bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term effects of repetitive head impacts on gray matter cortical thickness
Authors: Brekke Bailee , DeVivo Renee , McKee Ann C. , Stein Thor D. , Tripodis Yorghos , Phelps Alyssa , Weller Jason , Martin Brett M , Palmisano Joseph , Steinberg Eric , Turk Katherine W , Budson Andrew , O'Connor Maureen K , Au Rhoda , Qiu Wendy , Goldstein Lee E , Kowall Neil W , Stern Robert A , Killiany Ronald J , Mez Jesse , Alosco Michael L
Published: December 2021

Background

Repetitive head impact (RHI) exposure has been associated with the neurodegenerative disease chronic traumatic encephalopathy (CTE). Magnetic resonance imaging (MRI) and postmortem research suggest frontotemporal atrophy may be characteristic of CTE. The late effects of RHI on cortical volume remain poorly understood due to focus on male former professional American football players and lack of examination of specific lobar gyri. We leveraged the Boston University Alzheimer’s Disease Research Center (BU ADRC) to compare frontal, temporal, and parietal gyri gray matter thickness between participants with and without RHI exposure.

Method

39 participants exposed to RHI and 33 similar‐aged (+/‐ 5 years) participants without RHI from the BU ADRC, all spanning the cognitive continuum, underwent MRI on a 3T Philips. Freesurfer was used to derive regional gray matter cortical thickness values. For the frontal, temporal, and parietal lobes, we computed mean composites of superior, middle, and inferior gyri gray matter measures. Analysis of covariance compared participants with and without RHI, controlling for age, sex, race, education and hippocampal volume.

Result

Mean age was 62.31 (SD=8.87), 34 (47.2%) were female, and 65 (90.3%) were White. Of the RHI group, 23 (59.0%) played American football, 9 (23.1%) ice hockey, 5 (12.8%) were boxers, and 3 (7.7%) were amateur wrestlers. Compared to non‐RHI, RHI‐exposed participants had decreased gray matter thickness of superior (marginal mean diff [MD]=0.10, p<0.01) and middle frontal gyri (MD=0.06, p=0.03), and the middle temporal gyrus (MD=0.07, p=0.03). There were no differences in gray matter thickness for inferior frontal, superior or inferior temporal, or parietal gyri. Because the CTE tau lesion is uniquely at the sulcal depths, we examined the gray matter thickness of the banks of superior temporal sulcus and RHI participants had reduced thickness (MD=0.09, p=0.02).

Conclusion

Frontotemporal atrophy may be a characteristic late effect of RHI exposure. Further examination of thickness of different lobar gyri in the setting of RHI may facilitate disease differentiation. Larger samples will be important to examine how the effects of RHI on gray matter cortical thickness differ by sex, sport played, etc.
In vivo validation of therapeutic efficacy of a small molecule lead targeting tau self‐association in JNPL3 mice
Authors: Moe James G. , Lopez Patricia , Jimenez Heidy , Adrien Leslie , Eun John D , Wolin Adam , Koppel Jeremy , Davies Peter , Davidowitz Eliot J.
Published: December 2021

Background

Small molecules were screened and optimized for inhibiting tau self‐association, the initial step in the formation of soluble toxic tau oligomers and larger insoluble aggregates. This approach is differentiated from other tau aggregation inhibitor programs that have largely focused on inhibiting formation and/or dissociating large and relatively inert fibrils which could generate toxic tau oligomer seeds. Small molecules inhibitors are agnostic to specific post‐translational modifications, conformational changes or strains of tau aggregates, and have superior access to their target in the CNS relative to immunotherapeutic approaches. We have previously shown in vivo efficacy of a lead compound in preventive studies in htau (Davidowitz et al., 2020) and human tau P301L JNPL3 mouse models of tauopathy. The tau P301L mutation is the most common FTDP‐17 mutation and causes tau aggregation and motor deficits with age (Lewis et al., 2000).

Method

Blinded studies of homozygous female tau 4R/0N P301L JNPL3 mice were performed at an independent laboratory where mice were treated for five months by administration of our lead compound in feed from 7 to 12 months‐of‐age. The four groups of mice in the study were baseline (7 months; n=20), vehicle, and two treatment groups (40 and 80 mg/kg doses; n=25 each). To quantify levels of Sarkosyl‐insoluble tau, self‐associated tau, and phosphorylated tau in the treated and control groups of mice ELISAs were performed (Acker et al., 2012; Forest et al., 2019). Rotarod and open field studies were performed to evaluate motor behavior.

Result

Efficacy was shown in the cortex of treated mice that had reduced levels of self‐associated tau below baseline, baseline levels of insoluble tau aggregates, and reduced levels of aberrantly phosphorylated tau with statistical significance. In the hindbrain there was reduction of insoluble tau aggregates in the 40 mg/kg group compared to vehicle. Treatment groups showed improved Rotarod performance compared to baseline and vehicle groups.

Conclusion

Treatment with the lead compound reduced tau aggregation and improved motor behavior in aged JNPL3 mice and support preclinical development of the lead for clinical studies.
Characterising spoken interactions of healthy ageing adults with CognoSpeak, a web‐based cognitive assessment tool
Authors: Brewer Elena , Mirheidari Bahman , O'Malley Ronan , Reuber Markus , Christensen Heidi , Blackburn Daniel J.
Published: December 2021

Background

Automatic conversation analysis presents a useful aid for diagnosis and management of people with cognitive impairments, having already successfully differentiated between people with Alzheimer’s disease (AD) and healthy controls. Current clinical brief cognitive tests such as Addenbrooke’s Cognitive Examination are influenced by age, education and practice effects but it is unknown how these factors influence automated analysis of speech. This study characterised the effects of age, education and repetition on measures of speech and language of cognitively healthy ageing adults.

