bluuebunny/crossref_metadata_2025 huggingface dataset:
Subjective memory complaints: Fact or feeling?
Authors: Meynadasy Melissa A. , Hajcak Greg , Naar Sylvie , Sheffler Julia L.
Published: December 2020

Background

Subjective memory complaints (SMCs) are considered a requirement for diagnosis of Mild Cognitive Impairment (MCI; Petersen, 2004). However, the evidence for a relationship between SMCs and objective cognitive impairment is mixed and often contradictory (Crumley et al., 2014; Lenehan et al., 2012; Mitchell et al., 2014; Reid & MacLullich, 2006; Roberts et al., 2009). Some research has shown that SMCs are more strongly and consistently related to psychosocial factors such as anxiety, stress, and depression (Balash et al., 2013; Dux et al., 2008; Mowla et al., 2008; Yates et al., 2017). We sought to further examine these relationships by investigating the association of SMCs with multiple objective measures of cognitive functioning as well as its association with other mood and psychosocial characteristics in a community sample of older adults.

Method

SMCs were measured by the change subscale of the Metamemory in Adulthood questionnaire (Dixon et al., 1988). Objective cognitive functioning was measured with the California Verbal Learning Test, 2nd Edition (CVLT‐II) and P300 event‐related brain potential amplitude to infrequent target stimuli during a visual Go/NoGo task (i.e., indicator of allocation of attentional resources to motivationally salient stimuli). Perceived stress and psychological well‐being were measured with the NIH Toolbox Emotion Battery. Depression and Anxiety were measured with the Geriatric Depression Scale (GDS) and Geriatric Anxiety Scale (GAS), respectively.

Results

SMCs were positively associated with perceived stress, depression, and anxiety scores, p’s < .002, and negatively associated with psychological wellbeing, p = .028. However, SMCs were not associated with short or long delay verbal memory recall, p’s > .432, nor were they associated with P300 amplitude, p = .966. Further, P300 amplitude was positively related to long delay verbal memory recall, p = .018, and trending toward a significant relationship with short delay verbal recall, p = .086, supporting the use of neural markers of cognitive function to objectively assess potential cognitive impairment.

Conclusions

Overall, our findings support the notion that SMCs are related to mood and psychosocial characteristics rather than objective declines in cognitive functioning, questioning the utility of SMCs as a criterion in the diagnosis of MCI.
Elder abuse in the context of dementia: Development of film resources
Authors: Antoniades Josefine , Dow Briony , Gahan Luke , Brijnath Bianca
Published: December 2020

Background

People with dementia are uniquely vulnerable to elder abuse, including from their family members and carers. However, when confronted with instances of elder abuse, service providers often struggle to balance the carer’s needs and the older person’s rights. Without clear and consistent messaging and training, significant discrepancies can arise in provider’s responses to elder abuse in the context of dementia. Addressing this gap, this project aimed to co‐produce with providers and the community, three short films exemplifying best‐practice responses to cases of elder abuse in the context of dementia. This paper describes the development of the elder abuse films. Using co‐production methods, two workshops were conducted with Service Providers (n = 13) and community members (n = 8) respectively. In the facilitated workshops, participants were provided with draft scripts based on real‐life scenarios covering neglect, financial and physical abuse. Following the workshops, scripts were refined and circulated to participants for further feedback. Once refined, films were developed by professional film maker (WHY Documentaries (Wollongong, NSW)), and films were circulated to Service Providers for final feedback. The final three films were launched in March, 2020 and data analytics are currently being collected. This project highlights how the use of film and media can effectively be used in educating front line providers about sensitive topics such as elder abuse in the context of dementia to improve the detection, but also the responses to abuse in community settings.
Effects of mutations in the novel FTD‐ALS gene, CYLD, on SFPQ protein
Authors: Boccanfuso Lauren , Lee Albert , Chung Roger S , Oyston Lisa J , Kwok John B , Dobson‐Stone Carol
Published: December 2020

Background

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders that share similar clinical and pathological hallmarks, as well as overlapping genetic aetiologies. Previously, we identified that mutations in CYLD can cause FTD‐ALS. CYLD is a lysine‐63 deubiquitinase, and the FTD‐ALS causal mutation CYLDM719V shows significantly increased deubiquitinase activity [Dobson‐Stone et al. 2020, Brain 143:783‐799]. CYLD is known to interact with the protein products of at least three established FTD and ALS genes. We sought to determine whether other FTD‐ALS proteins were influenced by modulation of CYLD.

Method

We performed mass spectrometry quantitative proteomic analysis of HEK293 lysates overexpressing wild‐type and mutant CYLD (CYLDWT & CYLDM719V), followed by western blots of total cell lysates from SH‐SY5Y and HEK293 cells overexpressing CYLDWT, CYLDM719V and the deubiquitinase‐inactive mutation CYLDD681G. Densitometry analysis was performed in Image Lab (Bio‐Rad, USA) and normalised to total protein.

Result

Mass spectrometry analysis indicated significant differences in expression of TIA1, MATR3, VCP and SFPQ when CYLD was overexpressed. Validation by western blot showed that overexpression of CYLD increased relative protein expression of SFPQ (2.7 fold increase for CYLDWT versus empty vector, p = 0.0048) in SH‐SY5Y cells. This is likely due to deubiquitinase activity, as CYLDD681G did not show such an increase. SFPQ is a nucleic acid binding protein that has been shown to mislocalise from the nucleus to the cytoplasm in FTD and ALS. We are currently examining whether CYLD affects subcellular localisation of SFPQ by western blot and immunofluorescent microscopy analyses.

