkers improves sensitivity and specificity of early detection.
The interrelationship between medial temporal atrophy and APOE4 biomarker: A comparison between Hispanics and white non‐Hispanics
Authors: Garcia Patricia , Mendoza Lisandra , Padron Dileanna , Duarte Andres , Duara Ranjan , Loewenstein David A , Greig‐Custo Maria T , Barker Warren W , Rodriguez Miriam J
Published: December 2020

Background

The Apolipoprotein E (APOE) gene is a major risk factor in developing late‐onset Alzheimer’s disease (AD; LOAD; de Oliveira et al., 2017; de Oliveira et al., 2014). The relationships between E4 genotype, brain morphology and ethnicity may provide insights into mechanisms by which ethnicity is associated with risk for AD. Because most research on genetic biomarkers has been conducted with Caucasian samples, this study aimed to explore the relationship of E4 (+) status to regional brain atrophy among an ethnically diverse cohort (Hispanics and White non‐Hispanics [WNH]) that are cognitively normal (CN) or have Mild Cognitive Impairment (MCI). We hypothesized that E4 (+) would be associated with brain atrophy in both ethnic groups.

Method

Cross sectional analysis of 240 participants was conducted of which 80 (23.1%) were E4 (+) (mean age= 71.02, SD=7.11); mean education= 14.46 (SD=3.42); 64.9% (n= 48) of the cohort were female. When stratified according to cognitive functioning (CN, MCI), the E4 (+) cohort was comprised of 32 WNHs (46.4%) and 35 Hispanics (50.7%). Pearson correlations were conducted between E4 (+) and volumetric variables (normalized to intracranial volume) in medial temporal regions sensitive to AD pathology—hippocampus, entorhinal cortex (ERC), and parahippocampal cortex (PHC).

Result

A significant negative correlation was found between E4 (+) with L‐PHC (r= ‐.352, p= .022) and R‐PHC (r= ‐.348, p=. 024) among the combined CN group. When stratified by ethnicity, a negative correlation was seen in CN‐Hispanics between E4 (+) and L‐PHC (r= ‐.593, p= .002). No significant correlations were identified for WNH in both clinical groups and for MCI‐Hispanics.

Conclusion

Our findings indicate that E4 (+) status is associated with medial temporal brain atrophy among cognitively normal individuals. When examining ethnic groups, these correlations were evident among CN‐Hispanics. At the MCI stage, when brain pathology begins, these associations were not as strongly evident. Our findings highlight the importance of studying biomarkers among culturally diverse groups. Given the projected growth of Hispanics in the US, ongoing efforts should aim at disentangling cultural and genetic variables and their contribution to AD pathophysiology.
Virtual reality–based mindfulness training, sensory activation and mental assessment in dementia care
Authors: Paletta Lucas , Schüssler Sandra , Kober Silvia Erika , Zweytik Elke , Steiner Josef , Andreu Jean‐Philippe , Fuhrmann Ferdinand , Pszeida Martin , Dini Amir , Grabher Anna , Taberhofer Anna , Staubmann Wolfgang L , Draxler Theresa L , Lampl Christina L , Mayr Marlene L , Kölbl Gertraud L , Wood Guilherme L
Published: December 2020

Background

Recent studies underline the importance of cognitive reserve, which is supported by stress reduction, pleasure experience and meditation, for mental health. Mindfulness training is successfully applied to dementia and indicate a lasting positive effect on cognitive reserve, well‐being and motivation. The research project OpenSense investigated the potential of VR‐based intervention and assessment for dementia care in a proof‐of concept study. The VR‐based intervention was developed to foster mindfulness and sensory activation.

Method

VR‐based intervention was applied in persons with dementia (PwD) with Alzheimer’s dementia (AD; n=12, age M=85.0 years, MMSE M=21.5) and healthy controls (n=12, age M=75.1 years, MMSE M=30) using 30 minutes of panoramic video‐based multi‐sensory experiences presenting stimuli that empower relaxation (body‐scanning, beach, forest) and activation (bakery, orchestra). EEG‐based alpha‐band signals (8‐12 Hz) associated with relaxation and inhibitory control were recorded before, during and after intervention and eye tracking was applied during intervention.