Method

Audio recordings of memory related questions and verbal fluency tasks from 37 cognitively healthy adults’ conversations with CognoSpeak were analysed (mean age 73.11 ± 7.97). Linguistic analysis comprised of pause to speech ratio (pause length/speech length), age of acquisition of words, phonemes per minute, words per minute and total word count. Spearman’s correlations assessed relationships with age and education. 6 participants repeated testing at an average of 4.05 and 12.25 months later. Friedman’s ANOVA and post‐hoc related‐samples Wilcoxon signed ranks tests assessed longitudinal changes.

Result

Pause to speech ratio was significantly higher for recent memory questions than remote memory. Age of acquisition was significantly higher for phonemic fluency than semantic fluency. A moderate negative correlation was found for age with ACE‐R score and phonemic fluency. A strong positive correlation was found with education and ACE‐R score, and a moderate positive correlation with education and words per minute. No further relationships for age or education were found. Semantic fluency showed practice effects, whereas linguistic measures did not. Further follow‐up data will be available by July 2021.

Conclusion

These results support the theory of semantic memory preservation with age. It is indicated that age, education and time do not have large effects on linguistic measures, giving conversation analysis a practical advantage over the ACE‐R for longitudinal monitoring of people with Mild Cognitive Impairment or Subjective Cognitive Impairment.
Tube feeding in patients with dementia is associated with a longer palliative care unit stay
Authors: Zengin Hilal , Tasci Ilker
Published: December 2021

Background

Tube feeding (TF) was reported to alter the length of stay (LOS) in a palliative care unit (PCU) in patients with dementia. Admission of dementia patients to the PCU for many reasons including respite is tried to be kept as short as possible due to limited reimbursement in Turkey. Our past observations in our unit have suggested that patients with dementia on TF may be prone to a longer stay in the PCU. Therefore, our objective in this study was to explore the association of TF with the LOS in the PCU in patients with home discharge.

Method

In this single center study at a PCU of a tertiary training hospital, we retrospectively enrolled patients with dementia with a diagnosis on admission, between April 2017 and December 2020. Subjects with a history of intracranial surgery, brain tumors, hemiplegic stroke, hypoxic brain injury, and other neurodegenerative diseases were excluded. Very early (within 4 days) or extremely late (beyond 45 days of hospitalization) discharges were also excluded. The association between TF and LOS in the PCU was examined using logistic regression analysis.

Result

The study included 71 home discharges [mean (SD) age: 82.5 (7.0) years], females 58.1%]. Median (IQR) LOS was 15 (13.0) days (4‐44), and 45 patients (63.4%) were on TF. Median age, gender, and the ration of cancer, infectious etiology, renal failure, hypertension, diabetes mellitus, composite cardiovascular disease, sleep disturbance, depression symptoms, and pain (VAS≥1) were similar patients with and without TF. All patients on TF were bed‐bound and had more pressure ulcers (73.2% vs. 50%) compared to those without TF. Multivariate logistic regression analysis showed that controlling for study covariates TF on admission or TF placement in the PCU was independently associated with highest tertile of LOS in the PCU (OR:4.29, 95%CI: 1.03 ‐ 17.77, P=0.045, Nagelkerke R2=%28.5, Hosöer Lemeshow test p=0.643).

Conclusion

The present study showed that, in patients with an established diagnosis of dementia, TF is common and independently associated with a longer length of PCU stay. Nevertheless, the study was underpowered and the results deserve confirmation in larger studies.
Longitudinal changes of phosphorylated tau 181 and neurofilament light chain in plasma and their associations with tau‐ and amyloid‐PET
Authors: Perneczky Robert , Schneider‐Axmann Thomas , Rauchmann Boris‐Stephan
Published: December 2021

Background

To explore if changes over time of plasma phosphorylated tau (p‐tau) 181 and neurofilament light chain (NfL) predict future tau and amyloid β(Aβ) PET load and cognitive performance.

Method

Eight hundred sixty‐five Alzheimer's Disease Neuroimaging Initiative (ADNI) participants were included. Using established AD cut‐points for the CSF concentrations of Aβ42, total‐tau and p‐tau 181, subjects were classified according to the National Institute on Aging‐Alzheimer’s Association research framework, grouping markers into those of Aβ deposition (A), tau pathology (T) and neurodegeneration (N). Analysis of variance was used to compare the plasma biomarker data between the ATN groups. The rate of change over time of p‐tau 181 and NfL was obtained from linear mixed effects models and compared between the ATN groups. Linear regression analysis was used to investigate the association of baseline plasma biomarker concentrations and rates of change with future PET tau and Aβ load and cognitive performance.

Result

P‐tau 181 and NfL plasma concentrations increased along the AD spectrum, but only NfL showed greater rates of change in AD patients vs controls. Cognitive performance was associated cross‐sectionally with NfL in all sub‐groups, and with p‐tau 181 only in AD spectrum individuals. The baseline concentrations of both plasma markers, but only the rate of change of NfL, predicted future PET tau and Aβ load and cognitive performance.

