bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptual model of the purpose of meaningful occupation for people living with dementia developed through qualitative evidence synthesis
Authors: Strick Katherine Elizabeth , Garside Ruth , Thompson‐Coon Jo , Abbott Rebecca A
Published: December 2020

Background

Guidance for the provision of care for people with dementia asserts that occupation people find meaningful is essential for wellbeing, however definitions of meaningful occupation are often broad with the intrinsic meaning coming from within the person rather than the activity. As such the purpose of meaningful occupation, and how to gauge its effectiveness can be inconsistent. Through analysing the different purposes that occupation for people with dementia is perceived to have, this study created a conceptual model depicting the types of meaning that are seen as stemming from occupation.

Method

The conceptual model was developed through systematic review of 20 qualitative papers with synthesis based on meta‐ethnography.

Result

The fundamental purpose of occupation identified was to support the person with dementia to feel they were living a meaningful and fulfilling life. Three domains support a person to gain a sense of fulfilment through their occupations: A catalytic environment: For an occupation to be meaningful for a person with dementia it must be perceived by them as having value and legitimacy, this is supported by the physical and social environment around the person. A meaningful life: Living a meaningful life involves the person with dementia continuing to maintain links from across their life course in a way which supports their sense of personal value. This is reflective of their past, though also supports their present and future identity to evolve. Occupation as a tool: Occupation can also be used as a tool by people with dementia and those supporting them as a means to bring about a specific desired effect e.g. maintaining functional skills for independent living.

Conclusion

The model proposes how occupation could support meaning in multiple ways, and considers how these forms of meaning were influenced by the world views and values of the individual and context in which they were experienced.
Novel MRI markers of small vessel disease in relation to Alzheimer’s disease
Authors: van den Brink Hilde
Published: December 2020

Background

Vascular brain injury, particularly small vessel disease (SVD), is a common cause of cognitive decline and is detected on brain MRI in the majority of patients with dementia, including Alzheimer’s disease (AD). Established MRI markers of SVD related brain injury are white matter hyperintensities, lacunar infarcts, microbleeds and enlarged perivascular spaces. Yet, these MRI markers clearly do not cover the full extent of SVD related injury. Also, these lesions represent an end‐stage of injury to the parenchyma, rather than the actual abnormalities that occur in the small vessels themselves. In my presentation I will address a novel marker of more subtle parenchymal injury, cortical microinfarcts (CMI), and emerging markers of cerebral small vessel function.

Methods

Estimates from autopsy studies are that 100s to 1000s of CMI may be present in the brain of a single affected individual. High field strength imaging on 7Tesla MRI and further developments onto 3Tesla MRI has enabled in vivo detection of the largest CMI, and MRI rating criteria have been published. 7Tesla MRI is also used to zoom in on the small vessels themselves, and markers of cerebral small vessel function are emerging.

Results

MRI studies in patients with a clinical diagnosis of AD observe a CMI prevalence ranging between 8‐55%. These studies allow to investigate potential causes and consequences of CMI for the first time in vivo. It appears that CMI relate with worse clinical outcome and may be caused by various etiologies, including hypoperfusion, microemboli, and SVD pathology, in particular cerebral amyloid angiopathy. The novel measures of small vessel function that will be reviewed include measures of small vessel reactivity, and measures of blood flow velocity and pulsatility in individual penetrating arteries (diameter 100‐800 µm). Initial studies show abnormalities of these measures in patients when compared with healthy controls. I will review ongoing studies in patients with hereditary and sporadic SVD that aim to establish the value of these small vessel function markers in clinical research.

Conclusion

With these efforts we aim to advance insight into disease processes in SVD to help better understand the mechanisms underlying cognitive impairment and dementia.
Remote cognitive assessment approaches in the Dominantly Inherited Alzheimer Network (DIAN)
Authors: Hassenstab Jason , Aschenbrenner Andrew J. , Balota David A. , McDade Eric , Lim Yen Ying , Fagan Anne M. , Benzinger Tammie L.S. , Cruchaga Carlos , Goate Alison M. , Morris John C. , Bateman Randall J. ,   The Dominantly Inherited Alzheimer Network
Published: December 2020

Background

The “one‐shot” paradigm used in traditional in‐clinic cognitive assessments often produces unreliable data due to daily fluctuations in stress, sleep, test anxiety, and fatigue. In DIAN, an international study of familial Alzheimer’s disease (AD), these difficulties are compounded by the scarcity and younger age of the population. We have developed two assessment strategies to address these issues, which we are also validating in the Knight ADRC cohort. The first is a smartphone‐based cognitive assessment platform based on principles from ecological momentary assessment that uses frequent but extremely short (<60 seconds) tests of episodic memory, attentional control, and processing speed administered at random times over 7 days. We examine average performance and variability metrics across 7 days of assessments. The second is a web‐based assessment that focuses on repeated daily administration to measure long‐term memory decay and also skill acquisition learning. The rates of forgetting and rates of learning become the outcome measures.

Method

Digital assessments were completed on cognitively normal DIAN participants (n = 56 mutation carriers, n = 60 non‐carriers) and 120 mostly cognitively normal older adults from the Knight ADRC. Follow‐up evaluations were available for approximately 40 DIAN participants. Digital assessments were compared with standard in‐clinic cognitive tests and also with AD biomarkers including amyloid PET, cerebrospinal fluid (CSF) tau, tau PET, and structural MRI.

