bluuebunny/crossref_metadata_2025 huggingface dataset:
Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: A survey study
Authors: Waterink Lisa , Masselink Larissa A , van der Lee Sven J , Visser Leonie N.C. , Cleutjens Solange , van der Schaar Jetske , van Harten Argonde C. , Scheltens Philip , van der Flier Wiesje M. , Zwan Marissa D.
Published: December 2023

Background

Apolipoprotein‐E (APOE) genetic susceptiblity testing for Alzheimer’s disease (AD) dementia is becoming more important as clinical trials are increasingly targeting individuals carrying APOE4‐genotypes. As little is known about about the interest in knowing genetic risk for AD dementia in the general population. Our objective was to examine this in a sample of cognitively normal adults within a population‐based online research registry with the goal to implement APOEε4 status for trial recruitment.

Method

An online survey was completed by 442 cognitively normal participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia, and the knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOEε4/ε4 genotypes). All hypothetical scenarios were randomly presented to all participants. Cochran’s Q‐tests was used to analyse differences in frequencies across scenarios.

Result

The vast majority of participants was interested in participating in research and disclosure of their genetic risk (81%; Figure 1). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, while lower‐educated participants more often reported to be unsure. When provided with different risk scenario’s, interest in knowing their risk was somewhat higher in the scenario’s with higher risk (50% scenario (79%) and 30% scenario (77%)) than in the 10% scenario (73%; χ2(2) = 19.91;p<.001). Most individuals expected they would share their genetic risk with close relatives (77‐89%), would participate in medication trials (79‐88%), and would make long‐term arrangements, e.g. retirement, health care, will (69‐82%), with larger proportions for scenarios with higher hypothetical genetic risk.

Conclusion

Our findings indicate that the vast majority of cognitively normal adults participating in a research registry is interested in AD genetic risk research participation and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOEε4 genotypes. This suggests APOEε4 screening within an online research registry is potentially a well‐received method to accelerate inclusion for preclinical trials ultimately disclosing genetic risk.
Coping and mood in carers of people with Parkinson’s disease – an anonymized online survey
Authors: Magdalena Garcia , Velayudhan Latha
Published: December 2023

Background

Family and informal carers play a substantial role in the care of patients with Parkinson’s disease (PD) especially those who develop neuropsychiatric symptoms and dementia. As PD progresses, carers are at increased risk for poor health outcomes and greater levels of stress. Furthermore, negative emotional states, such as depression and anxiety with stress, are major risk factors for the development and maintenance of poor adaptive coping strategies. However, the literature examining these in PD carers is sparse. We aimed to identify and examine relationships between mood symptomatology and coping strategies in carers of people with PD.

Methods

An anonymised self‐administered online survey was conducted for data collection within the UK (Ethics Approval Ref‐LRU‐21/22‐28386). The survey consisted of questions regarding demographics, coping strategies and mood symptoms. A snowballing sampling was used to recruit via advertising in various Parkinson’s support groups within UK. Participants who were unpaid carers (family, partner or friend) of people with PD above the age of 18 years, fluent in English and had a device to do the online survey were eligible.

Results

105 carers for people with PD participated online between 23rd May 2022 to 15th July 2022. 96.2% of the carers were women and most in the age range of 45‐64 years (57.1%). 93.3% of the carers were spouse or partners, lived (89.5%) and taken care of the person with PD for over 5 years (54.3%), providing care ‘most of the time’ (59%). 61.9% PD persons had dementia and 29.5% had psychosis symptoms. We found that PD carers used more of non‐adaptive than adaptive coping strategies. 91.4% of carers had anxiety and 92.4% had depressive symptoms in varying frequency. Non adaptive coping strategies were associated with increased mood symptoms.

Conclusions

Carers with adaptive coping strategies had lower frequency of mood symptoms. Further research in larger samples is needed not only to understand the relationships of coping strategies and mood symptoms in carers of people with PD but also important to devise interventions to support these carers to improve their well‐being.
Microtubule‐binding region tau fragment tau368 as a biomarker of Alzheimer’s disease
Authors: Simrén Joel , Janelidze Shorena , Kac Przemyslaw Radoslaw , Karikari Thomas K , Smirnov Denis , Kvartsberg Hlin , Gonzalez‐Ortiz Fernando , Sjons Emma , Mattsson‐Carlgren Niklas , Brum Wagner Scheeren , Palmqvist Sebastian , Ashton Nicholas J. , Zetterberg Henrik , Galasko Douglas R. , Hansson Oskar , Blennow Kaj
Published: December 2023

Background

Recent studies suggest that microtubule‐binding region (MTBR) tau fragments may be markers of tau tangles in Alzheimer’s disease (AD) when used in ratio with total tau (MTBR‐tau/T‐tau) to normalize for T‐tau secretion. One such candidate marker is MTBR‐tau containing residue 368 (MTBR‐tau368). In this study, it was cross‐sectionally evaluated in participants from a memory clinic cohort and an autopsy series.

