bluuebunny/crossref_metadata_2025 huggingface dataset:
Childhood head injury, control beliefs, and later life cognitive function in the Health and Retirement Study
Authors: Turner Robert
Published: December 2020

Background

Mild traumatic brain injury earlier in life is a risk for dementia later in life. While research has rightly focused attention on strategies for reducing the risk of incurring brain injury in youth, less attention has been paid to potentially modifiable risk factors for dementia in the context of a sustained childhood brain injury. Psychosocial resources may play an important role in mitigating the risk of dementia associated with early life brain injury. We investigated the role of control beliefs in the relationship between early life brain injury and cognitive functioning in the Health and Retirement Study.

Method

Data were from four biennial waves of HRS, combining 2006 and 2008 (time 1) and 2010 and 2012 (time 2) (n=5,999). A linear regression model evaluated the relationship between self‐reported head injury ("Before you were 16 years old, did you have a blow to the head, a head injury or head trauma that was severe enough to require medical attention, to cause loss of consciousness or memory loss for a period of time") and perceived control at time 1. A second examined the relationship between self‐reported head injury at time 1 and working memory (immediate and delayed recall) at time 2, controlling for working memory at time 1. A final model examined control beliefs as a potential mediator. Controls included age, race, gender, depression, health conditions, education, and income.

Result

Mean age was 65.4 years, 78.2% White, 10.1% Black, 5% Latino, 6.5% other, and 10.1 percent reported early head injury. Those with a history of head injury in childhood reported lower personal control beliefs at time 1 (p<.001). History of childhood head injury (time 1) were modestly associated with working memory at time 2, after controlling for baseline working memory (p<.05). Control beliefs partially mediated this relationship.

Conclusion

HRS respondents with a self‐reported history of head injury in childhood reported lower personal control beliefs. In turn, control beliefs mediated the relationship between early head injury and later life working memory. Personal control beliefs may be an important modifiable risk for cognitive decline among those with a history of childhood head injury.
The development of a valid, reliable, harmonized segmentation protocol for hippocampal subfields and medial temporal lobe cortices: A progress update
Authors: La Joie Renaud , Olsen Rosanna , Berron David , Amunts Katrin , Augustinack Jean , Bakker Arnold , Bender Andrew , Boccardi Marina , Bocchetta Martina , Chakravarty M. Mallar , Chetelat Gael , de Flores Robin , DeKraker Jordan , Ding Song‐Lin , Insausti Ricardo , Kedo Olga , Mueller Susanne G , Ofen Noa , Palombo Daniela , Raz Naftali , Stark Craig E. , Wang Lei , Yushkevich Paul A. , Yu Qijing , Carr Valerie A , Wisse Laura , Daugherty Ana M.
Published: December 2020

Background

The medial temporal lobe (MTL, i.e. hippocampus and adjacent cortices) is particularly vulnerable to age‐related diseases: Alzheimer’s disease, other age‐related proteinothies (TDP‐43, AGD, etc) and vascular injury. Yet, the subregional pattern of vulnerability is thought to differ across etiologies; characterizing these differences using high‐resolution MRI may provide more insight in disease processes and better biomarkers. However, substantial differences in subfield definition has hindered the ability to compare results across laboratories or draw robust conclusions (Figure 1). The Hippocampal Subfields Group (HSG) is an international group seeking to remedy this problem by developing a histologically‐valid, reliable, and freely available segmentation protocol for high‐resolution T2‐weighted 3T MRI (http://www.hippocampalsubfields.com)

Method

Our workflow consists of five steps: 1) collecting histology samples labeled by multiple expert neuroanatomists to form a novel reference dataset to guide the development of the MRI segmentation protocol, 2) developing boundary definitions for each segment of the hippocampus, (head, body, and tail) and MTL cortices), 3) assessing HSG community agreement with boundary rules via online questionnaires and revising boundary rules based on questionnaire responses, and 4) testing reliability of the protocol definitions on multiple MRI datasets.

Result

For both the hippocampal body and head, we have developed a preliminary subfield segmentation protocol (i.e. completed steps 1‐2, see Figure 2 for a histology slice segmented by three anatomists). Step 3 was piloted for the outer boundaries of the body (i.e., the anterior/posterior, medial/lateral, and superior/inferior boundaries) using an online questionnaire describing each of the proposed rules. 29 labs participated and consensus agreement was reached for all rules, with only minor changes being made to improve comprehension and clarity. We are now creating and administering additional questionnaires for assessing agreement of the hippocampal body and head inner boundary rules (e.g., between the CA fields and dentate gyrus). Upon completion of the assessment/revision process for each set of rules, the final phase – reliability testing of the protocol – should begin mid 2020 for the body.