Result

Pre‐post EEG analysis showed significant increases in alpha power and brain connectivity for PwD with AD and controls (post > pre, p<.05). EEG baseline alpha power demonstrated higher values for healthy controls than for PwD (AD). Eye movement analysis demonstrated significant differences between PwD (AD) and controls: eye blink rate AD > controls, p=.004(**) from the observation of a 3 minutes video, and significant correlation (Rho=.607, p=.003(**); 3 minutes video) was achieved between eye movements and the Freiburg Mindfulness Inventory score.

Conclusion

The potential of VR‐based intervention based on mindfulness and sensory activation is very promising: the study demonstrated significant increases of EEG alpha power and brain connectivity where PwD usually suffer from decline and gaze data acquired during intervention indicate potential for non‐invasive assessment for decision support. OpenSense anticipates numerous opportunities for novel VR‐based care services for empowering cognitive reserve, inducing sensory activation, raising awareness and motivation for self‐regulation, and as pervasive assessment tool.
Gerocovid 19 and implications for territorial management of old people affected with dementia
Authors: Gareri Pietro , Cotroneo Antonino Maria , Nisticò Michelangelo , Perrone Rosalia , Signore Susanna Del , Incalzi Raffaele Antonelli
Published: December 2020

Background

This study is part of a wider observational project addressed to old people in different care settings. To assess the suitable strategies to deal with the lockdown created by the Covid‐19 emergency, to better care for the elderly outpatient and home patients suffering from cognitive disorders. Medical, social and psychological conditions will be evaluated for identifying the effects of Covid‐19 pandemics on older patients with dementia.

Method

The present study is retrospective and in part prospective and will involve 100 older adults. They will be administered MMSE for assessing cognitive functions, ADL, and IADL for functional status, CIRS for assessing comorbidities, 5‐items GDS for mood evaluation, and SF‐36 for detecting the perceived quality of life. Contacts with both outpatients and home patients will be managed either by phone, preferably by video call (Whatsapp, Facetime) or, in a few cases, via Skype.

Results

The results of tests, the prescription of aids, and treatment plans are recorded on an electronic registry as anonymized clinical data. Moreover, a general questionnaire about the clinical investigation site focusing on the specific preventive measures and the change of the operating methods at home was compiled on a dedicated Information Technology platform by all participating centers. Changes in blood pressure, use of personal protective equipment, the need for operators or patients to quarantine in the event of suspected/full‐blown infection will be reported. Other information will be requested on the effects of social distancing, the presence of formal/informal caregivers, and the methods of procurement. Psychological reactions to the effects of isolation at the baseline and three months (anxiety, depression, acceptance, denial), changes in sleep, and bowel function and differences according to housing conditions will be assessed as well.

Conclusion

The Gerocovid 19 could be a remarkable study for the management of outpatient and home patients affected with cognitive disorders.
Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic Caenorhabditis elegans
Authors: Benbow Sarah J , Strovas Timothy J , Darvas Martin , Saxton Aleen , Kraemer Brian C
Published: December 2020

Background

Aggregates of Aβ peptide and the microtubule‐associated protein tau are key molecular hallmarks of Alzheimer's disease (AD). However, the interaction between these two pathologies and the mechanisms underlying disease progression have remained unclear. Numerous failed clinical trials suggest the necessity for greater mechanistic understanding in order to refine strategies for therapeutic discovery and development.

Method

To this end, we have generated a transgenic Caenorhabditis elegans model expressing both human Aβ1‐42 peptide and human tau protein pan‐neuronally. We used behavioral, morphological and biochemical assays to assess pathological progression.

Results

We observed exacerbated behavioral dysfunction and age‐dependent neurodegenerative changes in the Aβ;tau transgenic animals. Further, these changes occurred in the Aβ;tau transgenic animals at greater levels than worms harboring either the Aβ1‐42 or tau transgene alone and interestingly without changes to the levels of tau expression, phosphorylation or aggregation. Functional changes were partially rescued with the introduction of a genetic suppressor of tau pathology.