Conclusion

Our study indicates that CYLD overexpression increases SFPQ protein expression via its deubiquitinase activity. However, it remains to be shown whether this mechanism is essential to the pathogenesis of FTD and ALS driven by CYLD.
CSF Biomarkers profile in siblings with Alzheimer’s disease carrying the ADAM10 nonsense mutation p.Tyr167*
Authors: Agüero Pablo , García‐Ayllón María‐Salud , Sáez‐Valero Javier , Sainz María José , Téllez Raquel , Guerrero‐López Rosa , Pérez Juilán Pérez , Jiménez‐Escrig Adriano , Gomez‐Tortosa Estrella
Published: December 2020

Background

The known genetic causes of EOAD are related to increased processing of the amyloid precursor protein (APP) through the amyloidogenic pathway, with subsequent pathological accumulation of Ab peptides. A decrease in non‐amyloidogenic processing of APP through α‐secretase proteolysis is also considered a straightforward mechanism triggering AD development. The disintegrin metalloproteinase 10 (ADAM10) has been identified as the major α‐secretase in the brain and some ADAM10 gene variants have been associated with higher susceptibility to develop late‐onset disease. In this study we analyze the CSF biochemical profile of two siblings with dementia of Alzheimer type (DAT) carrying a nonsense ADAM10 prodomain mutation to assess the physiopathological effect of the mutation.

Method

Clinical and biomarker study of a family with DAT associated with p.Tyr167* ADAM10 mutation. CSF analysis included AD core biomarkers (Lumipulse technology, Fujirebio) as well as Western blotting of ADAM10 species and the sAPPα and sAPPb peptides. A comparison was made with normal controls (n=12) and sporadic AD cases (n=12).

Result

The p.Tyr167* mutation was absent from public databases and segregated with the disease. CSF samples were available for two siblings. Ab42, total tau, and phosphorylated tau biomarkers in both were consistent with AD (Erlangen score of 4). ADAM10 isoforms in CSF (full‐length ∼ 55 kDa and truncated soluble ∼ 50 kDa) were decreased by around 50% and sAPPα peptide (both 110 and 120 kDa bands) was reduced by 70%, as compared to controls. sAPPb levels showed no changes. Interestingly, the sporadic AD cases showed a similar decrease in CSF ADAM10 levels to mutants, though their sAPPα and sAPPb levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings.

Conclusion

The CSF biochemical profile in these siblings is consistent with α‐secretase haploinsufficiency and illustrates the role of ADAM10 in the amyloidogenic process. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model of sporadic late‐onset AD due to an age‐related down‐regulation of α‐secretase activity.
Improved performance of Elecsys CSF Abeta measurement achieved using the simple, unified routine‐use protocol for CSF collection
Authors: Hansson Oskar , Stomrud Erik , Zetterberg Henrik , Rutz Sandra , Manuilova Ekaterina , Logan Chad , Corradini Veronika , Blennow Kaj
Published: December 2020

Background

Cerebrospinal fluid (CSF) biomarkers amyloid‐β1–42 (Abeta42), amyloid‐β1–40 (Abeta40), phospho‐tau (pTau) and total tau (tTau) can support the diagnosis of Alzheimer’s disease (AD); pre‐analytical handling differences are a known source of variability in measured levels of these biomarkers. An industry consortium chaired by the Alzheimer’s Disease Association developed a simplified Routine‐Use CSF sample handling protocol intended for universal adoption in clinical practice.

Method

CSF samples from patients with normal pressure hydrocephalus were collected per the Routine‐Use protocol for fresh CSF (n=3 aliquots per patient) and two clinical trial protocols (BioFINDER and Roche Trial) for frozen CSF (n=4 aliquots per patient). Abeta42, pTau and tTau concentrations were quantified by commercially available Elecsys® immunoassays; Abeta40 was measured using a research‐use only prototype immunoassay. Routine‐Use samples were measured for each biomarker within 48h of collection, and subsequently frozen and stored (–20°C; ≥1 week) and remeasured. BioFINDER and Roche Trial samples were stored (<–60°C; ≥1 week) before biomarker measurement. Freshly measured Routine‐Use results were evaluated versus comparator results by calculating mean percentage difference and aliquot‐to‐aliquot variability for all biomarkers. Similar analyses comparing Routine‐Use results following one freeze‐thaw cycle were performed using an updated Abeta42 CSF II (Gen2) assay (technical performance presented separately).

Result

In this interim analysis (N=24 patients), Abeta42 concentrations in Routine‐Use results were on average 13.6% (95% CI 10.3%, 17.0%; p<0.0001) and 31.7% (95% CI 26.0%, 37.3%; p<0.0001) higher than BioFINDER and Roche Trial results, respectively. Abeta40, pTau and tTau concentrations were similar across sample handling protocols. Lower aliquot‐to‐aliquot variability was observed for Routine‐Use Abeta42, Abeta40, Abeta42/40 ratio and pTau/Abeta42 ratio results versus comparator results (Table); for pTau and tTau, aliquot‐to‐aliquot variability was similar across protocols. Freeze‐thawing of Routine‐Use samples using the Gen2 assay resulted in a 2.24% (95% CI –3.88%, –0.60%; p=0.0096) mean decrease in Abeta42 concentrations and slightly elevated aliquot‐to‐aliquot variability versus fresh samples (mean coefficient of variation 2.61% versus 2.11%); pTau and tTau levels and the aliquot‐to‐aliquot variability were not significantly affected by freezing.