Conclusion

Once completed, the harmonized protocol will significantly facilitate cross‐study comparisons thus advancing insight in the role of hippocampal subfields across the lifespan in aging and disease.
Sex and cognition: Relationships with tau PET across the Alzheimer’s disease spectrum
Authors: Banks Sarah Jane , Andrews Murray J , Digma Leonardino A , Caldwell Jessica ZK , Sundermann Erin E , Brewer James B
Published: December 2020

Background

Recent evidence suggests that tau accumulates differently in the brains of men and women with Alzheimer’s disease (AD), with greater neurofibrillary tangles in women especially in the MCI stage. Women show a reserve in verbal memory but then more rapid decline in this domain once they are symptomatic. Since regional tau deposition is closely tethered to cognitive symptoms, we were interested in how relationships between tau distribution and cognition might differ by sex.

Method

Data were extracted from the AD Neuroimaging Initiative database for participants (136 women, 139 men) who were amyloid PET positive and had flortaucapir (“tau”) PET, across clinical diagnoses of normal cognition (NC), mild cognitive impairment (MCI) and AD. Vertex‐wise analyses were conducted in FreeSurfer, quantifying the vertices with above‐threshold SUVR and assessing regional distribution. We compared overall burden in men and women, and further investigated results by ApoE status and diagnosis and assessed how regional tau burden related to different cognitive scores.

Results

Women and men did not differ on overall amount of tau PET uptake, but there was a sex by diagnosis interaction on overall tau SUVr. On further analysis (figure 1) this was driven by higher SUVr in women in the MCI stage (F(1, 85) = 7.313, p = .008). Furthermore, women with a higher tau burden scored worse across verbal memory measures, whereas men with higher tau burdens demonstrated worse performance on processing speed and executive measures. This was reflected in topological representation of the tau burden by cognitive test (figure 2).

Conclusion

Sex differences in the expression of AD correspond to differences in tau especially at the MCI stage. Higher tau in women is reflected in reduced performance in verbal memory, while higher tau in men reflects worse performance on executive measures. These findings point to the differences in trajectories of tau deposition in men and women and the relationship of tau to sex differences in cognitive findings.
Repurposing of existing vaccines for personalized prevention of Alzheimer’s disease: Vaccination against pneumonia may reduce AD risk depending on genotype
Authors: Ukraintseva Svetlana , Yashkin Arseniy , Duan Matt , Akushevich Igor , Arbeev Konstantin , Wu Deqing , Stallard Eric , Tropsha Alex , Yashin Anatoliy
Published: December 2020

Background

Repurposing of existing vaccines could be a promising approach to Alzheimer’s disease (AD) prevention, exploiting potential heterologous effects of such vaccines. Adult vaccinations against pneumonia and the flu showed beneficial off‐target effects on mortality and morbidity in some studies, including on dementia‐related outcomes, suggesting that respective vaccines may be evaluated as repurposing candidates for prevention of AD and/or other dementias.

Method

We investigated associations between pneumococcal vaccine, with and without an accompanying flu shot, and the risk of AD among 5,146 elderly participants (65+) of the Cardiovascular Health Study, using covariates including sex, race, birth cohort, education, smoking, and rs2075650, a known genetic risk factor for AD in TOMM40 gene that may also be involved in brain vulnerability to infection through its connection to NECTIN2 (Yashin et al. 2018).

Result

Being vaccinated against pneumonia between ages 65‐75 was associated with a reduction in the risk of AD afterwards (OR = 0.70; P < 0.04) in logistic model with all covariates. A largest reduction in the risk of AD (OR = 0.62; P < 0.04) was observed in the vaccinated against pneumonia non‐carriers of rs2075650 G allele (risk factor for AD). Total count of vaccinations against pneumonia and the flu between ages 65 and 75 was also associated with a lower risk of AD occurrence later in life (OR = 0.88; P < 0.01); however, the effect was not seen for the flu alone.

Conclusion

Vaccination against pneumonia before the age 75 may reduce AD risk later in life, especially in people without genetic risk factor for AD (rs2075650, G allele). These results suggest that pneumococcal vaccine may be a promising candidate for repurposing for personalized AD prevention in carriers of particular genotypes. Validation of these effects in higher power datasets is warranted. The study was in part supported by NIH grants R56AG059428, 1R01AG062623, and 2R01AG046860.
Predictive value of visually rated tau PET imaging for amyloid status, atrophy, and syndromic diagnosis across a spectrum of neurodegenerative phenotypes
Authors: McGinnis Scott , Collins Jessica A. , Eckbo Ryan , Brickhouse Michael , Gomperts Stephen , Johnson Keith A. , Dickerson Brad C.
Published: December 2020

Background

We aimed to investigate the utility of qualitative visual rating of 18F‐flortaucipir tau PET to predict amyloid status, neurodegeneration and syndromic diagnosis across a range of phenotypes associated with underlying Alzheimer disease (AD) and non‐AD neuropathologies.

Method

FTP PET, PiB PET, and high resolution T1 MRI scans were rated independently by visual inspection by two raters blinded to clinical diagnosis in n=118 subjects, a subset of whom had clinical diagnoses of amnesic MCI/dementia (n=26), posterior cortical atrophy (n=12), logopenic primary progressive aphasia (n=8), nonfluent PPA (n=7), semantic PPA (n=5), corticobasal syndrome (n=7), behavioral variant frontotemporal dementia (n=2), progressive supranuclear palsy (n=2), dementia with Lewy bodies (n=6), Parkinson disease (n=11), or control (n=20). Scans were classified based on level of uptake [no elevation, questionable or mild elevation, substantial elevation] and distribution of uptake [suggestive of typical AD, limbic predominant AD, hippocampal sparing AD, FTLD, or indeterminate]. PiB PET and MRI scans were rated with respect to level and distribution of uptake/atrophy.