Methods

We included Aβ‐negative cognitively unimpaired (CU) individuals, individuals in the AD continuum (Aβ‐positive CU, mild cognitive impairment (MCI) and AD dementia), and with non‐AD dementia from the BioFINDER‐1 study, who all underwent [18F]‐flortaucipir‐PET. Further, we included CU and CI participants from UCSD Alzheimer’s disease research center (UCSD‐ADRC) who underwent lumbar puncture (LP) antemortem and then donated their brain for autopsy, examining AD neuropathologic change (ADNC) and non‐AD pathologies. All participants had immunoassay‐based CSF measures of T‐tau and MTBR‐tau368 by commercial immunoassays (Euroimmun [BioFINDER‐1] and Lumipulse [UCSD‐ADRC] T‐tau) and an in‐house Single molecule array (Simoa) assay, respectively. Statistical analyses were performed using linear models (covarying for age and sex) and Pearson correlations.

Results

Sixty‐seven individuals from UCSD‐ADRC (mean [SD] age at LP 74.3 [8.4] years, 4.3 [2.1] years before death) and 181 from BioFINDER‐1 (72.5 [7.4] years) were included for this study. There were no group‐level differences in MTBR‐tau368 levels alone in any of the cohorts. In the UCSD‐ADRC cohort, MTBR‐tau368/T‐tau was decreased in participants with high (estimated marginal mean [EM = 0.06) vs. low (EM = 0.09, P = 0.01) or no (EM = 0.1, P = 0.001) ADNC and with higher Braak stage (V‐VI; EM = 0.06 vs. III‐IV; EM = 0.08, P<0.05, and I‐II; EM = 0.09, P<0.001). In BioFINDER‐1, Aβ‐positive MCI and AD dementia had lower MTBR‐tau368/T‐tau (EM∼0.04) compared with all other groups (EM = 0.06‐0.07, P<0.05‐<0.001). Further, MTBR‐tau368/T‐tau inversely correlated with tau‐PET in Braak‐like regions III‐IV and V‐VI (r = ‐0.35 and ‐0.42, P<0.001). MTBR‐tau368/T‐tau was unchanged in individuals in the frontotemporal dementia (FTD) spectrum (behavioral variant FTD/semantic dementia, and corticobasal syndrome/progressive supranuclear palsy).

Conclusion

Concordant with recent data, MTBR‐tau fragments alone do not change in AD or other neurodegenerative disorders. However, when normalizing MTBR fragments to T‐tau secretion, their capability of reflecting the extent of tau pathology provides opportunities of staging AD using CSF biomarkers.
Physical activity delayed the onset of cognitive impairment in middle‐aged and older adults with diabetes ‐ Findings from the ELSA‐Brasil Study
Authors: Feter Natan , Schmidt Maria Inês , Santos Danilo , Duncan Bruce
Published: December 2023

Background

Physical inactivity and diabetes are known risk factors for cognitive impairment. Yet, few studies in large samples of cognitively diverse populations have been reported to assess this joint effect on cognitive function. Therefore, this study aimed to characterize the joint association of baseline diabetes and physical activity with cognitive decline and the risk of cognitive impairment in middle‐aged and older adults.

Methods

Longitudinal data of the Estudo Longitudinal da Saúde do Adulto (ELSA‐Brasil, Longitudinal Study on Adult’s Health), an occupational cohort of Brazilian adults aged 35‐74, were analyzed. A standardized questionnaire distinguished physically active (≥150 min/week) from inactive participants. Cognitive function was examined using standardized tests to assess memory, language, and executive function at baseline and during follow‐up visit. Global cognitive function summed all three aspects and was described as z‐score differences from the sample average over follow‐up. Linear mixed models, Cox proportional regression models, and Laplace regression models, adjusted for sociodemographic and behavioral variables, were used to assess the relationship of diabetes and physical activity with change in cognitive function over time.