Conclusion

The Routine‐Use protocol is reliable and robust (low fresh‐frozen effect), and has higher analyte recovery for Abeta42 and less aliquot‐to‐aliquot variability versus comparator protocols.
The Alzheimer’s disease protective R522 variant of PLCg2, consistently enhances PLCγ2 activation, depleting PI(4,5)P2 levels and altering cell function in in vitro and in vivo assays
Authors: Philips Thomas Ernest James , Maguire Emily , Menzies Georgina E , Sasner Michael , Williams Harriet M , Czubala Magdalena , Evans Neil , Cope Emma L , Sims Rebecca , Howell Gareth , Lloyd‐Evans Emyr , Williams Julie , Allen Nicholas D , Taylor Philip
Published: December 2020

Background

Recent GWAS studies have identified the R522 variant in PLCg2 as protective against late onset Alzheimer’s disease (AD). Expression of PLCg2 in the brain is predominantly found in microglia. PLCg2 has been shown to catalyse the hydrolysis of PIP2 to DAG and IP3 leading to increased intracellular Ca2+. Intracellular Ca2+ has been linked to NLRP3 inflammasome activation and increased phagocytic activity. This suggests that the R522 variant may alter the response time of microglia in conditions such as AD.

Method

Using CRISPR‐engineering novel PLCG2‐R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model were generated. From these, primary murine microglia, murine macrophages and hIPSC derived microglia cultures were created. The role of PLCg2 in the intracellular Ca2+ was investigated by detecting cytoplasmic Ca2+ increase, following activation of PLCg2 in human (anti‐CD32) and murine (anti‐FcgII/III) models. This was further investigated using specific PLCg inhibitors and a GapmeR knockdown system. The phagocytic and endocytic activity of these cells was investigated using pHrodo‐Red bound zymosan, E.coli and dextran, and fluorescent amyloid oligomers. PIP2 levels were detected using immunostaining and mass ELISAs. Molecular dynamic stimulation was used to ensemble and analyse the variant.

Result

Cells with the R522 mutation demonstrate hyperfunctionality manifesting as enhanced cellular Ca2+ store release in response to physiologically relevant stimuli. This resulted in increased PIP2 depletion in the cells with the R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLCγ2‐R522 associated abnormalities led to impairments to phagocytosis and enhanced endocytosis. The variant was found to be in the auto‐inhibitory domain.

Conclusion

These results indicate a gain of function mutation in PLCγ2 which increases calcium release from the ER but depletes substrate levels resulting in a smaller reservoir of PIP2 available for other functions. This is consistent with an alteration in the auto‐inhibitory domain. Phagocytosis, which has a larger PIP2 requirement, is decreased while endocytosis which has a lower PIP2 requirement is increased. PLCγ2 sits downstream of disease relevant pathways and as an enzyme is classically druggable thus raises the prospect of PLCγ2 as a therapeutic target for AD.
Region‐specific microglial dynamics in the brain of Alzheimer's patients
Authors: Mejias‐Ortega Marina , Sanchez‐Mejias Elisabeth , Navarro Victoria , Nuñez‐Diaz Cristina , Sanchez‐Varo Raquel , Jimenez‐Muñoz Sebastian , Davila Jose Carlos , Vitorica Javier , Gutierrez Antonia
Published: December 2020

Background

The neuroinflammatory process involving particularly microglial cells, constitutes a hallmark of Alzheimer´s disease (AD) and has been postulated as a critical factor in the disease progression since the identification of several genetic risk factors related to microglial functions. However, the microglial phenotypes in the human pathology have not been determined yet. In this sense, we have previously reported a limited activation and microglial degeneration in the hippocampus of AD patients in contrast to the proinflammatory response long observed in amyloidogenic models. Here, we have further examined the functional/phenotypic profile displayed by microglial cells (activation/degeneration) in two different and vulnerable brain areas of AD patients (frontal cortex and hippocampus).

Method

Cellular (immunohistochemistry and image analysis) and molecular (qPCR and western blots) approaches have been carried out in samples from non‐demented controls (Braak II) and AD cases (Braak V‐VI).

Result

Microglial cells from frontal cortex of AD patients showed a generalized and exacerbate activation similar to that observed in APP/PS1 mice. These strongly activated microglial cells, predominantly located surrounding amyloid plaques, could drive the AD pathology and, in consequence, could be implicated in the pathology progression. These findings in the frontal cortex were highly in contrast to the attenuated activation and degenerative morphology showed by microglial cells in the hippocampus of the same AD patients.