Result

41/42 subjects with FTP scans classified with substantially elevated signal had PiB scans classified with elevated amyloid, versus 7/11 subjects with FTP classified as having questionable/mild elevation in a distribution suggesting AD, 1/30 with questionable/mild elevation in a distribution suggesting FTLD, 0/9 with questionable/mild elevation in an indeterminate distribution, and 1/26 classified with no elevation in FTP signal. Similarly, 41/42 subjects with FTP classified as having substantially elevated signal had MRI scans classified as having atrophy suggesting neurodegeneration, versus 44/50 subjects with FTP classified as having questionable/mild elevation and 14/26 with no elevation in signal. FTP scans were read to be suggestive of AD‐typ in 21/26 subjects with an amnesic syndrome, suggestive of AD‐hs in 16/20 subjects with lvPPA or PCA, and suggestive of FLTD in 14/23 subjects with bvFTD, nvPPA, svPPA, CBS, or PSP.

Conclusion

Visually rated tau PET imaging reliably predicts amyloid status and atrophy suggesting neurodegeneration in subjects with substantially elevated signal reflecting neocortical tau. Distribution helps both to determine likelihood of underlying AD neuropathology in cases with questionable/mild signal elevation, and in some cases to predict syndromic diagnosis within the spectrums of AD and FTLD.
AU‐ARROW (Australia)
Authors: Martins Ralph N , Anstey Kaarin J , Baker Laura D. , Barin Edward , Dias Cintia B , Brown Belinda M , Burnham Samantha C , Chatterjee Pratishtha , Chen Juliana , Clarnette Roger , Deang Kristine , England Tim , Fuller Stephanie , Gardener Samantha L , Gleason Andrew , Grieve Stuart , Hillebrandt Heidi , Ireland Catriona , Kenny Peter , Kivipelto Miia , Mobbs Rowena , Naismith Sharon L , Peters Ruth , Rainey‐Smith Stephanie R , Raman Rema , Savage Greg , Sohrabi Hamid , Shah Tejal M , Steiner Genevieve Z , Taddei Kevin , Thompson Belinda , Villemagne Victor L L , Yates Paul A
Published: December 2020

Background

The highly encouraging findings from the Finnish Geriatric Intervention Study (known as FINGER) led to the global initiative for dementia risk reduction known as world‐wide FINGERS (WW FINGERS). As part of the collaboration, our Australian AU‐ARROW trial will follow the general protocol of the FINGER trial, and will also be aligned with the U.S. arm of the study, US‐POINTER, though will have minor cultural and dietary modifications to determine the validity of the intervention in an Australian setting.

Method

AU‐ARROW is a randomised, single‐blind 2‐year clinical trial that will recruit 600 participants aged 60‐79 satisfying specific inclusion/exclusion criteria, including normal cognition and one or more cardiovascular risk factors that place them at greater risk of cognitive decline. Participants will be distributed across two sites (a) Macquarie University Health Clinics, Sydney, NSW and (b) Sarich Neuroscience Research Institute, Edith Cowan University, Perth, WA, and will be randomised equally into either the innovative multi‐modal intervention group or the study control group, who will receive general lifestyle advice and annual health check‐ups, without treatment. Multi‐modal intervention consists of aerobic exercise, resistance training and stretching; dietary advice with monitoring to encourage adherence to the MIND diet; cognitive training sessions via the Brain HQ computerised online training system; and medical monitoring and regular health education sessions. Heart rate trackers, diet and exercise log books, and the monitoring of Brain HQ sessions will all help with adherence. Primary outcome measure is improvement in global cognitive score, measured using neurocognitive tests identical to those in the US‐POINTER protocol. Additional neurocognitive tests, physical function improvements, detailed diet monitoring and sleep monitoring will provide added data. The unique extra value of AU‐ARROW trial consists of the testing for Alzheimer’s disease (AD) blood biomarkers in all participants; as well as the AD Aβ amyloid‐specific ligand‐PET imaging, brain MRI and retinal biomarker tests that half of the participants will undergo. These tests will provide comprehensive data which have the ultimate purpose of increasing knowledge of the preclinical stages of AD, and help not only to develop preclinical AD diagnostic tests but also efficacy of AU‐ARROW’s intervention.
SUPERBRAIN (South Korea)
Authors: Choi Seong Hye , Jeong Jee Hyang , Moon So Young , Park Yoo Kyoung , Hong Chang Hyung , Na Hae Ri , Song Hong‐sun , Park Hee Kyung , Lee Sun Min , Choi Muncheong , Park Kyung Won , Kim Byeong C.
Published: December 2020

Background

Multidomain intervention is useful for the prevention of dementia. We have developed the programs of SoUth Korea study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), which consists of a facility‐based (FMI) and a home‐based multidomain intervention (HMI) program suitable for elderly Koreans. We aimed to investigate the feasibility of the SUPERBRAIN programs before a large‐scale randomized controlled trial.