Conclusion

Taken together, the data herein support a synergistic role for both Aβ and tau in driving neuronal dysfunction seen in AD. Additionally, we believe that the utilization of the genetically tractable C. elegans model will provide a key resource for dissecting mechanisms driving AD molecular pathology.
Preventing Loss of Independence through Exercise (PLIÉ) improves behavioral outcomes and increases default mode network connectivity in people with mild cognitive impairment
Authors: Martinez Steven , Barnes Deborah E , Mehling Wolf , Chesney Margaret A , Lee Jennifer Ann , Lee Amanda , Chao Linda L
Published: December 2020

Background

Preventing Loss of Independence through Exercise (PLIÉ) is an integrative group movement program developed to improve quality of life and daily function in people with mild‐to‐moderate dementia. We performed a single‐arm pre‐post pilot trial to examine the impact of PLIÉ in people with mild cognitive impairment (MCI) on behavioral and neuroimaging outcomes.

Methods

Study participants, recruited from the community, had received MCI diagnoses or reported subjective memory complaints plus Montreal Cognitive Assessment (MoCA) scores ≤ 26. PLIÉ classes were 1‐hour, 2 days/week over 12 weeks with 8‐12 participants per class. Pre‐post outcomes included validated measures of cognitive function, physical performance, self‐rated quality of life, mood, affect, mobility, social isolation, attention regulation, self‐regulation, and well‐being. Neuroimaging measures included structural magnetic resonance images (MRIs) and resting state fMRIs. Participants also completed PLIÉ satisfaction surveys. Standardized effect sizes (ES) were calculated based on pre‐post change divided by the baseline standard deviation, and paired t‐tests were used to compare pre‐post scores. Changes in functional connectivity of the Default Mode Network (DMN) were examined using two nodes, the anterior medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), as seeds.

Results

Eighteen participants completed the 12‐week program. Participants were 74.9±9.1 years old (11 men, 7 women) and predominately white. Half were US‐veterans. We observed pre‐post improvement on measures of cognitive function (ES=0.33, p=0.001), physical performance (ES=0.39, p=0.047), social isolation (ES=0.62, p=0.009), and self‐regulation (ES=0.55, p=0.006). Though not statistically significant, most other measures suggested improvement with clinically meaningful effect sizes. Neuroimaging revealed increased functional connectivity between nodes of the DMN, specifically between the hippocampus and the mPFC (p=.03) and between the PCC and bilateral parietal cortex after PLIÉ. Satisfaction ratings among participants were high (mean 3.95±.07; range 1‐4).

Conclusion

These preliminary findings provide proof‐of‐concept for the PLIÉ intervention in people with MCI and suggest that it may enhance cognitive function, physical performance, mood and well‐being, and increase DMN functional connectivity. Additional studies with a control group are warranted.
Role of gait and speed performance in predicting cognitive decline and dementia in people with Down syndrome: Preliminary findings
Authors: Gonçalves Aline Souza , Carvalho Claudia Lopes , Ramos Andressa Souza , de Fátima Rebouças da Silva Maria , Rigoleto Soares Cristiane Nogueira , Sant´Ana Livea Carla Fidalgo , da Costa Maria Lucia Gurgel , Fonseca Luciana Mascarenhas , Forlenza Orestes Vicente
Published: December 2020

Background

The longevity of people with DS has increased substantially in recent decades. This population shows signs of premature aging in many organs and systems. The neuropathology of Alzheimer's disease (AD) is overexpressed in DS. Cognitive and functional losses, such as decline in executive function and apraxia, interfere with the sequencing of movements and the integrity of gait. There is evidence that a decrease in gait may precede other clinical symptoms of dementia in AD in the general population, but we found no studies investigating gait performance and decline in DS. The aim of this study is to characterize gait and speed performance in a sample of adults with DS divided into three groups by diagnosis: stable cognition, prodromal dementia and AD.