Result

Reliabilities of all remote cognitive measures ranged from 0.90‐0.98. All measures (Smartphone and web‐based) correlated with age (r’s 0.22‐0.69), indicating worse performance with increasing age. Correlations with standard in‐clinic measures ranged from 0.24‐0.77, suggesting that remote tests are valid measures of cognition. Test‐retest reliability from repeated smartphone assessments was exceptional for two smartphone measures (ICC’s = 0.89‐0.94). Critically, smartphone measures and web‐based measures demonstrated sensitivity to all AD biomarkers, including amyloid PET, tau PET, CSF tau, and structural MRI. We will present data on relationships with AD biomarkers and data on technical validation of smartphone cognitive measures and adherence strategies for remote studies.

Conclusion

Remote assessments that rely on short‐term but high frequency testing can be deployed worldwide in adults of all ages and demonstrate excellent reliability and validity compared to standard in‐clinic cognitive assessments.
The CITIDEMAGE Study: Stressing the cholinergic hypothesis for the best outcomes in dementia patients
Authors: Gareri Pietro , Cotroneo Antonino Maria , Orsitto Giuseppe , Putignano Salvatore
Published: December 2020

Background

Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline; it works through an increase in acetylcholine intrasynaptic levels and by promoting phospholipid synthesis, (chiefly phosphatidylcholine), cellular function, and neuronal repair. Memantine is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist used for the treatment of mild to moderate Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AchEIs) are widely used in AD patients. When co‐administered they could have a synergistic action in patients affected with AD and mixed dementia (MD) too. The aim of the present study was to show the effectiveness of oral citicoline plus AchEIs plus memantine in outpatients affected with AD.

Method

This was a retrospective study involving 4 centers in Italy between 2016 and 2018 on 169 patients aged 65 years old or older affected with AD (mean age 78.7± 4.9 years old). 84 patients were treated with AchEIs plus memantine plus citicoline 1g/day given orally (group A), 85 patients were treated with AchEIs plus memantine (group B). In both groups memantine and AchEIs were used at the highest dosage tolerated. The tests included MMSE, ADL and IADL, NPI, CIRS, GDS‐short form, the EuroQoL and the Sleep questionnaire. Tests were administered at baseline (T0), after 6 (T1), and 12 months (T2).The primary outcomes were the effects of combined treatment versus AchEIs plus memantine on cognitive functions assessed by MMSE.The secondary outcomes were the possible side effects or adverse events of combination therapy versus AchEIs plus memantine, the influence on daily life functions, behavioral symptoms, quality of life and sleep.

Result

Patients of group A showed a mild increase in MMSE at six (15.85±2.86 vs 16.39±2.93) and 12 months (16.39±2.93 vs 16.43±3.08). The difference in MMSE score was significant when comparing the two groups, both at T1 (p=0.003) and T2 (p=0.011).There were also a significant improvement in GDS (p=0.000) and in EuroQoL scores (p=0.01).

Conclusion

The present study encourages the role of combined treatment in disease management and for slowing down the progression of AD.
Impact of the presence of AβN3pE and AβpSer8 in Aβ aggregates on the induction of Aβ seeding and spreading in the brains of APP23 mice
Authors: Robberechts Tessa , Ronisz Alicja , Ospitalieri Simona , Koper Marta J. , Kumar Sathish , Walter Jochen , Willem Michael , Li Xiaohang , Thal Dietmar Rudolf
Published: December 2020

Background

Amyloid β‐plaques are a hallmark lesion of Alzheimer’s disease (AD) and consist of aggregates of the amyloid β‐peptide (Aβ). Aβ peptides can undergo posttranslational modifications, including N‐terminal truncation with subsequent pyroglutamate formation at glutamate 3, and phosphorylation at serine 8, leading to the formation of AβN3pE and AβpSer8, respectively. These posttranslationally modified forms are present in the brain in addition to non‐modified Aβ. During disease development the composition of the Aβ aggregates changes from aggregates without detectable modified Aβ, in non‐demented individuals, into aggregates containing AβN3pE and AβSer8 in symptomatic AD cases. Brain‐derived Aβ aggregates are capable of inducing deposition and spreading of Aβ pathology when injected into the brain of APP‐transgenic mice. Therefore, the question arises whether the composition of Aβ aggregates has impact on its seeding capabilities as well as on the composition of the seeded Aβ plaques.

Method

APP23 mice were injected into the left hippocampus at two months of age. They received injections from three different brain homogenates. The first one lacked detectable Aβ (control), in a second homogenate only Aβ without detectable modifications was found (p‐preAD), and in the third homogenate both Aβ and AβN3pE were detected. Mice were sacrificed at six months and their brains were immunohistochemically analyzed for the presence and composition of the induced plaque pathology.

Result

APP23 mice injected with the AD or p‐preAD brain homogenates developed similar Aβ plaque loads and the plaques exhibited AβN3pE and AβpSer8 immunoreactivity. Mice receiving control brain homogenates developed very few plaques in the injected hemisphere, which were detectable with antibodies against Aβ and AβN3pE, but not with anti‐AβpSer8.