Conclusion

P‐tau 181 and NfL in plasma show different trajectories over time within the same individuals. These biomarkers may therefore provide complementary information for AD diagnosis and prognosis in clinical routine and research settings.
Serum proBDNF availability predicts memory gains in the FINGER multimodal lifestyle intervention
Authors: Håkansson Krister , Goikolea Julen , Daniilidou Makrina , Gerenu Gorka , Ngandu Tiia , Solomon Alina , Kivipelto Miia , Sandebring‐Matton Anna
Published: December 2021

Background

Brain‐derived neurotrophic factor (BDNF), including the mature form (mBDNF) and its precursor (proBDNF), has an important role in synaptogenesis, and is possibly also involved in pathophysiological mechanisms related to dementia. In this study we relate, for the first time, serum levels of both mBDNF and proBDNF with cognitive changes in elderly persons at risk of dementia during a multimodal life‐style intervention.

Method

Participants from the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER) were included in the analysis. BDNF and proBDNF levels were measured in serum of a subsample of 151 participants, aged between 60 and 79 years, with high compliance to the intervention protocol. The multidomain intervention comprised a combination of lifestyle changes (diet, exercise, cognitive training, and vascular risk management) over 24 months. Cognitive assessments were performed at baseline, after 12 months and after 24 months. BDNF levels and changes in BDNF levels were related to changes in overall cognitive performance and to changes in three cognitive domains over the intervention period through multiple linear regression models.

Result

We found a positive association between proBDNF levels, and improved memory performance after the FINGER intervention. This association was especially strong for changes in complex memory performance (B=0.84, 95% confidence interval (CI): 0.42 – 1.26, p=0.0001), suggesting that proBDNF availability can serve as a powerful predictor of memory benefits from lifestyle changes of the type that were implemented in the FINGER study. In this respect, proBDNF outperformed mBDNF, where no associations to cognition was seen, and all other investigated predictors, including age, sex, education, and ApoE4 status. Average levels of mBDNF and proBDNF did not change during the course of the intervention, but participants with larger increases in their proBDNF levels also had larger gains in memory performance.

Conclusion

These results suggest that circulating proBDNF is a key factor in the molecular processes underlying memory improvement.
Sphingosine 1‐phosphate (S1P) analogue FTY720 decreases ceramide levels and ameliorates memory performance in AD mice model
Authors: Luo Qian
Published: December 2021

Background

No effective therapeutic drugs were found for Alzheimer’s disease (AD), which focuses on amyloid plaques and neurofibrillary tangles in the past decades. Sphingolipid changes in AD patients and animals are getting more attention, especially the shift between ceramide and S1P in the brain, proposing an essential role in the amyloid‐β formation, neuroinflammation, and neuronal apoptosis in AD pathophysiology. Fingolimod (FTY720) is a drug that resembles sphingosine‐1‐phosphate (S1P) chemical structure and bioactivity. Therefore, we hypothesized that by increasing S1P signaling by means of FTY720, sphingolipid disbalance could be restored in the brain, and memory impairment observed in AD transgenic mouse models would be prevented.

Method

Two doses of FTY720 (0.1 mg/kg and 0.5 mg/kg daily) were given by oral gavage for 3 months to transgenic mouse models of AD on human apolipoprotein (APOE) APOE4 or APOE3 genetic background. During the drug administration, blood was withdrawn at different time points, and animals were challenged with behavioral tests for memory locomotion and anxiety. Brain was then collected for sphingolipids analysis by mass spectrometry and Aβ quantification.

Result

Sphingolipid analysis in the cortex showed that ceramide subsets elevated in AD mice. In the plasma, ceramides and sphingomyelins overall diminish in concentration over time. The behavioral tests analysis suggested that especially the low dose of FTY720 mildly prevented memory impairment in E4FAD and reduced anxiety behavior in APOE4 mice.

Conclusion

On cerebral sphingolipids, Fingolimod shifted the pathway towards reducing ceramide, especially in the cortex. Our data are supportive of targeting the sphingolipid metabolism as a valid pathway for developing new therapeutic drugs for AD.
Good practice in dementia care
Authors: Borza Liana Rada
Published: December 2021

Background

The current presentation will focus on good practice principles underlying the psychogeriatric services in the NHS England, outlining the central role of the multidisciplinary mental health team in promoting active ageing by formulating person‐centred care plans based on psychosocial interventions and psychoeducation. The social worker will be illustrated as the main partner of the psychiatric team in improving the quality of life of the people with dementia by overcoming clinical risk and ensuring a safe environment for these vulnerable adults. The current talk will also explore the role of the occupational therapist in engaging a person with dementia in activities of daily living (ADLs), thus contributing to his or her wellbeing. Moreover, this presentation will help us to understand how to facilitate the autonomy of a person with dementia and how to perform an accurate mental capacity assessment.
Development of a dual Aβ‐tau vaccine for the prevention of Alzheimer’s disease
Authors: Barbour Robin M , Bard Frederique , Elmaarouf Abderrahman , Louie LeeAnn , Prill Heather , Thomas Kimberly , Kinney Gene G , Zago Wagner M
Published: December 2021

Background

Alzheimer’s disease (AD) is characterized by two pathological hallmarks, Aβ plaques and tau tangles. Several antibodies targeting Aβ plaques showed signs of slowing clinical decline in AD. Antibodies targeting tau epitopes and vaccines targeting either Aβ or tau are in earlier clinical development stages. Since Aβ and tau may act synergistically in the cause and/or progression of disease, targeting both concomitantly may lead to better efficacy for prevention of AD. Here we describe the development of our dual Aβ‐tau vaccine for AD aimed to clear pathogenic Aβ and block tau transmission.