Methods

We used the Performance Oriented Mobility Assessment (POMA) to address balance, gait and the risk of falls and the Timed “Up and Go” test (TUG) to assess gait speed in a sample of 35 individuals with DS over 35 years of age. Dementia diagnosis was based on the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX‐DS). The 1‐factor, 3‐level ANOVA model was used in the 3 groups.

Results

9 participants (25.7%) had AD (mean POMA 12.0 ± 7.1; mean TUG 18.0 ±5.8), 8 (22.9%) were classified as prodromal dementia (mean POMA 19.0 ± 5.6; mean TUG 21.0± 6.1) and 18 (51.4%) were in the stable cognition group (mean POMA score 20 ± 4.5; mean TUG 17.0 ±5.5). Mean POMA scores were significant different among the groups (p<0.05) with higher impairment in the group with AD relative to those with prodromal dementia and stable cognition. We did not find difference for the TUG scores among the groups.

Conclusions

POMA results indicates that those with AD have worse balance, gait performance and higher risk of falls relative to those with prodromal dementia and stable cognition, suggesting that gait performance may be more affected in later stages of neurodegeneration. Gait speed does not seem to be useful differentiating the groups. Further longitudinal studies with bigger samples are needed to confirm our results.
Saffron for mild cognitive impairment and dementia: A systematic review and meta‐analysis of randomised clinical trials
Authors: Ayati Zahra
Published: December 2020

Background

Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well‐known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti‐dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia.

Method

An electronic database search of some major English and Chinese databases was conducted until 31th May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev‐Man 5.3 software was applied to perform the meta‐analyses.

Result

A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐cog) and Clinical Dementia Rating Scale‐Sums of Boxes (CDR‐SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales including ADAS‐cog, CDR‐SB and SCIRS. Saffron improved daily living function, but the changes were not statistically significant. Adverse events were mild.

Conclusion

Saffron has the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However due to limited high quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.
Novel regulation of death‐associated protein kinase 1 in Alzheimer’s disease
Authors: Chen Dongmei , Mei Yingxue , Lan Guihua , Gan Chen‐Ling , Zhang Tao , Xia Yongfang , Wang Long , Lee Tae Ho
Published: December 2020

Background

Death‐associated protein kinase 1 (DAPK1) is a serine/threonine kinase that plays an important role in regulating neuronal function and is genetically linked to Alzheimer’s disease (AD). We previously showed that DAPK1 expression is markedly increased in 75% of human AD brains. Moreover, we found that DAPK1 promotes tau protein accumulation and its phosphorylation at multiple AD‐related sites. However, it is not known whether and how DAPK1 expression or activity is regulated in AD, including tau hyperphosphorylation and functions.

Method

We investigated the effects of melatonin on DAPK1 regulation by examining DAPK1 protein stability, and tau hyperphosphorylation and functions using comprehensive approaches in cell culture models, ex vivo mouse models, and human patient tissues. We synthesized biotin‐melatonin to demonstrate direct binding of melatonin and DAPK1. Moreover, we assessed the correlation of melatonin‐regulated DAPK1 expression and Pin1 phosphorylation because DAPK1 increases tau hyperphosphorylation through inhibiting the catalytic activity of Pin1.

Result

We discovered that melatonin critically regulates DAPK1 by reducing its protein stability, thereby attenuating tau hyperphosphorylation in AD. Melatonin decreases DAPK1 expression in a dose‐ and time‐dependent manner in primary neurons and neuronal cell lines. Moreover, the regulation of DAPK1 by melatonin is not dependent on DAPK1 transcription because DAPK1 mRNA levels are not affected by melatonin. Melatonin promotes the ubiquitination of DAPK1 and decreases its protein stability through a proteasome‐dependent pathway. Furthermore, melatonin directly interacts with the ankyrin repeat domain of DAPK1. Inhibition of DAPK1 by melatonin and a pharmacological DAPK1 inhibitor synergistically reduces tau expression and phosphorylation at multiple AD‐related sites. Melatonin and a DAPK1 inhibitor promote neurite outgrowth and microtubule assembly, which are disrupted by tau hyperphosphorylation. Mechanistically, melatonin‐mediated DAPK1 degradation increases the activity of Pin1, a prolyl isomerase known to play a protective role against tau hyperphosphorylation and AD. Finally, DAPK1 and melatonin levels are inversely correlated in the brains of human AD patients.