Conclusion

The presence of Aβ seeds accelerates the accumulation of detectable amounts of AβN3pE and AβpSer8 and, thereby, promote the formation of fully mature Aβ aggregates similar to that seen in symptomatic AD patients. The acceleration of Aβ aggregate maturation, however, does not depend on the presence of posttranslationally modified Aβ forms in the seeds. Support: FWO.
Tau pathology mediates age effects on medial temporal lobe atrophy
Authors: Wisse Laura , Xie Long , Das Sandhitsu R. , De Flores Robin , Yushkevich Paul , Wolk David A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Age effects on the hippocampus are well established, but age‐effects on adjacent cortical regions less so. Moreover, aging has often been investigated using cross‐sectional designs, seldomly separating aging effects from the effects of β‐amyloid. We investigate the effect of aging on medial temporal lobe (MTL) subregions cross‐sectionally and longitudinally in β‐amyloid‐negative (A‐) cognitively normal (CN) older adults and the role of tau pathology, a potential mediator.

Method

T1‐MRI scans of 191 A‐ CN adults (71.7±6.0 years, 52.4% male) from ADNI‐GO/2 were segmented using a specialized method for MTL morphometry to obtain anterior/posterior hippocampus volumes, entorhinal cortex (ERC), Brodmann areas (BA) 35/36 and parahippocampal cortex thickness. Annualized atrophy rates were estimated with an unbiased deformation‐based morphometry method using follow‐up MRI scans within 2.1±0.1 years. All MTL subregions were corrected for sex and hippocampal volume also for intracranial volume. Cerebrospinal fluid levels of phosphorylated tau (p‐tau) were logtransformed. β‐amyloid status (A+/‐) was determined using a standard cutoff for amyloid PET.

Result

Cross‐sectionally age was significantly associated with hippocampal volumes and BA35 (Figure 1‐2). Longitudinally, MTL subregions showed atrophy rates significantly smaller than 0, and paired t‐tests revealed a significantly faster atrophy rate for BA35 than the other cortical regions (Figure 1). Older age was associated with increased atrophy rates in hippocampal volumes, ERC and BA35 (Table 1, Figure 3). A significant association was found for p‐tau levels with anterior and posterior hippocampus (trend) and with anterior and posterior hippocampal atrophy rates (Figure 4), which remained similar after a correction for age. Since the association for anterior/posterior hippocampus was similar, we performed a mediation analysis for total hippocampus, showing that aging leads to smaller hippocampal volumes (p<0.05) and faster hippocampal atrophy rates (p<0.10) through higher p‐tau levels (Figure 5), while covarying for β‐amyloid levels.

Conclusion

The cross‐sectional age effects on the MTL roughly matched longitudinal atrophy rates in A‐CN older adults, with most pronounced atrophy in the hippocampus and BA35, early sites of neurofibrillary pathology. The mediation analyses further supported an important role for tau pathology suggesting that Primary Age‐Related Tauopathy may partly mediate the observed age effects on the MTL.
Semantic impairment in very early Alzheimer disease
Authors: Liu Yi‐Chien ,   CTH MCI Research Group
Published: December 2020

Background

Comparing to episodic memory, semantic memory is less likely to be impaired in normal aging. Investigation of semantic memory may give us a better chance on detecting Alzheimer disease in early stage.

Method

In 2019, we collected 20 patients from our memory clinic. Half of them were diagnosed as amnesic MCI (mild cognitive impairment), half of them were their spouse. All of them received amyloid PET (florbetaben), brain MRI, ERP (evoked related potential) studies and detailed language evaluation. According to their clinical symptoms and status of amyloid deposition, they were grouping as normal, preclinical and prodromal stage.

Result

In picture description test, participants of prodromal group expressed fewer semantic contents and more filler words compared to others. No significant difference was found between preclinical and normal group. However, N400 (component of ERP, indicating semantic mismatch) showed difference between preclinical and normal group.

Conclusion

Semantic network impairment begins from preclinical stage of AD. Through detailed spoken language analysis, we could use it as early biomarker and trace disease progression.
Multimorbidity as a correlate of dementia among older people in Central Africa: The EPIDEMCA study
Authors: Guerchet Maëlenn M , Gbessemehlan Antoine , Mbelesso Pascal , Bandzouzi Bebene Ndamba , Yaffe Kristine , Clement Jean‐Pierre , Dartigues Jean‐François , Preux Pierre‐Marie ,   EPIDEMCA
Published: December 2020

Background

With global ageing, multimorbidity becomes a priority for global health research. Multimorbidity prevalence increases with age and is associated with poorer health outcomes. As people live longer, chronic conditions, including dementia, are rising in low‐ and middle‐income countries (LMIC) but the relationship between multimorbidity and dementia is not well studied despite its importance for dementia prevention. The aim of this study is to investigate the association between multimorbidity and dementia among older people in Central African countries.