Results

Participants (n = 12,214; 55.5% women; age [SD]: 51.4 [8.8]) had median follow‐up of 8.2 (0.6) years. During follow‐up, those physically active at baseline showed a slower less than average global cognitive decline (z‐score difference 0.22; 95%CI: 0.19, 0.24) and those with diabetes greater than average decline (z‐score difference ‐0.22; 95%CI: ‐0.26 ‐0.19). In those with diabetes, active adults aged 80 or older showed global cognitive function (z‐score ‐0.80; 95%CI: ‐0.90, ‐0.69) similar to inactive adults aged 70 (z‐score ‐0.69; 95%CI: ‐0.74, ‐0.65). While inactive participants had an increased risk of incident cognitive impairment independent of diabetes status (no diabetes: HR: 1.31; 95%CI: 1.13, 1.53; diabetes: HR: 1.21; 95%CI: 1.02, 1.44), among active adults, diabetes was not associated with incident cognitive impairment (HR: 0.93, 95%CI: 0.69, 1.27) compared to active participants with no diabetes. In participants with diabetes, physical inactivity anticipated in 3.15 (95%CI: 1.60, 4.69) years the onset of cognitive impairment. Results remained consistent after multiple sensitivity analyses.

Conclusion

Physical activity attenuated the impact of diabetes on cognitive function in middle‐aged and older adults.
Meta‐analysis on Individual Patient Data from Randomized Controlled Trials of Fortasyn Connect in Early Alzheimer’s Disease
Authors: van Hees Anneke MJ , Cetinyurek‐Yavuz Aysun , Counotte Danielle , Rudka Tomasz , Sijben John W.C.
Published: December 2023

Background

The specific nutrient combination Fortasyn Connect (available in Souvenaid®), has been shown to bring benefits to subjects with various stages of Alzheimer’s disease (AD). The objective of this meta‐analysis was to investigate the effect of Souvenaid on cognition and memory using individual patient data (IPD) from all published RCTs in the early phases of AD ranging from mild cognitive impairment (MCI) due to AD (prodromal AD) to mild AD.

Method

The study population comprised all drug‐naïve subjects with a diagnosis of prodromal or mild AD included in double‐blind, randomised controlled clinical trials (RCTs) testing the efficacy of orally administered Souvenaid. Electronic databases and Google Scholar were searched to find all relevant RCTs. This meta‐analysis compared differences between Souvenaid and control groups using the IPD of analogous scales measuring overall cognition and episodic memory domains that were specified as either primary or secondary endpoints.

Result

In total, 779 subjects from three separate RCTs were included (Souvenir I, Souvenir II, and LipiDiDiet). The IPD meta‐analysis showed a significant favorable effect of Fortasyn Connect on episodic memory; the mean difference (MD) was 0.211 (95% confidence interval: 0.05, 0.37); p = 0.01, which was confirmed when corrected for possible confounders and effect modifiers (MD: 0.24 [0.07, 0.41]; p = 0.006) (Figure; Table). The IPD meta‐analysis for overall cognition suggested participants receiving Fortasyn Connect performed better than controls in the combined dataset (MD: 0.16 [−0.00, 0.32]; p = 0.055), which was confirmed when corrected for possible confounding effects and effect modifiers (MD: 0.23 [0.06, 0.41]; p = 0.01) (Figure; Table).

Conclusion

The total body of evidence available from RCTs suggests that Fortasyn Connect has a favorable effect on cognition and memory in early AD without any safety concerns, and consequently that this intervention is a viable option in the management of MCI due to AD (prodromal AD) and mild AD.

Trial registration: clinicaltrialregister.nl (Souvenir I: NTR702; Souvenir II: NTR1975; LipiDiDiet: NTR1705).
Processing of acoustically degraded emotional prosody in Alzheimer’s disease and primary progressive aphasia
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Nelson Annabel , Warren Jason D , Hardy Chris JD
Published: December 2023

Background

Accurately interpreting a speaker’s nonverbal emotional vocal signals (their prosody) is often essential for successful communication. In the noisy conditions of daily life, this presents the brain with a difficult computational challenge that may be vulnerable to neurodegenerative pathologies. However, processing of acoustically degraded prosody has not been studied in these diseases.

Method

Here we addressed this issue in patients representing all major syndromes of primary progressive aphasia (N = 33) and Alzheimer’s disease (N = 18) versus healthy age‐matched controls (N = 24). As a model paradigm for the degraded ‘noisy’ speech signals of everyday life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on recognition of three canonical prosodic emotions (anger, surprise, sadness) at three noise‐vocoding levels. Correlations were also conducted with perception of degraded emotional prosody and measures of social cognition.

Result

Compared with health controls, all patient groups were impaired in the identification of ‘clear’ emotional prosody. This impairment in all groups was sustained when the emotional prosody stimuli were vocoded, with differences seen between 18 and six channels, and 12 and six channels. Cost analyses conducted showed a significantly larger cost of noise‐vocoding in lvPPA than in healthy controls. Accurate identification of degraded emotional prosody in patients was significantly correlated with measures of social cognition.