Methods

We recruited 152 participants from eight centers, among those without dementia aged 60‐79 years with at least one modifiable dementia risk factor. Fifty‐three were randomly assigned to the FMI arm, 53 to the HMI arm, and 52 to the control arm. The 6‐month multidomain intervention consisted of: management of metabolic and vascular risk factors, cognitive training and social activity, physical exercise, nutritional guidance, and motivational enhancement programs. The intervention program is determined feasible if the following success criteria are met: 1) a minimum retention rate of 75% at week 24; 2) a minimum adherence to the intervention program of 75%; and 3) at least no difference from the control arm on analysis of Repeatable Battery for the Assessment of Neuropsychological Status. Main secondary outcomes were disability, depressive symptoms, quality of life, vascular risk factors, physical performance, nutritional assessment, and motivation questionnaire. For exploratory evaluation, neurotrophic, neurodegeneration and neuroinflammation factors, microbiome, telomere length, electroencephalography, and neuroimaging measures were evaluated.

Results

Screening began in May 2019 and was completed in August 2019. The study was completed in February 2020. The retention rates were 88.7%, 94.3%, and 80.8% in FMI, HMI, and control arms, respectively. The adherence rates to the program were above 95% in FMI and HMI arms, respectively.

Conclusion

These multidomain intervention programs are feasible in at‐risk elderly people.
The impact of the intestinal microbiome on microglial inflammation
Authors: Frausto Dulce
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder associated with aging. While genetics have been shown to be important in the development of AD, environmental and lifestyle factors contribute significantly to the development and progression of AD. It is proposed that microglial inflammation leads to neuronal dysfunction in the brain and may be a driving factor promoting the development of AD. Although microglial inflammation increases with age, there are a number of lifestyle factors that can promote and/or ameliorate microglial dysfunction. These lifestyle factors include established modulators of the intestinal microbiota community structure and function, one of which is alcohol. Chronic alcohol consumption is associated with a greater risk of all types of dementia, especially vascular dementia and AD. Recently, alcohol has been found to promote AD progression in both animal and human studies. We propose alcohol influences microglial inflammation and dysfunction via a mechanism including secreted bacterial products. The objective of this study is to investigate the ability of bacterial‐derived products to influence microglial gene expression and inflammation. Specifically, we investigated the ability of bacterial products to influence alcohol‐induced microglial activation.

Method

In this study, microglia with and without alcohol exposure will be treated with supernatant from bacteria that are known to be altered following alcohol consumption or shown to be beneficial in blunting inflammation. Microglia will be analyzed for NLRP3 inflammasome activation and IL‐1 production.

Result

The results of this study demonstrate that secreted bacterial products modulate alcohol‐induced microglia activation including NLRP3 and IL‐1.

Conclusion

The proposed research is significant because it suggests that bacteria found in the mammalian intestine can influence microglia in the brain and therefore may critically influence neurodegenerative disease such as AD. Identification of the intestinal microbiota as a factor that promotes microglial inflammation and dysfunction will lay the groundwork for the development of therapeutic approaches that target the microbiota (i.e., consumption of prebiotics or probiotics) to prevent and treat age‐associated diseases, such as AD.
Intestinal microbiota elicits IL‐17A production in neutrophil by regulating RORγt signaling and accelerated the pace of inflammageing in cerebral small vessel disease
Authors: Hu Mengyan , Cai Wei , Lu Zhengqi
Published: December 2020

Background

Intestinal microbiota shapes the host immune system and influences the outcomes of various neurological disorders. Cerebral small vessels disease (CSVD) is highly prevalent among the elderly with its pathological mechanisms yet incompletely understood. The current study investigates the microbiota ecology in CSVD patients, particularly its impact on host’s immune system.

Method

Fresh fecal samples (∼500mg) were donated by recruited CSVD patients (n=55) or healthy controls (n=62) for high‐throughput 16S ribosomal RNA gene amplicon sequencing. Laboratory tests and standard magnetic resonance imaging (MRI) were performed in above 2 groups for cardiovascular risk factors screening and neuroimaging assessment respectively. The central immune organ of spleen from healthy wild type C57/Bl6 mouse and primary neutrophil cultures were used to explore the mechanisms of CSVD.

Result

Altered composition of gut microflora was associated with undesirable disease outcomes and exacerbated inflammageing status. Neutrophils were activated by CSVD associated microflora and obtain increased capacity of IL‐17A production when were exposed to the fecal bacterial extracts from CSVD patients. Mechanistically, RORγt signaling in neutrophils was activated by CSVD associated gut bacterial extracts to upregulate IL‐17A production.