Methods

A multicentre population‐based study was carried out in Central African Republic and Republic of Congo between 2011 and 2012 including both urban and rural sites. Participants aged ≥65 years old were interviewed using a structured questionnaire (sociodemographic data, clinical history) and underwent a physical examination. Multimorbidity (ie. the presence of two or more chronic diseases in the same individual) was ascertained as a count of up to 12 mental, cognitive and physical health conditions. Conditions were either collected through self‐report or assessed during the physical exam. DSM‐IV criteria were required for dementia diagnoses. The association of multimorbidity with dementia was assessed using logistic regression models.

Results

At baseline, 2002 participants were included across the two countries (mean age 73.3 ± 6.7 years, sex‐ratio M/F = 0.62) and 135 were diagnosed with dementia. Overall 55.3% of the participants had 2 or more chronic diseases, with hypertension, depression, heart disease, pulmonary conditions, and visual impairment as the most common comorbidities. A higher prevalence of multimorbidity was found in Congo than in Central African Republic. Dementia was significantly associated with the presence of multimorbidity (OR=1.45, 95%CI 1.01‐2.00), however the effect disappeared after adjustment on age, sex and study site. There was a non‐significant trend of greater odds of dementia with an increasing number of comorbidities.

Conclusions

The results support a high prevalence of multimorbidity among these older populations, especially among people with dementia. However, odds of dementia seemed to not be significantly impacted by multimorbidity in this context. Due to its high prevalence and low access to healthcare, this evidence remains of importance for medical care of comorbidities in older populations of sub‐Saharan Africa.
Impact of disease severity on quality of life, activities of daily living, and medical costs for people living with dementia in Japanese nursing home
Authors: Ashizawa Takumi
Published: December 2020

Background

Japan has the highest proportion of elderly aged 65 and over in the world, which accounts for 28.1% in 2018, and expected to reach 30.0% in 2025 and over 20% of those will suffer from dementia. This study aimed to evaluate the impact of severity of dementia on quality of life (QoL), activity of daily living (ADL), medical costs and caregiving costs in Japan.

Method

People living in nursing home under the Life Company Limited (N=2,114) were enrolled. Their QoL, ADL, and the severity of dementia were assessed by staff working in the facilities by using Euro‐QoL 5 dimension (EQ‐5D), Barthel Index (BI) and Mini‐Mental State Examination (MMSE), respectively. The medical and caregiving costs were derived from payment records and claim data between December 2018 and September 2019, respectively. All participants were sub‐categorized by MMSE score into three dementia groups of mild (21≦MMSE≦30), moderate (11≦MMSE≦20), and severe (0≦MMSE≦10). All results were assessed by using Shirley‐Williams test.

Result

Survey was conducted on Mar. 2019 and 1,491 people completed the entire questionnaires, of which, 592 used medical cares and 1,424 records for caregiving activities. Using MMSE scores, 561 were classified to mild group with mean age (SD) 84.9±8.7 years old and 67.7% accounted for women, 491 to moderate (87.3±6.9y, 73.9%) and 439 to severe (87.4±7.7y, 73.1%). Mean EQ‐5D scores for three groups were 0.75, 0.63 and 0.40, respectively. Mean BI scores were 78.5, 62.4, and 24.9, respectively. Significant decrements for both EQ‐5D and BI scores were observed for severe against mild or moderate groups. Annual out‐of‐pocket medical costs were not statistically differed by severity, or JPY11,445, 12,548 and 10,764 for mild, moderate and severe patients, respectively(not significant), while annual caregiving costs were increased as dementia becomes severer, or JPY2.1Mil, 2.4Mil and 2.8Mil for mild, moderate and severe patients, respectively (p<0.05)

Conclusion

Severity of dementia significantly impairs QoL and ADL, as observed from score decrements in EQ‐5D, BI and caregiving costs when severity worsened, while no significant difference was observed for medical costs.
iPSCs from Alzheimer’s disease patients display neuronal differentiation impairment of neural progenitor cells
Authors: Le Weidong
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common age‐related dementia associated with progressive neuronal loss. However, the cause of the disease is still unknown. Induced pluripotent stem cells (iPSCs) derived from somatic cells of AD patients provide unique opportunities to model the early development of AD.

Objective

The objective of this study is to use iPSCs system to determine the molecular mechanisms of neuronal loss in AD.

Methods

We used iPSC lines generated from fibroblasts of two familial AD (FAD) patients with autosomal dominant mutations in presenilin 1 (PSEN1) (S169del) or (A246E). We characterized the AD‐iPSCs characteristic properties of human pluripotent stem cells and differentiate them into functional neurons.

Result

We found abnormally enhanced neuronal differentiation in AD iPSC‐derived neural progenitor cells (AD‐NPCs), and a reduction in the number of NPCs in AD‐NPCs during differentiation. Consistently, we detected a decreased proliferation and an increased apoptosis in differentiating AD‐NPCs. In addition, we identified the same phenotypes when PSEN1 with the mutation of A246E was introduced into control iPSCs. Furthermore, knockdown of mutated PSEN1 in AD‐NPCs significantly attenuated the premature neuronal differentiation. Our results suggest that PSEN1 mutation causes reduction in the NPC pool, which might be relevant to the neuronal loss in the brain of AD patients. Additionally, our genome‐wide transcript analyses identified differentially expressed genes relevant to neuronal differentiation and cell cycle in differentiating AD‐NPCs.