Method

A variety of linear immunogens containing both Aβ and tau peptides separated by various linkers and dendritic cell cleavage sites were screened in mice and guinea pigs for the generation of balanced titers to Aβ and tau. A subset was also evaluated in cynomolgus monkey. Animals were immunized intramuscularly with peptide‐conjugated immunogens formulated with an appropriate adjuvant. Bleeds were taken 1‐2 week after each injection. Serum titers were determined against Aβ and tau. Fresh frozen human AD or control brain sections were stained with sera from immunized and control animals. The neutralizing activity of immune sera was also assessed against soluble Ab oligomers. T‐cell reactivity was also investigated.

Result

We found dual vaccine constructs that provided balanced and immunogenic responses against Aβ and tau proteins. Immune sera bound avidly to Aβ plaques and tau tangles in human AD brain sections at concentrations expected to be achieved in CNS under in vivo conditions. Immune sera also inhibited the binding of soluble Aβ aggregates to hippocampal neurons. Immunogens did not elicit cytotoxic T‐cell responses to Aβ or tau.

Conclusion

We developed dual vaccine constructs that induce optimally balanced titers against Aβ and tau in cynomolgus monkeys. Antibodies were immunoreactive to both Aβ plaques and neurofibrillary tau tangles in human AD brain sections and blocked the binding of soluble Aβ aggregates to neurons, without eliciting T‐cell responses to Aβor tau. These results support the development of a dual Aβ‐tau vaccine with the ability to target pathogenic Aβ and tau for the prevention of AD.
Is there a critical life stage to promote physical activity for preserving cognitive function? Results from a population‐based birth cohort
Authors: Feter Natan , Leite Jayne S , Rombaldi Airton
Published: December 2021

Background

Physical activity improves cognitive function across the life course, reducing the risk of all‐cause dementia in older ages. We aimed to identify the life course model that best describes the association between physical activity throughout life and cognitive performance at age 50.

Method

Adults aged 50 participants of the National Child Development Survey (NCDS) were followed from birth (1958) to 2013. Physical activity was accessed using a self‐reported questionnaire in each wave. Participants were classified as physically active or inactive. Short‐term memory was assessed by word recall test while the executive function was assessed by letter cancelation and animal naming tests. Scores from both cognitive domains were reported as standard deviation (SD). The most appropriate life course model (critical, sensitive, or accumulation) to explain cognitive performance at age 50 was identified by partial F‐tests.

Result

Data from 4,103 adults were analyzed (53.8% women). At age 50, most participants were employees (74.3%), non‐smokers (80.3%), and overweight or obese (64.7%). Whilst 175 (4.0%) of participants were physically inactive at age 7, 44.9% practiced physical activity once a week or less at age 50. Physical activity at age 42 was defined as a critical period for better memory and executive function at age 50 in men. Among women, physical activity at age 23 was identified as a critical period for executive function while the sensitive model best explained the association between physical activity through the life course and memory at age 50. Women who were physically active at age 23 had a better executive function (1.13 [95%CI 1.06, 1.20] SD) than inactive counterparts. Better performance on memory test was observed in women physically active at age 7 (0.18 [95%CI: 0.02, 0.34] SD), 23 (0.11 [95%CI: 0.03, 0.18] SD) and 50 (0.08 [95%CI: 0.01, 0.15] SD). Physically active men at age 42 showed better performance in memory test (0.12 [95%CI: 0.03, 0.21] SD) and executive function (0.11 [95%CI: 0.04, 0.18] SD) than inactive respondents.

Conclusion

Early childhood and adulthood for women and late‐adulthood for men were identified as important life stages to promote physical activity for preserving cognitive function at age 50.
Validation of dementia diagnostics toolbox using interactive iPad technology
Authors: Chandra Jay , Muthupalaniappan Siva , Shang Zisheng , Bose Soham , Deng Richard , Pecyna Eryk , Chen Alexander , Lin Raymond , Butts Dignity , Capo‐Battaglia Athena
Published: December 2021

Background

Conventional means for dementia diagnosis rely on qualitative tests usually administered after significant pathogenesis. Past studies suggest the utility of more quantitative analytical approaches such as handwriting/drawing tasks (Impedevo et al., 2018). Such tools would provide low‐cost, portable, and instantaneous quantitative diagnostics for more efficient patient screening. However, efforts to realize these methods have faced challenges such as low sample size, incomplete feature extraction, and lack of task diversity. We attempted to create a tablet application that uses pen‐tracking technology to surmount these challenges.

Method

As fine motor control provides fundamental markers of neurological health (Bisio et al., 2017; Thomas et al., 2017), rigorous statistical analysis of simple drawing tasks on a tablet permitted differentiation between neuronormative patients and dementia patients with high fidelity. We have started testing our data analysis pipeline with open access datasets: PaHaW (Drotár et al., 2016), Isuniba (Impedovo et al, 2013), ParkinsonHW (Isenkul et al., 2014). These datasets contain drawing data for healthy individuals and those with both dementia and other neurodegenerative diseases. They contain similar raw data that the in‐house iPad app collects. From that raw data, we extracted predictive features, including velocity, acceleration, jerk, curvature, and measures of variation.

Result

We have successfully created an iPad app that is able to record the dynamic handwriting process with an Apple Pencil. Our platform has the potential to generate more standardized datasets with improved documentation compared to existing archives. Patients trace complex figures such as spirals and infinity symbols at varying speeds over multiple trials. Additionally, the subjects are asked to remember and draw a shape that was presented to them at the beginning of the test. The app collects key data such as the position of the pen tip, velocity of pen movement, pen angle relative to the surface, and pressure exerted on the surface.