Conclusion

Our findings revealed a previously unrecognized implication of gut‐immune‐brain axis in CSVD pathophysiology, with therapeutic implications.
Comparing longitudinal changes in speech‐based digital measures in cognitively healthy, possible cognitive impairment, and MCI/AD individuals
Authors: Robin Jessica , Xu Mengdan , Kaufman Liam D , Simpson William
Published: December 2020

Background

In Alzheimer’s disease (AD), changes to speech and language differentiate individuals with AD from healthy controls and may be detectable years prior to clinical diagnosis. Speech‐based digital biomarkers are objective, naturalistic measures, which could detect early signs of mild cognitive impairment (MCI) and AD and track disease progression. The objective of this study was to compare speech‐based digital measures across older adults who were cognitively healthy, had possible cognitive impairment based on cognitive screening measures, or had diagnoses of MCI or AD.

Method

103 community‐dwelling older adults and 27 individuals with MCI or AD were recruited for this study in North America. Participants completed a tablet‐based speech assessment at Baseline and 6 month timepoints. Verbal responses were recorded, transcribed and analyzed to produce 8 composite measures pertaining to different aspects of speech and language. Participants were divided into a cognitively healthy group (>25 on the MoCA at baseline and at 6‐months), a possible cognitive impairment group (≤25 at both timepoints), and the MCI/AD group. Two‐way mixed ANOVAs were used to compare language scores across groups and assess change over time.

Result

There was a significant effect of group on five of the eight language composite scores: information units, local and global coherence, word finding difficulty and syntactic complexity, with the cognitively healthy group performing the best in all cases. There were significant overall declines in information units, global coherence and discourse mapping over the 6‐month period, but the interactions of time and group did not reach significance. Phonemic and semantic fluency scores also had significant main effects of group and significant declines over time. MoCA scores did not change over 6 months.

Conclusion

This study demonstrates that speech‐based biomarkers are sensitive to detect differences in individuals based on cognitive status and MCI/AD diagnosis. A number of these measures declined over a 6 month period, unlike MoCA scores, but the rate of change did not differ significantly across groups. Ongoing work with larger samples and longer study periods will continue to examine which aspects of speech and language are most sensitive to cognitive status and disease progression and validate novel digital biomarkers.
CSF biomarkers within a Belgian allochthonous population
Authors: Lebrun Louisien , Hanseeuw Bernard , Ivanoiu Adrian
Published: December 2020

Background

Neuropsychological testing is difficult in allochthonous older individuals due to language, sociocultural, and educational differences with autochthones. Using biomarkers could help making early diagnosis of neurodegeneration in this population, but so far very few studies have investigated biomarker differences between allochthones and autochthones. We aimed to characterize the Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers (protein TAU, amyloid β42, tau/amyloid β42 ratio and pTau) in autochthonous and allochthonous patients. Besides ethnic origin, we matched our groups for sex and age.

Method

Between 2010 and 2014, patients had CSF sampling in Belgium, either at the Saint‐Luc Memory Clinic, Brussels (n=309) or at other hospitals (n=2096) which sent their CSF samples to the Saint‐Luc Neurochemistry lab. We conducted three linear regressions each predicting one CSF biomarker with demographic variables: age, sex and presumed ethnic origin. For this last variable, we categorized the patients according to their names and surnames in: autochthones and allochthones. Secondary analyses in a subset (n =346) adjusted for age and sex.

Results

Allochthones (65,9 +/‐ 9,0) attended the Memory clinic at a younger age than autochthones (70,5 +/‐ 9,3) (mean +/‐ SD). The Mann‐Whitney test we conducted has shown a significant difference for age (p<0,0001). The multiple regressions have pointed out the age to have a significant effect on all the biomarkers (p=0,0001), the sex a significant effect on TAU (p<0,05) and the ethnic origin on both TAU and tau/amyloid ratio (p<0,02). Adjusting for age and sex [median (interquartiles)] TAU 263 (165,5 – 508,3) for Italians, 277 (174,5 – 447,5) for Maghrebis, 207 (128,5 – 298,5) pg/ml for autochthonous), pTAU 44,5 (32 – 71) for Italians, 44 (31 – 58,5) for Maghrebis , 32 (23 – 44) pg/ml for autochthonous and the TAU/amyloid ratio 0,62 (0,31 – 1,34) for Italians, 0,54 (0,28 – 1,37) for Maghrebis, 0,32 (0,21 – 0,74) for autochthonous) were significantly higher in the allochthones than in the autochthones after conducting a Mann‐Whitney test.

Conclusion

Allochthones have higher TAU and pTau pathology than autochthones even after adjusting for age and sex. Different genetic background or sociocultural aspects that were not captured here might explain the observed differences.
Healthcare providers’ perceptions of the efficacy of antipsychotics in dementia‐related psychosis
Authors: Chen Jeanny , Bell Stephen , Brain Cecilia
Published: December 2020

Background

Antipsychotics are commonly used to treat dementia‐related psychosis, i.e. hallucinations and delusions in dementia due to the lack of approved pharmacological options. The treatment need is large as rates of hallucinations and delusions have been approximated to affect about 2.4 million people in the U.S. alone.1‐15 This vulnerable population should however be carefully monitored in regard to the risk‐benefit of receiving dopamine D2 blocking APs.16

Methods

249 U.S. healthcare providers (HCPs), including physicians, nurse practitioners, and physician assistants, completed an online survey. For those of their patients with dementia who were treated with APs for hallucinations and delusions, the HCPs were asked to estimate the percentages for whom the symptoms were (1) completely stopped; (2) stabilized (not stopped) and without relapses; (3) stabilized but with relapses; and, (4) not stabilized. In the survey, “relapse” was defined as “a symptom becoming worse after a period of stability.” Respondents were also asked to estimate the percentages of their AP‐treated patients who were on their first, second, third, or fourth (or higher) AP agent. In the data analysis, mean percentages were computed.