Conclusion

Collectively, our study uncovers previously unappreciated early NPC dysfunctions in FAD‐NPCs and provides new cues to elucidate molecular mechanisms underlying AD development.
U.S. POINTER Imaging: Study design and launch
Authors: Lockhart Samuel N. , Baker Laura D. , Carrillo Maria C. , DeCarli Charles , Espeland Mark A. , Harvey Danielle J. , Jack Clifford R. , Jagust William J. , Jung Youngkyoo , Koeppe Robert A. , Lovato Laura , Snyder Heather M. , Toga Arthur W. , Vemuri Prashanthi , Woolard Nancy , Landau Susan M. ,   the U.S. POINTER Study Group
Published: December 2020

Background

Recent studies suggest that lifestyle changes (physical exercise, Mediterranean diet adherence, cognitive stimulation, vascular risk management) may protect against cognitive decline and reduce AD pathophysiology. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate whether lifestyle interventions can protect cognitive function in older adults (60‐79 years) who are at increased risk for cognitive impairment and dementia. The POINTER Imaging ancillary study will assess effects of the POINTER lifestyle interventions on neuroimaging biomarkers of AD and cerebrovascular pathophysiology, and whether baseline neuroimaging measures predict cognitive responses to the interventions.

Method

The POINTER Imaging ancillary study aims to enroll 1250 participants from the five U.S. POINTER sites. Ancillary study participants will undergo PET imaging (Baseline, Month 24) to measure Aβ ([18F]Florbetaben) and tau ([18F]MK‐6240) burden, and MRI (Baseline, Months 12 & 24) to measure brain morphometry, white matter (WM) hyperintensities and microstructure, and cerebral blood flow. U.S. POINTER provides standardized cognitive, clinical, genetic (e.g. APOE), and lifestyle activity assessments, and demographics for integration with neuroimaging data.

Result

The study design and methods for the POINTER Imaging ancillary study will be presented. The study will examine whether: (1) neuroimaging biomarkers at baseline (Aβ, tau, hippocampal volume, WM hyperintensities) predict intervention‐related cognitive changes and (2) biomarker outcomes are differentially modified by participation in lifestyle interventions. It will also examine changes in exploratory biomarkers (tensor‐based morphometry, microstructural integrity, microbleeds, cerebral blood flow).

Conclusion

The POINTER Imaging study aims to address gaps in our understanding of how a variety of lifestyle practices (diet, exercise, cognitive stimulation and vascular risk management) influence brain health. In particular, the study will determine whether imaging measurements of AD and cerebrovascular pathophysiology are amenable to improvement with the POINTER lifestyle interventions. It also aims to determine pathological profiles of individuals who benefit most from such interventions.
Severe systemic inflammation promotes persistent brain metabolic abnormalities
Authors: Bellaver Bruna , da Silva Eduarda J.F. , da Rocha Andreia Silva , Ferreira Pamela C.L. , Fontella Fernanda U. , Vasconcellos Alessandra Amaral , das Ros Lucas U. , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R.
Published: December 2020

Background

Severe systemic inflammation can spread to the central nervous system, promoting neuronal dysfunction. Individuals who survive to a severe inflammatory episode, have greater chances to develop cognitive impairment. In this context, brain inflammatory changes have been considered a risk factor for Alzheimer’s disease (AD). We previously demonstrated, a significant [18F]FDG hypometabolism 24 h after the induction of severe systemic inflammation by cecal ligation and perforation (CLP), a sepsis model. However, whether severe systemic inflammation causes long‐term effects on brain energy metabolism remains unclear. Here, we aim at Investigating persistent consequences of a severe systemic inflammatory episode on brain energy metabolism. We hypothesized that brain energetic metabolism does not completely recover from a systemic inflammatory episode, which could be a trigger for neurodegeneration.

Method

Wistar rats (90 days old) were submitted to CLP and, examined in vivo via Micro‐PET [18F]FDG imaging 30 days later. Albumin and cellularity in the cerebrospinal fluid (CSF) were assessed by HPLC and flow cytometry, respectively, as an index of blood brain barrier (BBB) integrity. HPLC was also used for evaluating glutamate levels in CSF and glutamate uptake was evaluated in hippocampal and cortical slices using a radioactive assay.

Result

We found a persistent brain [18F]FDG hypometabolism in the CLP group. A 4‐fold increase in albumin levels was observed, along with a prominent increase in cellularity in the CSF of CLP animals. Additionally, decreased glutamate uptake in cortex (32%) and hippocampus (16%) along with increased levels of glutamate in CSF was found in the CLP group (Figure 1).

Conclusion

These results that an episode of severe systemic inflammatory causes persistent brain metabolic disturbances and BBB damage. It is very likely that the long period of BBB disruption, allowing for communication between peripheral mediators/cells and the brain, compromises brain energy metabolism. Together, these findings suggest a link between peripheral inflammation and neurodegeneration.
Repetitive negative thinking is associated with subjective cognitive decline in older adults
Authors: Schlosser Marco , Demnitz‐King Harriet , Whitfield Tim , Marchant Natalie L.
Published: December 2020

Background

Subjectively experienced cognitive decline (SCD), particularly when accompanied by worries, has been associated with an increased risk for dementia. Repetitive negative thinking (RNT) is a transdiagnostic process that manifests across several mental health disorders previously associated with increased vulnerability to dementia. RNT has thus been proposed as a candidate psychological risk factor for dementia and, relatedly, could contribute to the manifestation of SCD.