Conclusion

Regional differences in the microglial response exhibit the heterogeneity and complexity of the microglial phenotypes and suggest different functional states of these glial cells in a region‐specific manner. All together, these data need to be considered for better understand the immunological mechanisms underlying AD progression. Modulating brain inflammatory responses might be a promising avenue to prevent cognitive dysfunction in AD patients. Supported by PI18/01557 (AG) and PI18/01556 (JV) grants from ISCiii of Spain and Junta de Andalucia UMA18‐FEDERJA211 (to AG), all co‐financed by FEDER funds from European Union.
Characterization of hippocampal amyloidosis induced by amyloid‐β in behaving mice
Authors: Iborra‐Lázaro Guillermo , Mayordomo‐Cava Jennifer , Sánchez‐Rodríguez Irene , Temprano‐Carazo Sara , Djebari Souhail , Gruart Agnès , Delgado‐Garcia Jose Maria , Navarro‐López Juan D. , Jimenez‐Diaz Lydia
Published: December 2020

Background

In early stages of Alzheimer’s disease, disruption of learning and memory processes that rely on hippocampal performance correlates with aberrant patterns of synchronous neuronal activity that arise prior to evident neurodegeneration. These disturbances emerge as a result of neuronal hyperexcitability and synaptic dysfunction induced by soluble forms of amyloid‐β (Aβ) peptide, which trigger an imbalance between excitatory and inhibitory neurotransmission systems. The molecular mechanisms underlying these alterations remain unclear but functional evidence points to alteration of neuronal excitability playing a pivotal role in early Aβ‐induced AD pathogenesis. Although Aβ
1‐42 and Aβ
1‐40 are widely known for their clinical relevance, Aβ
25‐35 has been proposed as the biologically active fragment. In contrast to other Aβ isoforms, Aβ
25‐35 does not generate ion‐permeable pores in neuronal membrane, but it has been shown to induce major neuropathological signs related to early AD stages. Hence, it has been extensively used to study the pathophysiological events related to Aβ‐induced neuronal dysfunction. It remains to be explored, however, whether Aβ
25‐35 mimics the neurotoxic effects on the hippocampus exhibited by other clinically relevant species such as Aβ
1‐42 (Sánchez‐Rodriguez et al., 2017, 2019, 2020).

Methods

Here, we systematically characterized the effects of Aβ
25‐35 on hippocampal function at different —behavior, networks and synapses— levels of complexity in behaving mice prepared for chronic intracerebroventricular injections. Likewise, animals were implanted with electrodes for in vivo recordings at the hippocampal CA1 area and electrical stimulation of the Schaffer collateral pathway.

Results

Our data showed evident learning and memory impairments in hippocampal‐dependent tasks such as novel object recognition and open field habituation tests. Underlying these deficits, local field potential (LFP) recordings revealed an altered oscillatory activity. Additionally, theta and gamma rhythms, crucially involved in successful memory encoding, were abnormally increased. Lastly, we also found impairments in long‐term synaptic plasticity at the CA3‐CA1 synapse, where Aβ
25‐35 transformed long‐term potentiation (LTP) into long‐term depression (LTD).

Conclusions

Taken together, these results support the notion that Aβ
25‐35‐mediated effects on synaptic properties and neural network activity mimicked those exerted by Aβ
1‐42. Thus, we verified the potentiality of the Aβ
25‐35 peptide to study the hippocampal pathophysiology of early amyloidosis.
Risk for Alzheimer's disease: a review of long‐term episodic memory encoding and retrieval fMRI studies
Authors: McDonough Ian M , Festini Sara B , Wood Meagan M
Published: December 2020

Background

Many risk factors have been identified that predict future progression to Alzheimer’s disease (AD). However, clear links have yet to be made between these risk factors and how they affect brain functioning in early stages of AD.

Method

We conducted a narrative review and a quantitative analysis to better understand the relationship between nine categories of AD risk (i.e., brain pathology, genetics/family history, vascular health, head trauma, cognitive decline, engagement in daily life, late‐life depression, sex/gender, and ethnoracial group) and task‐evoked fMRI activity during episodic memory in cognitively‐normal older adults.

Result

Our narrative review revealed widespread regional alterations of both greater and lower brain activity with AD risk. Nevertheless, our quantitative analysis revealed that a subset of studies converged on two patterns: AD risk was associated with (1) greater brain activity in frontal and parietal regions, but (2) reduced brain activity in hippocampal and occipital regions. The brain regions affected depended on the assessed memory stage (encoding or retrieval).

Conclusion

Although the results clearly indicate that AD risks impact brain activity, we caution against using fMRI as a diagnostic tool for AD at the current time because the above consistencies were present among much variability, even among the same risk factor.
Identification of hippocampal volume as a mediator of the association between APOE4 and dementia
Authors: Brenek Sixtine , Debette Stéphanie , Auriacombe Sophie , Amouyel Philippe , Chouraki Vincent , Meirhaeghe Aline , Damotte Vincent
Published: December 2020

Background

The apolipoprotein E ε4 allele (APOE4), vascular risk factors and neurodegenerative factors are known to be associated with dementia. This study aimed at identifying any mediating effect of those risk factors in the association existing between APOE4 and dementia.

Methods

1,197 participants from the French Three City Dijon Study without prevalent tumor or dementia were included. Among these participants, 72 developed dementia during the 12 years of follow‐up. Using regression and mediation analyses, we studied whether known risk factors for dementia i.e diabetes mellitus, hypercholesterolemia, hypertension, hippocampal volume or white matter hyperintensities could mediate the association between APOE4 and dementia. Regression models were adjusted for age, sex, education level (and total intracranial volume when imaging metrics were considered).