Conclusion

Our study demonstrates a novel role of melatonin in the direct regulation of DAPK1, and that synergistic targeting of DAPK1 by melatonin and DAPK1 inhibitors offers an attractive approach to block tau hyperphosphorylation in AD.
Theta‐gamma coupling and ApoE genotype in patients at risk for Alzheimer’s dementia
Authors: Patterson Rachel A , Brooks Heather J , Zomorrodi Reza , Kumar Sanjeev , Blumberger Daniel M , Graff‐Guerrero Ariel , Fischer Corinne E , Flint Alastair , Herrmann Nathan , Kennedy James L , Lanctot Krista L , Mah Linda , Mulsant Benoit H , Pollock Bruce G , Rajji Tarek K ,   PACt‐MD Study Group
Published: December 2020

Background

Theta‐gamma coupling (TGC) is an electroencephalography (EEG) marker of working memory and depends on robust synaptic plasticity within the recurrent prefrontal cortical networks (Rajji et al. 2017, Buszaski et al. 2012). ApoE4 allele has deleterious effects on synaptic plasticity (Teter et al. 2004). Thus, the primary objective of this analysis is to determine whether there is a relationship between ApoE4 genotype and TGC during the performance of a working memory task (N‐back).

Method

We used baseline data from a large Alzheimer’s dementia prevention trial. Participants were diagnosed with Mild Cognitive Impairment (MCI), past history of Major Depressive Disorder (MDD), or both (MCI+MDD) and had completed N‐back‐EEG and ApoE genotyping. TGC was measured across right and left frontal electrodes. Participants were grouped based on E4 presence (ApoE2/E3 or ApoE3/E3 [noncarriers] vs. ApoE3/E4 or ApoE4/E4 [carriers]).

Result

We included 248 participants (MCI= 125; MDD= 44, MCI+MDD= 79; 153 females/95 males). There were 182 ApoE4 noncarriers (age= 71±6.5; Theta power= 16,290±14,764; Gamma power= 5793±5663; TGC= 0.00251±0.00227; PiB frontal amyloid=1.4371±0.32) and 66 noncarriers (age=71±5.0; Theta power= 17,235±14,312; Gamma power= 6473±5287; TGC= 0.002184±0.001622; PiB frontal amyloid= 2.09±0.78). Multiple linear regression results show that ApoE4 carriers had reduced TGC (β= 0.205, p= 0.042, Cohen’s d= 0.28) after controlling for age, sex, diagnosis, theta power, gamma power, and PiB frontal amyloid. Gamma power was also a significant predictor of TGC.

Conclusion

Our results suggest that presence of ApoE4 allele contributes to the modulation of TGC during a working memory task. As ApoE impacts synaptic plasticity, our findings suggest that synaptic plasticity or other ApoE‐related mechanisms underlie TGC. Rajji, T.K., et al., Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. Cerebral Cortex, 2017. 27(2): p. 1482‐1490. Buzsaki, G. and X.J. Wang, Mechanisms of Gamma Oscillations, in Annual Review of Neuroscience, Vol 35, S.E. Hyman, Editor. 2012. p. 203‐225. Teter, B., ApoE‐dependent plasticity in Alzheimer's disease. Journal of Molecular Neuroscience, 2004. 23(3): p. 167‐179.
Time‐frequency analysis in a working memory task in pre‐clinical stage and symptomatic stage of Alzheimer’s disease
Authors: Doval Sandra , Serrano Noelia , Sanz David López , Fernández Ricardo Bruña , Losada María Luisa Delgado , Higes Ramón López , Dolado Alberto Marcos , Maestú Fernando
Published: December 2020

Background

The characteristic deterioration of the working memory (WM) in Alzheimer’s disease (AD), is also one of its first symptoms. Alterations of oscillatory activity have been evidenced in frequency bands in underlined neuronal processes during WM task execution; in comparison to healthy individuals; since the first clinical manifestation of the disease – in patients with mild cognitive impairment (MCI) ‐ until the lasts phases of the disease. However, those alterations in the WM have not been widely studied in individuals that refer subjective cognitive decline (SCD) without objective evidence of cognitive deterioration.