Method

In a cross‐sectional online survey, 491 older adults (mean age = 64.9 years) completed measures of RNT and other theoretically informed psychological risk/protective factors for dementia, namely, personality (including neuroticism), purpose in life, worry, rumination, and meditation practice. SCD was assessed continuously via the Cognition Function Short Form and categorically via endorsement (yes/no) of worries about memory.

Regression models, using a stepwise backwards elimination, were built to assess associations between SCD and all psychological risk and protective factors. Final prediction models retained all explanatory variables associated with SCD at p < 0.01. Age, sex and education were retained in all models.

Result

RNT was the only psychological variable associated with SCD (SE = ‐0.52; 95% CI: ‐0.59 to ‐0.44; p<0.001), with higher RNT levels associated with worse self‐perceived cognitive function. A total of 16.1% of participants reported feeling worried about their memory. RNT was the only variable associated with worries about memory (OR = 2.20; 95% CI: 1.70 to 2.86; p<0.001).

Conclusion

This study empirically corroborates the theoretical relationship between SCD and RNT. SCD is a relatively newly defined clinical stage, and thus requires more research to better understand the clinical characteristics of the group. SCD has been associated with elevated anxiety and neuroticism (Jessen et al., 2014), but we show that neither worry (a core symptom of anxiety) nor neuroticism add explanatory power to predict SCD symptoms over and above RNT. The relationship between RNT and SCD therefore appears not to be based on the time orientation of negative thoughts (worry being future‐directed and RNT time‐independent). RNT, whether it be a prodromal symptom or independent risk factor, is a promising marker of dementia risk given its association with SCD.
Evolutionary neurotoxicology of manganese (Mn) and its implications for Mn‐induced mixed dementia
Authors: Hernandez Raul B. ,   Laboratory of Bioinorganic and Environmental Toxicology
Published: December 2020

Background

Manganese (Mn) is an essential element for all living systems, involved in several biological processes, but chronic and/or acute exposure for this metal can lead to adverse outcome pathways, especially neurotoxicity. In this manner; we hypothesized that if these alterations are conserved cross‐species, this must improve the understanding of the toxicological mechanisms of this metal. Thus, this study aimed to investigate the evolutionary neurotoxicology mechanisms of the manganese.

Methods

Different biological models (Saccharomyces cerevisiae ‐ yeast, Danio rerio ‐ zebrafish, Mus musculus ‐ cerebellar granular neurons and Homo sapiens ‐ human neuroblastoma SH‐SY5Y cell line) were exposed for chmical species of Mn and studied through different bioanalytical approaches such as cell viability‐MTT‐assay; sensitivity‐gene‐screening assay; b‐galactosidase assay; ribosome profiles; translation protein efficiency assay; semi‐quantitative proteomics ‐ tandem mass tag; metallomics; transcriptomics (human gene expression microarray kit and qRT‐PCR); bioinformatics (gene ontology and prediction of protein‐protein interaction, which were conducted at the String database and the comparative toxicogenomic database respectively. The results were expressed as mean ± SEM of at least 3 experiments; LC50 and statistically significant differences were estimated by ANOVA (analysis of variance followed by Bonferroni’s tests), using the GraphPad Prism 4.0 Software Inc, San Diego, CA, USA

Result

We revealed that chemical species of Mn2+ (0.001‐1.5 mM) disrupt metal homeostasis (K, Ca, Fe and Cu); protein metabolism, including translation, post‐translation, and protein degradation as well as associated pathways such as those involved in energetics, cell signaling, cell cycle and neurotransmitter metabolism, in a suite of organisms, from yeast to mammalian. Collectively these cross‐talking alteration of cell pathways potentially can explain with more precision the mechanism of neurotoxicity of this metal. Additionally, analysis in the comparative toxicogenomic database suggested that Mn‐induced neurotoxicity shares mechanism with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease; but sometimes involving different genes or proteins, which needs to be considered before drawing comparisons to humans.

Conclusion

The evolutionary neurotoxicology of the manganese showed in this study represent a new paradigm for Mn‐induced neurotoxicity and neurodegeneration and open a new avenue to study the role of other essential trace elements in similar pathogenic processes.
Sex differences in CSF biomarkers for neurodegeneration and blood‐brain barrier integrity
Authors: Skillback Tobias , Blennow Kaj , Zetterberg Henrik , Shams Sara , Machado Alejandra , Pereira Joana B. , Lindberg Olof , Mielke Michelle M. , Zettergren Anna , Rydén Lina , Westman Eric , Wahlund Lars‐Olof , Skoog Ingmar , Kern Silke
Published: December 2020

Background

CSF neurofilament light protein (NfL) is an important biomarker in several neurologic diseases. CSF NfL concentrations are known to increase with age, but sex differences have been less examined. The CSF/serum albumin ratio (QAlb) is a biomarker for blood‐brain barrier integrity, which has previously been found to be higher in men. As NfL and QAlb are used in clinical routine, the impact of demographic factors on these biomarkers is important to understand.