Results

Hippocampal volume was a partial mediator of the association between APOE4 and dementia (mediation ratio = 8.7%, p=0.008). No mediation effect was found for hypercholesterolemia. No mediation analyses could be undertaken for the others factors due to the lack of their association with APOE4 in our sample.

Conclusion

In this study, the association between APOE4 and dementia was partially mediated by hippocampal volume, suggesting a deleterious role of APOE4 in the hippocampus. This result warrants further replication in other cohorts, with higher sample sizes.
Validation of neuroinformatics algorithms, claims‐triage score, and proprietary brain health protocol for dementia care management for insurance markets: Establishing a gold standard in the Silver Tsunami
Authors: Rao Anitha , Miller Benjamin , Kulman Tanzila , Aggarwal Neelum T
Published: December 2020

Background

As the population ages globally, there will be an increased demand placed on the insurance sector to improve outcomes and quality of care for patients with neurodegenerative diseases. Established guidelines and standards of care exist and provide a framework for healthcare providers (HCP) to diagnose cognitive impairment (CI) and rule out other conditions that may mimic or exacerbate CI. Based on prior real world evidence, these guidelines are seldom adopted by HCPs and insurance claims processing teams.

Methods

As part of chronic illness insurance claims processing, proprietary neuroinformatics algorithms computed a patent‐pending claims triage score (CTS) and a digital brain health protocol (BHP). The CTS consists of a 1–5 score that provides a framework for utilization management and cognitive claims processing for chronic illness verification. An external neurology task force reviewed and validated the CTS and proprietary BHP to confirm they met standards of care and practice guidelines put forth by the American Academy of Neurology. Additional claims data was collected as part of the process.

Results

A total of 67 CTS and BHPs were completed (F = 41, M = 26). CTS had a sensitivity and specificity over 95%. Distribution of CTS are as follows: Score 1 (3%), Score 2 (15%), Score 3 (41.7%), Score 4 (25.3%), and Score 5 (7.4%). The external neurology task force agreed with the suggested workup computed by the neuroinformatics algorithms 98% of the time. Inter‐rater reliability was high. MMSE scores ranged from 1–30 and SPMSQ scores ranged from 0–10.

Conclusion

Practice guidelines optimize care and improve patient outcomes. No such standardized validated protocol exists for the insurance market to process chronic illness claims and this research highlights a first to market approach that combines predictive analytics and medical guidelines to impact the evaluation of neurodegenerative diseases in the insurance market.
Acceptability of a mental health care pathway to address dementia risk factors in primary care settings: A qualitative study
Authors: McAiney Carrie A , Berry Camryn , Parascandalo Fiona , Kates Nick , Saperson Karen , Dham Pallavi , Malik Noor , Rajji Tarek K
Published: December 2020

Background

Given the projected increases in dementia prevalence across the world, it is imperative that we identify and mitigate the potential impacts of reversible risk factors for developing dementia. Depression, anxiety and mild cognitive impairment (MCI) are examples of such risk factors. However, despite their relatively high prevalence rates among those age 60 and over, these conditions often go unrecognized and untreated. A growing body of evidence suggests that evidence‐based interventions in primary care can increase detection and treatment rates of these conditions, and may help to prevent or prolong the development of dementia. This presentation reports on qualitative data collected as part of a longitudinal cohort study examining the implementation and effectiveness of an Integrative Care Pathway (ICP) for depression, anxiety and MCI in primary care settings.

Method

A qualitative descriptive design was used to examine the acceptability of the ICP by primary care providers. Two sets of focus groups were conducted with five participating primary care practices during the study. Participants varied by practice and included family physicians, nurses, allied health professionals, and administrative staff. Focus groups were audio‐recorded, transcribed verbatim, and analyzed using conventional content analysis.

Result

The findings indicate that providers had mixed reactions in terms of the acceptability of the ICP. The fact that the ICP was evidence‐based was a strength of the pathway and gave providers and patients reassurance regarding the management of depression, anxiety and MCI. However, the realities of primary care practice, particularly in terms of time constraints, indicated the need for flexibility in how the ICP is applied.

Conclusion

Having access to evidence‐based resources can support primary care providers in managing mental health risk factors for dementia. However, resources need to reflect the culture and practices of primary care settings in order for them to be acceptable to providers.
Prevalence of cognitive deficit in elderly with depressive symptoms
Authors: Rosa Giovana Carolina Láo , Borges Sheila de Melo
Published: December 2020

Background

Depression often presents with memory complaints and can impair memory functions. As dementia, depression is one of the major geriatric syndromes that compromises the quality of life of this population. Therefore, the aim of the present study was to assess the prevalence of cognitive impairment in the elderly with suggestive scores of depressive symptoms and to verify the relationship between cognitive screening tests and depressive symptoms in this population.

Methods

A cross‐sectional study was carried out with 66 elderly people attended by Primary Health Units in the municipality of Santos, State of São Paulo, Brazil. To contemplate the objective of the present study, age, education and sex were analyzed, as well as cognitive screening tests such as the Mental State Mini‐Exam (MMSE), verbal fluency test (FV) animals category and the Clock Drawing Test (CDT). In addition, we analyzed data from the Geriatric Depression Scale (GDS‐15), which is a screening test for depressive symptoms.