Results

The HCPs estimated that: (1) Of patients treated with APs for hallucinations, efficacy outcomes were: 39%, symptom completely stopped; 23%, stabilized without relapses; 34%, stabilized but with relapses; and, 25%, not stabilized. (2) For delusions, corresponding percentages were 16%, 23%, 34%, and 27%. (3) Of their patients currently being treated with APs, 39% are on their first AP agent, 28% are on their second, 15% their third, and 8% are on their fourth agent (or higher).

Conclusions

U.S. HCPs estimated that for about 60% of their patients with dementia treated with APs for dementia‐related‐psychosis, the patients' hallucinations and delusions were poorly controlled—either never stabilized at all, or stabilized but with relapses. The high proportion of AP‐treated patients (51%) who require two or more lines of AP therapy also attests to the difficulty U.S. HCPs have in controlling hallucinations and delusions with APs.
Two‐point dynamic observation of Alzheimer’s disease cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus
Authors: Jingami Naoto , Uemura Kengo , Asada Megumi , Kuzuya Akira , Takahashi Ryosuke , Kinoshita Ayae
Published: December 2020

Background

Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one‐point observation.

Objective

To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients.

Methods

We analyzed CSF concentrations of tau, amyloid‐β (Aβ) 42 and 40, and leucine rich α‐2‐glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two‐point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo‐peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF).

Results

Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aβ42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively.

Conclusions

Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH. CSF circulation is disturbed in iNPH and old style one‐point CSF biomarker observation can be misestimated. This study detected dynamic changes of CSF biomarkers in iNPH during routine tap test and revealed the linkage between 1ml Last Drip of lumbar CSF and ventricular CSF.
Developing non‐invasive, objective assessment tools for social apathy in neurocognitive disorders: The role of action kinematics
Authors: Manera Valeria , Galperti Guenda , Rovini Erika , Zeghari Radia , Mancioppi Gianmaria , Fiorini Laura , Plonka Alexandra , Mouton Aurelie , Zory Raphael , Corveleyn Xavier , Robert Philippe , Cavallo Filippo , Gros Auriane
Published: December 2020

Background

Apathy, a reduction in goal‐directed activities in the domains of behavior, cognition, emotion and social interaction, is one of the most common behavioral symptoms in Neurocognitive Disorders (NCD)[1]. Current apathy assessment strongly relies on self‐reports or clinical scales, which are subjective and dependent on the information provided by patients and caregivers. For this reason, growing attention is devoted to defining more objective, measurable and non‐invasive apathy proxies. In the present study we investigated the interest of recording action kinematics in a short reach and grasp protocol[2] for the assessment of apathy social component, characterized by a reduction of the willingness to interact with others.

Methods

19 subjects with Mild NCD (6M, age=75,7±6,3y, MMSE=26,0±3,0) were recruited at the Nice Memory Center. Based on the Apathy Motivation Index (social motivation subscale[3]), subjects were classified as socially apathetic (N=9) vs non‐apathetic (N=10). SensRing, a novel ring‐shaped wearable sensor[4], was placed on their dominant hand’s index finger. Subjects were asked to reach and grasp a can to place it into a cup (individual condition) and pass it to a partner (social condition). Several parameters were extracted, including movement velocity, acceleration, jerk (representing the smoothness of the movement) and execution time.

Results

Non‐apathetic participants showed a significantly lower peak velocity (p=0,009) and a lower jerk (p=0,038) in the social vs individual condition when moving the can to the final position, suggesting a more careful approach in placing the object in the partner’s hand vs a cup. Non‐apathetic participants showed no significant differences between conditions in any of the extracted parameters.

Conclusion

Previous studies showed the interest of recording patients’ level of weekly motor activity for apathy assessment. Here, for the first time, we showed that a 5‐minutes reach and grasp protocol may be able to show differences between socially apathetic and non‐apathetic subjects with Mild NCD, thus providing a tool easily usable in the clinical practice. Future studies with a bigger sample are needed to better characterize these findings. [1] Manera et al., 2019, doi.org/10.1002/gps.5125. [2] Becchio et al., 2008, doi.org/10.1016/j.concog.2007.03.003. [3] Ang et al., 2017, doi:10.1371/journal.pone.0169938. [4] Rovini et al., 2020, EMBC‐2020.
“Hero Behind the Curtain”: Multicultural workers in culturally diverse dementia care
Authors: Antoniades Josefine , Croy Samantha , Kent Mike , Ellis Katie , Brijnath Bianca
Published: December 2020

Background

The number of culturally and linguistically diverse (CALD) people with dementia in Australia is projected to rise. CALD groups are diagnosed later and access care services less than other Australians. Accessing services is fraught with barriers for CALD communities and service providers face challenges in meeting the needs of CALD clients. We explore the experiences of multicultural service providers working with members of their own communities, focusing on strategies employed to facilitate access and provide care to CALD people with dementia and their families.