Method

Participants were derived from two samples. The first was a population‐based cohort of 308 70‐year olds from the Gothenburg H70 Birth Cohort Study, Sweden. The second data set comprised CSF NfL and QAlb results from 8995 and 39252 subjects respectively, generated in clinical practice between 2005‐2012 in Gothenburg, Sweden. In the population‐based study, QAlb and NfL concentrations were examined in relation to sex, cardiovascular risk factors, and MRI signs of cerebral white matter lesions. In the clinical routine cohort, sex differences in QAlb and NfL were tested in relation to age.

Result

In the population‐based sample, men had higher QAlb and NfL concentrations than women. NfL was not related to cerebral vascular pathology, but QAlb correlated positively with several measures of white matter lesions. In the clinical routine cohort, men also had higher QAlb and NfL concentrations from adolescence and throughout life.

Conclusion

QAlb ratios and CSF NfL levels are higher in men throughout life. The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.
Web‐based requisitioning, tracking and laboratory result reporting system for clinical trials using a central laboratory
Authors: Figurski Michal J. , Berlas Shaila , Korecka Magdalena , Foroud Tatiana M. , Galasko Doug R. , Shaw Leslie M.
Published: December 2020

Background

Chemical biomarkers are increasingly important in clinical trials. Many multi‐center trials use single core laboratory to process biomarkers, to ensure comparability of results. Sample shipment is accompanied by transmission of data between centers, core lab, and other entities. Often physical forms are used: transmitted via email, fax, or as paper forms. Consequently, flow of information about samples is restricted. Core laboratories receive inquiries about sample receipt on a daily basis. The process of information look‐up is a substantial burden on the lab personnel, more so when paper forms are involved, and especially when samples were not actually received.

Method

To alleviate the issues that arise in this setting, we created a secure web‐based system that integrates information about sample, shipment and test results. The application (“R3+ system” for Requisitioning, Tracking and Result Reporting) allows participating centers to enter information about samples being shipped (Requisitioning), track shipment and the progress of the sample as it’s received and analysed by the core laboratory (Tracking), and see results of analyses, along with full Audit Trail and automated timestamping of all steps (Result Reporting). Records, both current and past, can be retrieved at any time.

Result

The first project using the application is BioSTAC: a multi‐center trial evaluating biomarkers Abeta42, Tau and p‐Tau, in CSF samples shipped overnight at ambient temperature. Participating centers received no training in using R3+ except instruction on registering an account. Within the first 2 months of operation, 14 users from 11 centers registered their accounts. 24 samples have been requested and reported via this application to 6 centers. No usability or security issues were reported. BioSTAC users have requested to utilize the app in other projects, thus two other projects are now actively using this platform.

Conclusion

Implementation of the web‐based system for storage and transmission of data about the samples in clinical trials has proven to be easy to use and an efficient means of communication, as it replaces email, fax and paper forms, and eliminates the need for querying paper records. Users typically report high satisfaction using this system, while core laboratory personnel save time on administrative tasks.
A portable brainwave technology in detecting functional brain changes in aging and dementia: A pilot study on feasibility of the application in residential care older adults
Authors: Arvan Tara , Sepheri Kattie , Hajra Sujoy Ghosh , Pawlowski Gabriela , Fickling Shaun , D’arcy Ryan C.N. , Song Xiaowei
Published: December 2020

Background

A portable brainwave technology based on electroencephalography (EEG) / event‐related potential (ERP) has been established; i.e., the so called Brain Vital Signs ‐ BVS. Previous studies reported the development of the BVS framework and the characterization of BVS features in healthy younger adults. In the present study, we investigated the feasibility of application of this novel brainwave technology in older adult residents in long‐term care, and analyzed the relationship of the BVS scores in relation to age and dementia diagnosis.

Method

Fifty‐one residents in long‐term care (mean age=81.4±9.5 years; range =56‐98; 66% female) with or without dementia (31:20) participated in the study. Each participant was tested, in their residence facility, at baseline and followed for up to 12 months during which two more tests were conducted. At each test time, participants were scanned twice using the BVS device, with which the electrodes placed on the frontal, central, and posterior sites along the midline of the head. Three ERP components, N100 (perception), P300 (attention), and N400 (cognition) were identified and converted into normalized comparative scores, based on which BVS sub‐scores assessing the amplitude, latency, and the area under the curve of each component were computed. The BVS total score was generated based on the sub‐scores applying a weighted algorithm. Inter‐rater reliability was examined using Intraclass Correlation Coefficient. The BVS scores were correlated with age, and compared for dementia and cognitive status.

Result

Data were consistently collected from residential‐care older adults at each of the three time points with 100% success rate, suggesting the feasible application of the portably brainwave technology. Inter‐rater reliability rate was as high as 0.991‐1.000. The BVS total scores and several of the component scores were moderately related to age; e.g., Spearman correlation coefficient r=.262, p=.027 for P300 amplitude and r=‐.286, p=.016 for N400 latency. Some of the component scores differed by dementia status (e.g., t=‐2.03, p‐value= .046 for P300 latency).