Conclusion

We plan to deploy our in‐house iPad app in clinical trials to collect pen‐tracking data with which to facilitate differential diagnoses for neurodegenerative diseases afflicting Alzheimer’s and Parkinson’s patients. The validation of such a platform would improve upon existing diagnostic datasets and lower major barriers to dementia screening.
Reduced oral intake is the primary cause of referral of patients with dementia to the internists in Turkey
Authors: Kaya Seher , Tasci Ilker
Published: December 2021

Background

During acute care admissions of dementia patients, an internist consultation is ordered in the first step due to the complexity of these patients. In this study, to determine what types of care are expected in the internal medicine wards, we examined the causes of referral of patients with dementia to an internal medicine clinic.

Method

In this single center study, we retrospectively enrolled patients with dementia who were consulted and admitted to the internal medicine clinic of tertiary care hospital between April 2018 and December 2020. The causes of admission were identified from the medical records. Patients consulted but not hospitalized were excluded. Patients with a history of neurodegenerative disorders other than Alzheimer’s dementia, vascular dementia, dementia with Lewy bodies and Parkinson’s dementia were excluded.

Result

The analysis included 71 patients [mean (SD) age: 85.0 (9.1) years, female 54.9%]). Lower education (<5 years, 87.3%), low estimated glomerular filtration rate (<60 ml/min, 84.5%), hypertension (80.3%), composite CVD (CAD, stroke or peripheral arterial disease, 56.3%), coronary heart disease (46.5%), diabetes mellitus (32.4%), stroke history (22.5%), anemia 45.1%, polypharmacy (>4 drugs, 39.4%), and overall multimorbidity (4 or more comorbidities, 70.4%) were prevalent. The most common cause of referral resulting hospitalization was reduced oral intake by 57.7%. Acute kidney failure (9.9%), glycemic disturbances (7.0%), blood pressure disturbances (2.8%), cancer related problems (2.8%), urinary infection (2.8%), and other disorders (2.8%). In 14.1% of patients the cause of neither referral nor admission was identified by the referring physician and the internist. Men vs. women (71.9 vs. 46.2%, p=0.029) and patients with BMI<30 vs. >30 (62.5% vs. 14.3%, p=0.037) were more frequently, whereas patients with diabetes vs. without diabetes (30.4 vs. 70.8, p=0.001), and composite CVD (47.5 vs. 71.0, p=0.047) were less frequently admitted with reduced oral intake.

Conclusion

The present study showed reduced oral intake as the leading cause of admissions of dementia patients to the internal medicine ward. Given the well‐known complexity of these patients, this finding may justify the recent efforts by the international societies to increase the involvement of internists in the management of undernutrition in acute and chronic care.
Machine learning for neuropsychological assessment of Alzheimer’s disease and behavioral variant frontotemporal dementia
Authors: Matias‐Guiu Jordi A , García‐Gutiérrez Fernando , Pytel Vanesa , Hernández‐Lorenzo Laura , Delgado‐Álvarez Alfonso , Valles‐Salgado María , Delgado‐Alonso Cristina , Cabrera‐Martín María Nieves , Matias‐Guiu Jorge , Ayala José Luis
Published: December 2021

Background

Diagnosis of Alzheimer’s disease and behavioral variant frontotemporal dementia is often challenging. In spite of comprehensive clinical and cognitive assessments, the use of biomarkers is usually needed. We aimed to develop machine learning based models for the diagnosis of AD and bvFTD using only cognitive testing. These techniques may allow selecting the most relevant tests for an optimized neuropsychological diagnosis.

Method

We included 329 participants: 171 patients with AD, 72 patients with bvFTD, and 87 healthy controls (HC). All patients met the current diagnostic criteria, had a neuroimaging compatible with FDG‐PET, and had at least two years of follow‐up confirming the diagnosis. A comprehensive neuropsychological protocol was performed. Evolutionary algorithms were developed, including NSGA‐II. F1‐score was calculated, as a measure of accuracy. Algorithms were developed for the following classification problems between AD vs FTD, AD vs HC, FTD vs HC, and AD/FTD vs HC.

Results

Differentiation between FTD vs HC, AD vs HC and FTD/AD vs HC reached an F1 superior to 90%. Differentiation between FTD vs AD was slightly inferior (F1 80‐85%). Test selected by the NSGAII algorithm for AD vs FTD were as follows: Symbol Digit Modalities Test, Stroop test, Trail Making Test, Corsi blocks, and ACE‐III. For FTD vs HC, the algorithm selected Free and Cued Selective Reminding Test, Trail Making Test, Rey Figure (copy type), Boston Naming Test, and ACE. For AD vs HC, the following test was selected: Rey Figure, Trail Making Test, Corsi test, and verbal fluency.