Methods

We conducted 25 in‐depth video‐recorded interviews with multicultural service providers working with CALD clients in Victoria, New South Wales and Western Australia. Interviews were conducted both in language and in English, and were translated and transcribed verbatim. The data were analysed thematically.

Results

Participants identified cultural expectations around family caring and stigma associated with extrafamilial care as significant challenges, leading to reluctance to engage with services. Drawing on understandings of different communities’ approaches to dementia and norms around care for older people, participants were able to address concerns and enable access to much needed services in culturally acceptable ways. In residential aged care, participants described strategies to make aged care more palatable, emphasising the family’s continued role in care as they allowed providers to ‘take over the dirty jobs’. Familiarity and a sense of belonging were fostered for clients with dementia through attention to culturally‐specific needs, whilst building relationships with families to address deep‐seated guilt at placing their loved ones in residential care.

Conclusions

The perspectives of multicultural workers in CALD dementia care provide insight into opportunities for provision of culturally‐appropriate care. The study highlights the significant contributions of multiethnic workers in providing care that is flexible, person‐centred and attentive to cultural needs of CALD clients with dementia and their families.
Validation of a telemedicine tool for patient monitoring in clinical dementia trials
Authors: König Alexandra , Zeghari Radia , Guerchouche Rachid , Linz Nicklas , Ramakers Inez HGB , Lemoine Pascale , Bultingaire Vincent , Robert Philippe
Published: December 2020

Background

With the current pandemic crisis, now even more than ever, remote solutions such as telephone or telemedicine platforms are of great importance to provide isolated elderly people with timely access to health care. This study aims to determine feasibility and reliability of an automated tool utilizing artificial intelligence (AI) to facilitate large‐scale population‐based neurocognitive pre‐screening and monitoring of potential clinical trial participants.

Method

21 participants (out of 120 still to include) over age 55 with and without cognitive impairment were administered in two conditions, once by telemedicine and once by face‐to‐face, a neuropsychological assessment consisting of 8 neurocognitive tests. The administration procedure was randomized. Each participant was asked to complete an acceptability questionnaire regarding the experience of being evaluated through a telemedicine tool.

Results

Similar results were obtained on the several cognitive test measures when comparing the remote to the face‐to‐face administration method. Word recall (r=0,928) and picture naming task (r=0,939) showed the strongest correlation. Acceptability of the tool was relatively high with preference even in the remote method for more convenience.

Conclusion

Results support the feasibility and reliability of remote cognitive testing through administration via a telemedicine tool. These systems can be used for remote disease monitoring, enabling patients to be assessed in their own homes and improve utilization of expert assessors allowing them to conduct neurocognitive testing remotely.
Studying ABI3 variant immune contributions to Alzheimer’s disease in a transgenic mouse model
Authors: Liang Xinyan
Published: December 2020

Background

Alzheimer’s Disease (AD) is a progressive disorder populating in a world‐wide range, which causes dementia with accumulation of amyloid‐beta (Aβ) and hyperphosphorylated tau. AD destroys memory and disrupts cognition, as well as impairs thinking, behaving and person’s ability to function independently. Numbers of genes now have been confirmed through large scale genetic studies as significant AD risk genes, including ABI3. Abelson interactor (ABI) family is an adaptor protein family commonly participating in regulation of actin cytoskeleton in cell. As a member of ABI family, ABI3 can modulate cell motility process like inhibiting tumor metastasis and migration. Genetic variants of ABI3 have been found to be strongly associated with late onset AD (LOAD) in various human populations, but the molecular mechanisms of how they influence AD pathogenesis remain unknown.

Method

In order to further study the pathological mechanisms of ABI3 in AD in vivo, we created an Abi3 transgenic mouse model on C57BL/6 background carrying a human ABI3 mutation (S209F) by CRISPER/Cas‐mediated genome engineering. ABI3 S209F mutation is encoded by a very rare variant rs616338 (MAF=0.008, OR = 1.43 for AD with P = 4.56 × 10−10). In this transgenic model, a corresponding mouse S212F mutation was introduced into Exon 5 on Chromosome 11 by homology‐directed repair, and homozygous Abi3F/F mice were generated by crossing the F1 heterozygotes. In addition, we also crossed Abi3F/F with the 5xFAD model of AD to determine the influence of this ABI3 mutation on AD pathology and cognitive functions in vivo.

Result

We hypotheses 5xFAD mice who carrying the ABI3 mutation may exhibit exacerbated AD pathologies compared with 5xFAD with wildtype ABI3, including accelerate Aβ aggregation and neuroinflammation. As ABI3 is exclusively expressed in immune cells in the brain and peripheral, this new Abi3F/F model will be an effective method for us to understand the immune contribution in AD pathogenesis and perhaps the crosstalk between peripheral and central in the disease as well.