Results

The mean age was 70.8 ± 7.6 years, with the majority being women (n = 53; 80.3%); with a mean of 7.4 ± 4.0 years of schooling. The mean score of the GDS‐15 was 7.4 ± 1.6 points, with a higher frequency of mild depressive symptoms in the test classification (n = 63; 95.5%). Regarding cognitive tests, the mean of the MMSE was 25.5 ± 3.0 points, of the FV it was 13.6 ± 4.9 animals spoken in one minute and the TDR had a mean of 2.9 ± 1.6 points. To assess the correlation between the score of the cognitive screening tests and the classification of the GDS‐15, the Spearman's Correlation Coefficient (r) test was used. For statistical significance, we accept a p‐value <0.05. We observed a weak and negative correlation for GDS‐15 with MMSE (r = ‐0.26; P = 0.03), with CDT (r = ‐0.27: P = 0.02). There was no correlation with VF (r = ‐ 0.08: P = 0.5).

Conclusions

The study, both the MMSE and the CDT were shown to be more compromised in the population studied, these tests also being those that showed a correlation with the GDS‐15 scale.
Neocortical‐type Lewy bodies and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change in community‐dwelling older persons
Authors: Agrawal Sonal , Yu Lei , Nag Sukriti , Arfanakis Konstantinos , Barnes Lisa L , Bennett David A , Schneider Julie A
Published: December 2020

Background

Lewy bodies are common in aging and often co‐occur with Alzheimer's disease (AD). There is recent and expanding recognition of another common proteinopathy, limbic predominant age‐related TDP‐43 neuropathologic change (LATE‐NC), in the aging brain and all 3 proteinopathies are associated with the APOEε4 genotype. Most studies have focused on the association of LATE‐NC and AD, but there are few studies that specifically focus on LATE‐NC and Lewy body disease. The objective of this study was to test the hypothesis that neocortical Lewy bodies are independently associated with LATE‐NC.

Method

Participants without dementia from three longitudinal clinical‐pathologic studies, the Rush Memory and Aging Project, the Religious Orders Study, and the Minority Aging Research Study were included. Uniform neuropathologic examinations provided measures of LATE‐NC, neocortical Lewy bodies, and AD. LATE‐NC pathology was defined as the distribution of TDP‐43 in the brain by using a staging system: stage 0, no TDP‐43 deposition; stage 1, TDP‐43 deposition localized to the amygdala; stage 2, extension to the hippocampus and/or entorhinal cortex; stage 3, further extension to the neocortex. Lewy bodies were assessed in the neocortical regions by immunohistochemistry. Ordinal logistic regression models were used to examine the association of neocortical Lewy bodies with the odds of having more severe LATE‐NC after controlling for demographics, global AD pathology score, and APOEε4.

Result

1564 participants [mean age‐at‐death= 89.5 years (SD= 6.7); mean education=16.2 years (SD= 3.6); 68% women; 26% APOEε4] were included in the analyses. Neocortical Lewy bodies were present in 214 (13.7%) of descendants. 136 (63.5%) subjects with neocortical Lewy bodies had LATE‐NC pathology [stage 1 (n=40), stage 2 (n=32), and stage 3 (n=64)]. Neocortical Lewy bodies were associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.55; 95% Confidence Interval = 1.17–2.04) after controlling for demographics and AD pathology. These results persisted after adjusting for presence of APOEε4.

Conclusion

These findings suggest that neocortical Lewy bodies are independently associated with LATE‐NC in the older brain. Future research is needed on the diagnosis, prognosis, and pathogenesis of mixed neocortical Lewy body disease and LATE‐NC and related neurodegeneration in aging brain.
Individual electromagnetic profiles for the prediction of episodic memory change in early stages of dementia
Authors: Colomo Alejandra García , Sanz David López , Nebreda Alberto , de Frutos Jaisalmer , Fernández Ricardo Bruña , Losada María Luisa Delgado , Higes Ramón López , Maestú Fernando
Published: December 2020

Background

Recent literature defines Alzheimer’s disease (AD) as a continuum consisting of three differentiated stages, preclinical, prodromal and dementia, in which the progressive neurological deterioration gives rise to a growing cognitive decline. According to this idea, presenting subjective cognitive decline (SCD), on its own or in association with a diagnosable mild cognitive impairment (MCI), increases the risk of developing AD‐related dementia in the following years. AD is usually described as a disconnection syndrome. Studies performed with magnetoencephalography (MEG) and diffusion weighted imaging (DWI) have shown alterations in patterns of functional connectivity, power spectrum, fractional anisotropy, and mean diffusivity even in the initial stages of the disease. These patterns could constitute an early biomarker, and thus allow for an early diagnosis and, hopefully, treatment. The main purpose of this study is to determine which, if any, MEG and DWI variables allow for an early differentiation of subjects with SCD or MCI who will show a worse cognitive evolution.

Method

We studied 64 Spanish individuals (age 71,44 ± 4,74), fourteen of which were diagnosed with MCI. The remaining 50 participants did not exhibit any objective neuropsychological impairment, but presented subjective cognitive complaints and were thus categorised as SCD. Participants were followed longitudinally and evaluated at two points in time approximately 3 years apart. All participants underwent a neuropsychological evaluation, a MEG scan, and a magnetic resonance imaging scan. From these scans, we calculated: functional connectivity, power spectrums, fractional anisotropy, and mean diffusivity values. The resulting values were used as predictors of the cognitive change experienced in episodic memory by means of a stepwise general linear model.