Conclusions

We have developed a machine‐learning approach to perform feature selection and modeling of neuropsychological test scores, with a high level of discrimination between groups. Our study suggests the interest of applying machine learning for an optimized use of cognitive tests and to improve the interpretation of neuropsychological assessment. . These algorithms allow maximizing the diagnostic capacity, selecting the tests with best characteristics, and the automation, which may be useful for diagnosis.
Visualization of brain targets with 89Zr‐immuno‐PET using a novel bispecific amyloid ß monoclonal antibody
Authors: Stergiou Natascha , Wünsche Thomas , Mes Iris , Schreurs Maxime , Verlaan Mariska , Kooijman Esther , Windhorst Albert D. , Dongen Guus AMS , Helboe Lone , Vergo Sandra , Christensen Søren , Asuni Ayodeji A , Jensen Allan , Bang‐Andersen Benny , Vugts Danielle , Beaino Wissam
Published: December 2021

Background

Recent preclinical and clinical studies in the diagnosis and treatment of Alzheimer Disease (AD) focus on antibody based radioligands and therapeutics by targeting amyloid‐β (Aβ).1 So far, imaging brain targets with bispecific antibodies (using transferrin receptor protein1 as shuttling mechanism) has only been investigated using 124I.2 The disadvantages of 124I limit drastically its clinical potential.3 Therefore, 89Zr is suggested as more suitable positron emitter for labelling of antibodies4, especially in combination with DFO*, the next generation chelator candidate for clinical 89Zr‐immuno‐PET.5 In this study, we evaluated [89Zr]Zr‐DFO*‐NCS labeled bispecific Abeta‐mAb‐scFab8D3 and its mutated analogue Abeta‐mAb‐scFab8D3 T1/2 with faster pharmacokinetics for Aβ imaging and targeting in a preclinical Alzheimer mouse model.

Method

Abeta‐mAb‐scFab8D3 ± T1/2 and the nonspecific isotype control B12‐mAb‐scFab8D3 ± T1/2 were modified with DFO*‐NCS, and subsequently radiolabeled with 89Zr.6 The radiolabeled biologicals (1 mg/kg) were intravenously injected in APP/PS1 transgenic mice as well as in littermates which served as controls (n=5 per group). Blood pharmacokinetics were determined up to 3 (T1/2) or 7 days post injection (p.i.). PET/CT and PET/MRI scans were acquired for 1h at different time points.

Result

The PET images showed a clear brain uptake for the bispecific Abeta‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, while the corresponding B12‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, as well as Abeta‐mAb‐scFab8D3 ± T1/2 in the littermates showed no specific uptake. Abeta‐mAb‐scFab8D3 demonstrated 2‐fold higher brain uptake (2% ID/g) than Abeta‐mAb‐scFab8D3 T1/2 (1% ID/g).

Conclusion

89Zr‐DFO*‐immuno‐PET revealed high and specific uptake of the bispecific Abeta‐mAb‐scFab8D3 in the brain. In this context, we demonstrated that slow kinetics of the biologicals contribute to improve Aβ targeting. The new bispecific Abeta‐mAb‐scFab8D3 looks very promising and supports further development toward companion and complementary diagnostics for AD. References: 1. Selkoe, D. J. Nature Reviews Neurology 15, 365–366 (2019). 2. Sehlin, D. et al. Nat. Commun. 7, 10759 (2016). 3. Verel, I. et al. Cancer Biother. Radiopharm. 18, 655–661 (2003). 4. O’Brien, H. A. J. Radioimmunoimaging Radioimmunother. 17, (1983). 5. Chomet, M. et al. Eur. J. Nucl. Med. Mol. Imaging 1–14 (2020). doi:10.1007/s00259‐020‐05002‐7. 6. Vugts, D. J. et al. Eur. J. Nucl. Med. Mol. Imaging 44, 286–295 (2017).
Fluency in spontaneous speech predicts individual variance in executive function among seniors
Authors: Spencer Kiah A , Meltzer Jed A , Robin Jessica , Xu Mengdan , Rose Mira Kates , Bialystok Ellen
Published: December 2021

Background

Several recent studies have used automated linguistic analysis of naturalistic speech in a picture‐description task (e.g. Cookie Theft) combined with machine learning approaches to distinguish the speech of those with dementia from healthy age‐matched controls. Extension of these techniques to predict continuous variables related to cognitive status offers a means to track the severity of dementia over time and evaluate the effectiveness of interventions. Here we examine the relationship of speech variability to executive function, the ability to manage conflicting information in speeded task performance. Higher executive function confers protection against the clinical manifestation of dementia despite underlying neurodegeneration.

Method

In a new sample of 76 healthy adults aged 65‐75, we measured executive function using an extensive test battery, and elicited spoken picture descriptions in the same individuals. The battery included N‐back, Simon task, verbal fluency, Color Word Interference (CWI or Stroop test), Trails A & B, the elevator subtests of the Test of Everyday Attention, and Logical Memory. Two picture description narratives were recorded and subjected to automated analysis generating over 400 linguistic features, grouped into 8 composite measures.

Result

Exploratory factor analysis revealed one factor accounting for most variance in the executive function battery. This factor exhibited significant correlations with four of the eight speech composite measures, from strongest to weakest: word finding difficulty, local coherence, lexical richness, and syntactic complexity, reflecting greater fluency in spontaneous descriptive speech. No significant correlations were found with repetitiveness, global coherence, information units, and sentiment. Ongoing analyses include factor characterization of the language measures with a larger normative sample.

Conclusion

Older individuals with higher executive function, as captured by common laboratory tests, also exhibit more fluent speech as quantified by automated linguistic analysis. Word finding difficulties may reflect overall slowing of cognitive processes and access to long‐term memory. Automated speech analysis may ultimately serve as an inexpensive and repeatable measure to track cognitive status over time in older adults at risk of dementia.
Utility of Birmingham Cognitive Screen (BCoS) to differentiate vascular cognitive impairment and Alzheimer’s disease
Authors: Apostolopoulos Dimitrios , Bickerton Wai‐Ling , Brett Lucy , Laverick Rosanna , Rotshtein Pia , Hosseini Akram A.
Published: December 2021

Background

Clinical and cognitive assessments are widely used as screening tools for dementia. There is need to find cognitive tools that could differentiate dementia syndromes. This study explores the use of the Birmingham Cognitive Screen (BCoS), a one‐hour assessment of 5 cognitive domains, in revealing differential neurocognitive profiles for Alzheimer’s disease (AD), and vascular cognitive impairment with deep brain structure ischaemia (VCI‐DBSI).