Method

The power of the underlined oscillatory activity during the maintenance period after an interruptor in a WM task was calculated by conducting a time‐frequency analysis. The results of three groups were compared: Controls (n = 46); SCD (n = 40), and MCI (n = 35).

Result

Statistically significant results were found between‐group. Patients with MCI evidenced a decrease in alpha band in temporal, parietal and occipital sensors of both hemispheres in comparison to controls (clusterF = 3.22e+04, p= 4.99e‐05, η2=0.09). SCD group showed a decrease in beta band in left hemisphere in frontal and parietal sensors (clusterF=3.65e+03, p=0.02, η2=0.06) in comparison to controls. SCD evidenced a decrement in theta band in the left hemisphere in fronto‐temporals sensors (clusterF=4.05e+03, p=0.02, η2=0.06).

Conclusion

As a conclusion, the subjective perception of SCD seems to have a biological correlate, assessable through alterations in the neuronal activity associated with WM maintenance.
Prevalence of neuropsychiatric symptoms related to dementia in individuals with Down syndrome
Authors: Fonseca Luciana Mascarenhas , Mattar Guilherme Prado , Haddad Glenda Guerra , Burduli Ekaterina , McPherson Sterling M , de Figueiredo Ferreira Guilhoto Laura Maria , Filho Geraldo Busatto , Yassuda Monica Sanches , Bottino Cassio M.C. , Hoexter Marcelo Queiroz , Chaytor Naomi S.
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are significant manifestations of dementia, with important consequences for patients and caregivers. Despite the established genetic link between Down syndrome (DS) and Alzheimer’s disease (AD), studies investigating NPS in individuals with DS and dementia are scarce. The Neuropsychiatric Inventory (NPI) was developed to identify symptoms of dementia and while it is widely used for the assessment of individuals with dementia in the general population, we have found no studies using the NPI in those with DS. The aim of this study is to characterize NPS in a sample with DS with heterogeneous cognitive profiles using the NPI

Method

Participants (N=92) with DS, ≥30 years of age were assessed with the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX‐DS). They were classified by a psychiatrist into three categories: AD, prodromal dementia, and stable cognition. Another psychiatrist blinded to the CAMDEX‐DS dementia diagnosis, evaluated the participants using the NPI. Chi‐square tests were used to check for significant differences in frequency of symptoms.

Result

Thirteen participants (14.1%) had AD, 17 (18.4%) were classified as prodromal dementia and 62 (67.5%) were in the stable cognition group. Prevalence of delusion, depression, anxiety, disinhibition, irritability, appetite abnormalities and total NPI did not differ between groups. Anxiety and irritability were common across all groups (∼50% of the total), while euphoria was not present in any participant. Hallucination, agitation, apathy, aberrant motor behaviour and night‐time behaviour disturbance showed significant difference among the groups (p<0.05), with higher prevalence in the group with AD.

Conclusion

The results indicate that individuals with DS and AD have some of the symptoms that are characteristically present among the general population with AD. Future studies are needed to understand if AD in DS is associated with a similar pattern of NPS observed among people with AD in the general population or may follow a specific NPS pattern. The high frequency of some NPS in individuals with DS and stable cognition should be considered in the diagnostic process in order to reduce the odds of generating a false positive.
Identification of NPTX2 as a prognostic biomarker of Alzheimer’s disease through a longitudinal CSF proteomics study in ADNI subjects
Authors: Libiger Ondrej , Shaw Leslie M , Watson Mark , Nairn Angus C , Umaña Kelly , Canet‐Avilés Rosa M , Jack Clifford R , Breton Yannick‐André , Cortes Laetitia , Chelsky Daniel , Spellman Daniel S , Baker Susan , Raghavan Nandini , Potter William
Published: December 2020

Background

Many biomarkers have been identified which are relevant to studies of Alzheimer’s disease (AD), especially pertaining to the evolution of amyloid plaque, tau tangle pathology and loss of brain tissue. There remains, however, the need for additional biomarkers that reflect pathologic processes affecting neuronal function during pre‐clinical and prodromal stages, to help accelerate drug development efforts.