Result

We found an optimal predictive model (R2 = 0,500; p < 0,01) consisting of variables such as the alpha power in the left inferior parietal lobe (β = 15,387) and the mean diffusivity of the left cingulate part of the cingulum bundle (β = 149,720).

Conclusion

This region and tract have been previously reported to play a role in episodic memory, supporting the evidence that their functional or structural affectation could be an early marker of neuronal deterioration and disease progression.
Sex differences in associations between brain microstructure and cognitive aging
Authors: Reas Emilie T , Hagler Donald J , Lee Ronald R , Dale Anders M , McEvoy Linda K
Published: December 2020

Background

Cytoarchitectural brain changes during normal aging remain poorly characterized, with further uncertainty whether patterns of brain aging underlying cognitive dysfunction differ by sex. Prior studies have demonstrated that the diffusion MRI technique restriction spectrum imaging (RSI) predicts cognitive decline and pathology in Alzheimer’s disease (Reas et al., 2017,2018,2019), but sensitivity of RSI to typical brain aging has not been assessed.

Method

This study used RSI to examine sex differences in associations of brain microstructure with age and cognition in community‐dwelling participants of the Rancho Bernardo Study. Ninety women and 57 men aged 56‐99 completed RSI and cognitive assessment (global cognitive function, executive function, verbal memory, visual memory, logical memory). RSI metrics of restricted, hindered, and free water diffusion were computed in cortical gray matter, hippocampus, and white matter fibers. Sex‐specific correlations assessed associations of RSI with age and with cognitive function. Mediation analyses examined whether RSI measures mediated effects of age on cognitive performance.

Result

Age‐related increases in free water, and decreases in measures thought to reflect intraneurite (restricted) and extraneurite (hindered) diffusion, and neurite complexity, were observed throughout gray matter and fibers. Associations remained after adjusting for cortical thinning, and regional associations emerged after adjustment for global microstructure. Associations of microstructure with age and with cognitive function were stronger and more widespread for women than men. Adjustment for age attenuated RSI‐cognition correlations for both sexes, as well as sex differences in these associations. Microstructure partially mediated effects of age on cognitive performance for men and women. Whereas age more strongly correlated with RSI and cognitive measures for women, RSI measures more strongly mediated age effects on cognitive function for men.

Conclusion

Microstructural brain changes, which may reflect cell shrinkage, demyelination, axonal and dendritic loss, or reduced neurite complexity, occur with typical aging and correlate with performance in multiple cognitive domains. Age‐related microstructural injury is more pronounced for women, and patterns by which microstructure mediates cognitive aging differ by sex. Normal aging may be accompanied by cytoarchitectural damage that underlies cognitive decline, and the mechanisms by which age‐related neural injury impairs cognitive function may differ between men and women.
Demographics and brain models variably predict cognition in an ethnoracially diverse sample by cohort
Authors: Gannon Bethany Kaye Amele , Fletcher Evan M
Published: December 2020

Background

Considerable heterogeneity in cognitive trajectories has been well documented in studies of older individuals from diverse samples, including minority communities. Such studies often have not included brain factors in their models. Modeling demographic factors and neuroimaging brain data as predictors of cognition in a diverse sample set is crucial to further delineate differences in associations to cognitive outcomes by ethnoracial cohort.

Method

Four ethnoracial cohorts of older participants with variable baseline cognitive statuses were sampled from the UC Davis Aging and Diversity Cohort (Table 1). We modeled cognitive baseline and change outcomes for episodic verbal memory and executive function, using predictors consisting of demographic and brain variables in an ethnoracially diverse sample. Brain measures were brain gray and white matter signatures of cognition (Fig. 1a, b) and white matter hyperintensity burden (WMH) at baseline. For longitudinal, we retained the WM measures but used signature atrophy regions of cognitive change. We hypothesized that distinct profiles of predictor variables might emerge by ethnoracial group.

Result

Table 2 presents an overview of our model fit by R2 metric across all four ethnoracial groups. Baseline fits were higher for non‐white ethnoracial groups than for Whites. Longitudinal fits were similarly high for all cohorts having sufficient data. Table 3a, b reveals varying explanatory profiles for baseline predictors. For non‐brain variables, education was most consistently significant, with others also significant in several models. Brain GM was consistently significant except in Asians; meanwhile WM signatures were significant only in Asians. In longitudinal models (Table 4a, b) brain tissue atrophy was most consistently significant, along with WM measures among Whites. No non‐brain variables were significant.

Conclusion

Our findings support baseline ethnoracial variability expressed in our initial hypothesis, while also suggesting that brain GM and tissue atrophy measures may be strong predictors regardless of cohort. Education is frequently significant across cohorts at baseline, consistent with existing research. GM baseline and tissue atrophy are consistent predictors except in Asians, contrasting our hypothesis. WM factors vary by cohortgrouping, exhibiting significance in Asians and Whites, suggesting ethnoracial profile differences in support of our hypothesis and requiring further research.
Structural MRI changes in a two‐year follow‐up in subjective cognitive decline
Authors: Bubbico Giovanna , Lauriola Mariella , Minerva Michele , Iorio Angelo DI , Esposito Roberto , Perrucci Mauro Gianni , Tartaro Armando
Published: December 2020

Background

Subjective cognitive decline (SCD) is a state in which a subjectively perceived decline in cognition appears in the absence of an objective decline detected by neuropsychological tests. It tends to occur at the late phase of preclinical AD and has been proposed as a pre‐MCI stage (Rabin et al., 2017). Hippocampal atrophy is a well‐known feature of AD (Halliday, 2017).