Conclusion

We believe that studying AD with ABI3 Tg mouse models can allow us to have better understanding on the immune contribution to AD pathogenesis and provide valuable strategies on clinical therapy.
Molecular profiling of serotonergic neurons from nonhuman primate embryonic stem cell R366.1
Authors: Reddy Arubala P , Bunquin Lloyd S , Sawant Neha , Reddy Hemachandra
Published: December 2020

Background

In the past decade, knowledge of Alzheimer’s disease advanced exponentially. Many in vitro and in vivo models emerged to conduct the mechanistic target‐oriented study. Midbrain pathogenesis is comparatively newer and unexplored in NDDs Research. We have developed a rhesus embryonic stem cell differentiated from NHP cells . Learning the neurodegenerative study in humans is impossible in human, hence cell model are essential to understand.

Objective

: This study is to investigate the blueprint of Rhesus stem cell Rh 366.4 in the differentiation of5HT of midbrain Isodendritc core. Newborn neurons are expressing 5HT character further analyzed using TAC and IPA analysis software, and all serotonin‐related mRNA using Human low‐density array.

Method

Rhesus monkey embryonic stem cells R366.4 (XY) differentiated to serotonin enriched neurons. RNA extracted from ESC colony, Embryoid body, stage N1, proliferation stage N2, and differentiated 5HT neurons. RNA isolated from the previously conducted study hybridized to Affymetrix chip Clariom D Human chip as it has entire RNA species expressing more than 135000 probe set. The more comprehensive and dynamic range of the newer chip. Data analyzed using TAC 4.0 and Ingenuity Pathway Analysis (IPA). In the previous study shows the 366.4 GATA3 driven, FGFR2 dominate, and Sonic hedgehog (Shh) and FEV1 enriched neural cells have many characteristics of serotonin neurons of the dorsoventral axial plate.

Result

N3 cells 5HT neurons compare to ESC R366.1: Canonical pathway altered are: axonal guidance, integrin signaling, synaptogenesis signaling. network: Cellular movement development, growth, cell proliferation, and survival. Top5 network: cell death and survival, nervous system development. Results: ESC366.4 cells compare to N3 cells (5HT Neurons): Canonical pathways altered are Oxidative phosphorylation, EIF2 signaling, mitochondrial dysfunction, protein ubiquitination. Upstream regulator: function: RNA/DNA damage repair, cell death, and survival, post‐translational modification, nervous system development. Top5 network function: related to disease mechanism of metabolism, development disorder, metabolic disease Analysis active Detail bioinformatic analysis will be presented in the poster.

Conclusion

R366.1 cell differentiated in early serotonergic neurons, and many pathways and miRNA will be reported 1st time. The ESC R366.1 is a potential cell line close to human homology essential to study in neural grafting, molecular targets, and cellular metabolism.
Simulating the outcome of a clinical intervention from a data‐driven model of Alzheimer's disease progression
Authors: Nader Clement Abi , Ayache Nicholas , Robert Philippe , Lorenzi Marco
Published: December 2020

Background

The recent outcomes of clinical trials in Alzheimer's Disease (AD) underline the critical importance of timing for drug intervention, and the need to identify optimal intervention windows along the disease history to maximize cognitive benefit. In this work, we propose a data‐driven progression model of AD allowing simulation of the effect of disease modifying drugs along the entire history of the pathology.

Method

We propose a generative model of disease progression, aimed at identifying the dynamical relationships between multi‐modal clinical and imaging data. Our data consists of AV45‐PET, FDG‐PET, MR images, and clinical scores for 311 ADNI individuals (49 healthy, 113 MCI, 33 MCI converted to AD, and 116 AD patients) for a total of 2188 longitudinal measures. The model is based on a dynamical system relating the multi‐modal information, and is formulated under realistic clinical hypothesis to provide plausible disease progression simulation and predictions.

Result

Figure 1 shows the modelled disease progression for grey matter atrophy, glucose hypometabolism, amyloid concentration, and cognitive decline. We notice a global increase of amyloid, while grey matter atrophy and glucose hypometabolism map prevalently temporal and parietal regions. Clinical scores exhibit a non‐linear profile, accelerating during the latest disease stages. The individual disease severity associated to such progression shows significant separation across clinical groups (p<0.01, Figure 2). Finally, our model allows to simulate the intervention outcome of hypothetical modifiers blocking amyloid deposition at a given time. Table 1 shows the values of ADAS11 and MMSE at conversion time, depending on the time at which we simulated amyloid blockage. Mild differences are obtained when complete blockage is performed at least 3 years before conversion, while stronger significant effects appear at intervention time of 10 years before conversion.

Conclusion

We presented a model of AD progression, allowing to simulate the effect of disease modifying drugs on the clinical outcome at any stage of the natural history of AD. The model is flexible and future extensions are currently under study, to account for different kind of PET tracers, and for APOE4 genotyping.