Method

An observational study that received ethical approval by the UK National Research Ethics Committee was carried out with participants recruited from the Midlands in the UK. A total of 128 participants between the ages of 39 and 75 met the inclusion criteria and categorised into three groups. 43 AD (Alzheimer’s disease ), 38 VCI‐DBSI ( Vascular Cognitive Impairment‐Deep Brain Structure Ischaemia ), and 47 healthy controls. Fourteen BCoS tasks were entered into 3 binomial logistic regression models to differentiate AD and VCI‐DBSI groups from controls and each other.

Result

Gender proportion (p=0.002) and years of education (p=0.025) differed between groups and so were controlled for. 14 BCoS tasks differed significantly between groups (all p<0.002). The resulting three logistic regression models were statistically significant (all p <0.001) and explained 62‐87% of variances while correctly classifying 85.2‐94.4% of cases. Compared to controls, AD participants were more impaired in memory and VCI‐DBSI participants were more impaired in attention/executive function.

Conclusion

The BCoS showed good discriminatory ability between AD, VCI‐DBSI, and control groups based on memory and attention/executive function, indicating potential as a differentiating biomarker for use in the office.
Unpacking cognitive composites: A longitudinal analysis
Authors: Cox Timothy , Shishegar Rosita , Lim Yen Ying , Robertson Joanne , Lamb Fiona , Laws Simon M , Porter Tenielle , Fripp Jurgen , Doecke James D , Maruff Paul T , Savage Greg , Rowe Christopher C , Masters Colin L , Villemagne Victor L , Burnham Samantha C ,   the Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group
Published: December 2021

Background

The development of cognitive endpoints that can accurately assess changes in cognition over short time frames is crucial for clinical trials and research of Alzheimer’s disease (AD). Understanding the changing influence of contributing test scores on composites throughout the disease course provides the opportunity to optimise cognitive composite scores for different stages of AD.

Method

AIBL participants with declining cognitive performance were included in this study N=1275 [688 cognitively unimpaired (CU), 277 mild cognitively impaired (MCI), 310 AD; aged 73±9; 718 females]). Two cognitive composite scores (Episodic Memory (EM) and PACC) and their component test scores (California Verbal Learning Test‐II Delayed Recall (CVLT‐II DR), Logical Memory Delayed Recall (LMII), Rey Complex Figure Test 30 minute delayed recall (RCFT‐DR) and CVLT‐II DR, LMII, Digit Symbol Substitution Test (DS), MMSE, respectively) were evaluated. We first examined the relationship between each of component tests score for each composite. We then compared the extent to which longitudinal trajectories of each component test score and each cognitive composite score differed at each disease stage.

Result

CVLT‐II DR contributed the most to the EM composite followed by RCFT‐DR and LMII with the influence remaining unchanged across each disease stage. For PACC, CVLT‐II DR contributed the most to the initial decline, with MMSE and LMII contributing similar amounts and DS contributing the least. CVLT‐II DR contributed substantially to changes in PACC earlier in the disease course but MMSE drove the PACC change in later stages of disease. Initially, both composites follow similar longitudinal trajectories. However, the EM composite reaches a floor not observed for the PACC.

Conclusion

Understanding the temporal contribution of component tests scores on cognitive composites could provide improved cognitive endpoints tailored to use. For instance, MMSE is sensitive to change later in the disease trajectory and therefore should be included in a composite endpoint for trials in prodromal or clinical AD, however is unlikely to have value for preclinical AD trials.
Does the prevalence of different clinical variants of early onset dementia increase with age in people younger than 65? Data from an epidemiology study in Modena province, Italy
Authors: Salemme Simone , Vinceti Giulia , Adani Giorgia , Tondelli Manuela , Galli Chiara , Carbone Chiara , Fiondella Luigi , Filippini Tommaso , Vinceti Marco , Chiari Annalisa , Zamboni Giovanna
Published: December 2021

Background

Early onset dementia (EOD) has significant impact on patients and families. In a recent epidemiological study conducted in the province of Modena, Italy, we reported that the most frequent EOD in persons aged 30‐64 years was the amnestic variant of Alzheimer’s Disease (AD), followed by the behavioral variant of frontotemporal dementia (FTD). Previous studies have shown that ageing increases prevalence of AD even in patients younger than 65. However, it is not known whether different variants of AD and other causes of EOD are equally affected by ageing. Here we studied prevalence of the different clinical variants of EOD by age group.

Method

We identified all EOD patients seen in the network of dementia services of the Modena province, from 2006 to 2019. We included all patients with a diagnosis of dementia with symptom onset before age 65 alive on census date. We stratified them according to their age group and computed crude and sex‐adjusted prevalence rates.

Result

Prevalence of all AD showed a nearly exponential growth ranging from 1.8/100,000 in the 40‐44 age group to 141.4/100,000 in the 59‐64 group. Among AD variants, prevalence of the amnestic variant was the most influenced by the age, increasing from 17.5/100,000 in the 40‐44 group to 102.6/100,000 in the 59‐64 group, while prevalence of posterior cortical atrophy and logopenic variant of primary progressive aphasia (PPA) showed an almost flat growth curve. Prevalence of all FTD increased linearly from 1.8/100,000 in the 40‐44 group to 86.6/100,000 in the 59‐64 group, with such increase being all driven by the behavioral variant (bvFTD), which increased from 1.8/100,000 to 66.1/100,00. Non‐fluent and semantic variants of PPA did not increase with age, although an association with age may have been underestimated by their low frequency.