Conclusion

The study suggests that BVS can be feasibly applied in studying older residents in long‐term care. Ongoing analysis effort is to better understand age‐ and dementia‐ associated changes of the BVS scores for practical result interpretation.
Relationship between regional atrophy and amyloid‐β load in Alzheimer’s disease and mild cognitive impairment
Authors: Bao Yiwen , Cheung Eva YW , Chau Anson CM , Zhang Huiqin , Zhang H , Chiu Patrick Ka‐Chun , Shea Yat Fung , Kwan Joseph SK , Mak Henry
Published: December 2020

Background

Mild cognitive impairment (MCI) is a transition stage between cognitively unimpaired and Alzheimer’s Disease (AD). Accumulation of amyloid‐β (Aβ) is considered as upstream event in the development of AD, while grey matter (GM) atrophy occurs in the late stage (Jack et al., 2010). In the cognitive continuum from MCI to AD, the correlation between two biomarkers are still not clearly known. From neuropathological perspective, the regional relationship between Aβ and GM atrophy is deficient.

Method

Aβ deposition was assessed by 18F‐Flutemetamol‐positron emission tomography (PET) and magnetic resonance imaging (MRI) was used to estimate grey matter volume (GMV). 17 AD subjects and 28 MCI subjects were recruited in our study and underwent both MRI and PET scanning. Based on fused MRI and PET images, Statistical parametric mapping (SPM) and voxel‐based morphometry (VBM) were used to obtain 18F‐Flutemetamol Standardized uptake value ratio (SUVR) and GMV respectively in 8 paired standardized region‐of‐interests and at global level. The correlations were assessed by partial correlation test controlling for age and sex.

Result

The mean differences of Aβ‐SUVR between AD and MCI were significant (p<0.0001) in most region‐of‐interests (ROIs) and globally. Compared to MCI group, AD group had significantly smaller GMV in hippocampus and mesial temporal lobe (p<0.0001) as well as globally(p<0.01) and in lateral temporal lobe (p<0.05). In AD group, GMV was negatively correlated with Aβ burden in left sensorimotor region (r=‐0.617, p<0.05), while positively correlated in mesial temporal lobe (left: r=0.682, p<0.0; right: r=0.522, p<0.05) and left hippocampus (r=0.548, p<0.05). For MCI group, GMV was negatively correlated with Aβ burden in right precuneus/posterior cingulate only (r=‐0.481, p<0.05).

Conclusion

Our result indicates that the relationship of amyloid deposition and neurodegeneration might vary during the cognitive continuum. In MCI stage, Aβ burden may lead to severe atrophy in right precuneus/posterior cingulate, early site where Aβ deposition occurs. However, in AD stage, Aβ accumulation might lead to sensorimotor (left) atrophy and compensatory increase in GMV in mesial temporal lobe sites and left hippocampus where Aβ builds up relatively late.
Efficacy of Serious exerGame in Alzheimer’s disease and related disorders: Results of the AZgame multicenter study
Authors: Philippe Robert , Derreumaux Alexandre , Albrengues Claire , Foulon Pierre , Fabre Roxanne , Mercier Gégoire , Manera Valeria
Published: December 2020

Background

Serious exerGames (SeG) promotes cognitive simulation with physical activity in a positive emotional context. Results of the first pilot usability study with X‐Torp (Bensadoun & al, JAD, 2016) suggest that this SeG represents a usable as enriched environments, for healthy subjects and persons with MCI and Alzheimer's Disease. The aim of the AZgame multicenter study using X‐Torp is to evaluate the efficacy and the cost‐utility in patients suffering from Alzheimer’s disease in comparison to the usual management.

Method

X‐Torp use the Microsoft® Kinect™. The scenario mode combines action game dynamics, with exploration of open environments fin order to stimulate motor activities and mini‐games in order to stimulate cognitive activities. (full description available here: http://www.innovation-alzheimer.fr/azgame-eco-2/). 91 subjects (mean age 81.7 years, mean Minimental state Examination MMSE 18.3 sd 3.6) with a DSM 5 diagnosis of minor (n = 26) or major (n = 65) Neurocognitive disorders were recruited in 16 centres including memory consultation, day care center, nursing home. Center were randomised in Intervention (using XTorp) and control center with regular care.In the intervention group patients used Xtorp for 12 weeks, 2 sessions of 30 mn per week. Patients underwent cognitive (MMSE), functional (EQ5D) and behavioural assessment (NPI and Apathy Inventory) at base line, at the end of the intervention (Week 12) and 12 weeks after the intervention (W 24).

Result

When comparing cognitive, functional and behavioural scores between base line W12 and W24 mixed model analysis (time x group interaction) indicated no significant interaction for the MMSE and the EQ5D. On the behavioural point of view patients of the Intervention XTorp group showed an improvement at the NPI total score and at the apathy Inventory. Mixed analysis (time BL, W12, W24 x group) indicated a significant interaction for the NPI total score (p value = 0.03) apathy inventory score (p value = 0.008) with a significant increase in apathy in the non‐active subjects.

Conclusion

According to these results use of X‐Torp, a therapeutic video game with motion capture improved neuropsychiatric symptoms and most particularly apathy. This effect is also observed 12 weeks after the end of the intervention.