Method

Brain morphometry was observed in a 2‐years follow‐up. Participants were assigned to the SCD or non‐SCD group according to the SCD research criteria: SCD‐Q score ≥7 was classified as SCD (Rami et al., 2014). Among seventy community‐ dwelling individuals who had been enrolled at baseline (Lauriola et al., 2017), thirty‐five (64.6 ±5.6 y, 15M/20F) took‐part in the follow‐up phase. All participants underwent complete neuropsychological battery and a 3T Structural Magnetic Resonance Imaging (MRI) examination (Philips Achieva X Series). High‐resolution structural images were acquired through a 3D magnetization‐prepared rapid acquisition gradient echo sequence: matrix 256 × 256, field of view 240 × 240 × 170 mm, slice thickness 1 mm, no gaps, in‐plane voxel size 1 mm × 1 mm, flip angle 12°, repetition time = 8.2 ms, echo time = 3.8 ms. Structural T1‐weighted images were processed using FSL software (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki, version 6.0). Gray matter differences were assessed with VBM (voxel‐based morphometry), as implemented in FSL (FMRIB Software Library v6.0).

Result

Significant differences (p=0.03, corrected for multiple comparison) were observed between SCD and non‐SCD partecipants in the hippocampus global total intracranial normalized volume (TIV). Atrophy maps on hippocampal areas showed major involvement of the para‐hippocampal region, of the left mesial temporal lobe (Fig. 1).

Conclusion

SCD hippocampal volumetry reduction might be considered a negative prognostic finding as a potential prelude to an evolution in early dementia.
Plasma microRNA vary in association with the progression of Alzheimer’s disease
Authors: Guévremont Diane , Tsui Helen , Knight Robert , Fowler Christopher J , Masters Colin L , Martins Ralph N , Abraham Wickliffe C , Tate Warren P , Cutfield Nick , Williams Joanna M ,   Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group
Published: December 2020

Background

Early intervention in Alzheimer’s disease (AD) requires development of an easily administered test able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis, we sought to identify disease‐stage specific biomarkers.

Method

Using TaqMan microfluidics arrays and a statistical consensus approach, we assessed plasma levels of 182 neurodegeneration‐related microRNA, in cohorts of amyloid‐positive, mild cognitive impairment and AD participants, relative to their respective controls.

Result

Plasma microRNA were shown to be dynamically altered with AD progression. Distinct disease stage microRNA biomarkers were identified, and these were shown to predict membership of the groups (AUC >0.8). Bioinformatics demonstrated that these microRNA target known AD‐related pathways. Furthermore, a significant correlation was found between three microRNA and amyloid‐ß load.

Conclusion

Our results show that microRNA signatures alter during the progression of AD, relate to the underlying disease pathology and may prove to be useful diagnostic markers.
What’s in a name? Semantic, as well as episodic, memory plays an important role in the diagnostic sensitivity of the free and cued selective reminding test in MCI
Authors: Colvin Mary K. , Daly Maureen , Laffer Alexandra , Sherman Janet C.
Published: December 2020

Background

The Free and Cued Selective Reminding Test (FCSRT) is highly sensitive in the detection of AD, even at early stages (Grober, et al., 2008; Papp et al., 2015; Slachevsky et al., 2018). By controlling encoding and retrieval, the task is especially sensitive to memory consolidation deficits that characterize AD. During the learning phase, patients name items that are paired with semantic cues aimed to boost encoding and retrieval. However, benefit from the semantic cues requires intact semantic memory and access. As the “cognitive signature” of AD includes reduced semantic processing (Henry and Crawford, 2004.), we asked whether this reduction impacts FCRST performance.

Method

170 patients (M
age=74.1±6.2, M
edu=16±3.0; 57% male) clinically referred for neuropsychological evaluation to address cognitive decline completed the FCSRT and semantic access measures, the Boston Naming Test (BNT) and semantic (animal) fluency. Neuropsychologists independently and blindly assigned diagnosis specifying NCD severity (Mild v. Major) and type (amnestic v. non‐amnestic). To determine the impact of semantic processing on FCRST performance we examined whether naming accuracy (NA): (1) differed between patient groups on first FCSRT learning trial; (2) was impacted by item prototypicality, 3) was predicted by BNT and semantic fluency performances, and (4) predicted subsequent FCSRT performance (total free, and total cued recall accuracy).

Result

Ss included 50 Mild NCD, amnestic; 59 Mild NCD, non‐amnestic; 23 Major NCD, amnestic; and 38 Major NCD, non‐amnestic. NA on the first FCSRT learning trial was higher for Mild than Major NCD and non‐amnestic than amnestic patients without severity x type interaction. Across all groups: NA was predicted by BNT (p < .05) and semantic fluency (p < .05), and was better for high than for low prototypicality items. Also across all groups, NA predicted subsequent memory for the items, including total free recall accuracy (p < .001) and total cued recall accuracy (p < .001).

Conclusion

The diagnostic sensitivity of the FCSRT in AD is likely impacted not only by reduced episodic memory but also by reduced semantic memory and access. Understanding what underlies the sensitivity of the FCSRT may ultimately help improve the detection of early cognitive changes in AD.