Method

A retrospective investigation of longitudinal changes in concentrations of five analytes (CgA, NPTX2, VGF, SCG2, FABP3) was performed in CSF of ADNI subjects. Rates of longitudinal change in these candidate proteins were compared between: a) Cognitively normal subjects (CN; n = 76) versus subjects with mild cognitive impairment (MCI; n = 111) at baseline; b) Subjects categorized as p‐Tau181/Aβ1‐42 ratio positive versus negative at baseline; and c) ‘Progressors’, i.e., subjects who progressed from CN to MCI or MCI to Dementia within a predefined period versus subjects categorized as ‘non‐progressors’. Following a pre‐specified analysis plan involving mixed‐effects linear models adjusting for relevant covariates, the association between changes in each analyte’s concentration and subjects’ clinical progression was quantified.

Result

NPTX2, a protein involved in synaptic function, showed the strongest association with baseline clinical diagnosis of MCI, and a positive p‐Tau181/Aβ1‐42 ratio – the biomarker profile indicative of AD. Differences in the rates of decline in NPTX2 concentration between subjects classified as CN and MCI as well as between p‐Tau181/Aβ1‐42 ratio positive and negative subjects were highly significant (p=0.008 and p<0.0001 resp.), suggesting a complex interaction between the rate of decline in subjects at various stages along the disease continuum. Of the five analytes, only the rates of change in NPTX2 concentrations differed between progressors and non‐progressors (mean difference: 0.08 ± 0.02 ng/mL/year); p = 0.0004), further validating the association of changes in NPTX2 concentration and clinical prognosis. Additional exploratory analyses indicated the presence of a correlation between NPTX2 rates of change and declining cognition measured by MMSE (coef. = 0.3, p = 0.02), and Adas‐Cog 13 (coef. = ‐0.3, p = 0.01).

Conclusion

These results suggest that NPTX2 concentration may serve as a prognostic biomarker of accelerated cognitive decline in at least a subset of individuals with AD.
A systematic review of neuroimaging findings in subjective cognitive decline
Authors: Parker Ashleigh F , Ohlhauser Lisa , Scarapicchia Vanessa , Smart Colette M , Gawryluk Jodie
Published: December 2020

Background

Individuals with subjective cognitive decline (SCD), who self‐report changes in cognition, but are within the normal range on neuropsychological testing, are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (Jessen et al., 2014). This study aimed to synthesize findings of neuroimaging studies using various modalities to investigate changes in the brain in those with SCD.

Method

PubMed and PsycINFO databases were searched for neuroimaging studies of individuals with SCD. Quality assessment was completed using the Appraisal tool for Cross‐Sectional Studies (Downes, Brennan, Williams, & Dean, 2016).

Result

In total, 108 neuroimaging studies investigating SCD samples were identified. Specifically, 45 studies used MRI, 8 used EEG, 5 used MEG, 3 used CT, 26 used PET, 2 used SPECT, and 19 studies used multi‐modal neuroimaging methods. Many studies investigated differences between healthy controls and those with SCD. Across imaging modalities, findings revealed significant differences in brain structure and function between these groups.

Conclusion

It is valuable to synthesize the results of studies found in this area to identify neuroimaging biomarkers present in those with SCD. Identifying changes in the brain using objective and physiologically based measures at this early clinical stage will help to characterize the progression of Alzheimer’s disease. In future neuroimaging investigations of SCD, it would be useful for studies to include larger sample sizes, examine groups longitudinally, and use multi‐modal neuroimaging methods. Incorporating these components in future studies could provide a better understanding of changes in the brain that are associated with subsequent conversion to mild cognitive impairment or Alzheimer’s disease.