Conclusion

In patients younger than 65, prevalence rates of amnestic AD and bvFTD increase with ageing, while other clinical variants of AD and FTD does not seem to show that pattern. These results contribute to a better understanding of the different clinical variants of EOD and their risk factors.
The association of vascular risk factors with cognitive impairment in ART‐treated HIV‐positive adults aged 50 years or older in Northern Tanzania
Authors: Flack Katherine , Rainey Emma , Urasa Sarah , Koipapi Sengua , Kalaria Rajesh , Mukaetova‐Ladinska Elizabeta , Howlett William , Dekker Marieke , Walker Richard , McNally Richard , Paddick Stella‐Maria
Published: December 2021

Background

The ageing of the global HIV‐positive population brings with it the novel challenges of geriatric medicine, such as management of comorbidities including cardiovascular disease and HIV‐associated neurocognitive disorder (HAND). Recent literature from high‐income countries suggests vascular risk factors, which are increasingly prevalent throughout sub‐Saharan Africa (SSA), are stronger predictors of HAND than HIV‐disease severity. There is a paucity of evidence surrounding the association between HAND, vascular risk factors and end‐organ damage (EOD) in older cohorts of people living with HIV (PLWH) in SSA. This study aimed to establish prevalence, and evaluate the relationship between vascular risk factors, EOD and HAND in individuals aged ≥50 receiving HIV treatment in Tanzania

Method

A systematic sample of outpatients with HIV on combined antiretroviral therapy (cART) were recruited in Kilimanjaro and assessed for vascular risk factors (hypertension, hypercholesterolaemia, diabetes, smoking etc) and markers of vascular EOD (prior myocardial infarction and LVH on ECG, stroke on neurological examination or MRI‐brain, estimated‐glomerular filtration rate and retinal arteriovenous ratio measurements). HAND were defined by AAN criteria following a detailed locally normed neurocognitive assessment battery, neurological and clinical examination and informant history, and will subsequently be confirmed by consensus panel.

Result

Complete data were available for 145 individuals (mn age 56, 72.7% female). Provisional HAND prevalence was high (64.7%, 31.4% symptomatic) despite well‐managed HIV‐disease (70.5% suppressed viral load). 34.0% of the cohort were hypertensive, 10.5% obese, 33.3% had hypercholesterolaemia, 5.3% had diabetes and 4.6% smoked. Vascular EOD prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (LVH). No significant association was found between vascular factors and HAND. Conversely symptomatic HAND was significantly correlated with lower BMI (p=0.034) and lower total serum cholesterol (p=0.014).

Conclusion

HAND prevalence was high, however prevalence of vascular risk factors was lower than in recent Tanzanian community studies. The lack of association between vascular factors and HAND does not support the hypothesis that HAND is driven by vascular damage. However, the high prevalence of HAND observed suggests an alternative aetiology within this cohort. Further research is urgently required to explore factors contributing to the high burden of neurocognitive impairment among PLWH in SSA.
Developing an effective strategy to implement non‐pharmaceutical interventions amongst residents with dementia in residential care facilities: Caregivers’ perspectives
Authors: Gillis Katrin , Stifkens Kathleen , Lahaye Hilde , Van Bogaert Peter
Published: December 2021

Background

Non‐pharmaceutical interventions based on unfulfilled needs amongst residents with dementia reduce symptoms of agitation, aggression and depression. However, to implement these interventions in daily practice in residential care facilities, caregivers need to (a) analyse resident’s behaviour, (b) recognize unfulfilled needs and (c) apply an individualized non‐pharmaceutical intervention.

Objectives

To develop an effective strategy for the implementation of such complex approach, insights in caregivers’ perception of barriers and facilitating factors are needed.

Methods

A total of thirteen focus group interviews with fifty‐six caregivers from twelve residential care facilities was conducted between October 2019 and February 2020.

Results

Despite a person‐centred vision and culture in residential care facilities, caregivers recognize that dealing with altered behaviour amongst residents with dementia is challenging and that non‐pharmaceutical interventions are seldom used. However caregivers are willing to invest in a team‐based person‐centred approach, different perspectives on priorities in care processes seem to influence the implementation. Participants refer to the importance of an open team culture where safety is guaranteed. An open culture stimulates an attitude of reflection, which is necessary to attune person‐centred care to different perspectives. Therefore the presence of clinical and facilitating leadership is crucial to ensure motivation, a sense of competency, communication, problem‐solving competences, practical organization of non‐pharmaceutical interventions and continuity in care processes. Ward managers and clinical leaders prefer to be supported by an implementation coach who provides education and training to the team members and who facilitates from a neutral perspective moments of intervision on a regular base.

Conclusions

Caregivers recognize the presence of a person‐centred vision and culture, team willingness and different perspectives on priorities in care processes as influencing factors for the implementation of non‐pharmaceutical interventions. Strong clinical and facilitating leadership and the availability of an implementation coach may support caregivers in dealing with different perspectives on priorities in care. Implications for clinical practice: An educational package, intervision sessions and a leadership trajectory are recommended elements of strategy to implement non‐pharmaceutical interventions based on unfulfilled needs amongst residents with dementia.