Conclusion

Our findings open a window on a dimension of real‐world emotional communication that has often been relatively overlooked in dementia, and suggest a novel candidate paradigm for investigating and quantifying this systematically.
Using GENFI participant engagement to inform observational research and clinical trials
Authors: Russell Lucy L. , Greaves Caroline V , Bocchetta Martina , Heller Carolin , Rinaldi Daisy , Mueller Doreen , Bessi Valentina , Ber Isabelle Le , Synofzik Matthis , Borroni Barbara , Rohrer Jonathan D.
Published: December 2023

Background

It is vital that we include the views of individuals with frontotemporal dementia (FTD) and their families in the design of clinical trials. This study aims to establish what types of trials and treatments individuals with familial FTD would like to participate in.

Methods

135 participants from the GENFI cohort of at‐risk genetic FTD family members (34% of whom were known mutation carriers) completed a structured online questionnaire about clinical trials via Qualtrics. There was a total of 27 questions with a mix of multiple choice and free text questions. Topics included willingness to participate, understanding about likely proximity to symptom onset, and willingness to undertake different methods of therapeutic drug delivery including gene therapies.

Results

54% of individuals were definitely willing to participate in clinical trials with 39% stating it would depend on what the specific trial involved. Only 6% said they would not take part in a trial. The presence of a placebo group was a factor in trial participation with 31% stating they would decline to take part if there was a chance they did not receive the active drug. In light of a recent study suggesting plasma neurofilament light chain (NfL) may be a marker of proximity to symptom onset, we asked people if they would be willing to find out their NfL level as part of the trial, and 85% said they would. Most individuals said they would be willing to have IV infusions or lumbar punctures as part of the trial, although this did depend on the frequency with which they were required. For trials where drug administration would require more invasive measures, e.g. injections directly into the cisterna magna or the brain itself, only about 50% of people said they would be willing to take part. Lastly, if participation in a gene therapy trial precluded an individual from participating in future studies, only 30% said they would definitely consider being involved.

Conclusions

Observational studies and clinical trials are designed to make a difference to people’s lives, and it is important to consider patients and family members throughout the development pipeline of treatments.
Plasma biomarkers rates of change across the preclinical stage of Alzheimer’s disease: a longitudinal study
Authors: González Escalante Armand , Milà‐Alomà Marta , Ashton Nicholas J. , Shekari Mahnaz , Salvadó Gemma , Ortiz‐Romero Paula , Montoliu‐Gaya Laia , Benedet Andrea Lessa , Karikari Thomas K , Rodriguez Juan Lantero , Vanmechelen Eugeen , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Zetterberg Henrik , del Campo Marta , Gispert Juan Domingo , Blennow Kaj , Vilor‐Tejedor Natalia , Suarez‐Calvet Marc
Published: December 2023

Background

Whether plasma biomarkers steadily increase during the preclinical stage of Alzheimer’s disease (AD) is unknown. Herein, we aimed to determine the rate‐of‐change of plasma biomarkers throughout preclinical AD. This may be important to determine the optimal time window for treatment.

Method

We included baseline and follow‐up plasma biomarkers measurements (follow‐up: 3.37±0.40 years) of 240 cognitively unimpaired participants of the ALFA+ cohort (mean age: 60.75±4.85 years). Plasma Aβ40, Aβ42, GFAP and NfL were measured with the Simoa N4PE Advantage Kit, and plasma p‐tau231 with a Simoa‐validated in‐house assay.

For each participant we calculated the difference between follow‐up and baseline levels, and corrected for sex, time between measurements, and age. We computed z‐scores from the corrected values, and we applied a bootstrapped regression approach to model the rate‐of‐change of each plasma biomarker as a function of baseline age or Aβ PET centiloids (CL).

Moreover, we also computed the plasma biomarkers rate‐of‐change in three stages of preclinical AD: (I) CSF/PET Aβ‐negative group, (II) CSF Aβ‐positive/PET Aβ‐negative (CL < 30), and (III) CSF/PET Aβ‐positive.

Significance was determined if the 95% confidence interval of the rate‐of‐change did not overlap with zero.

Result

Significant acceleration in the rate‐of‐change of plasma GFAP was observed with ageing (Fig. 1), becoming significant at 60 years. There was also a significant accelerated change of p‐tau231 from 55 to 68 years.

Plasma NfL was the only biomarker whose rate‐of‐change accelerated with Aβ accumulation, and that rate became significant at 40CL (Fig. 2). Consistently, we observed a significant acceleration of plasma NfL when there was overt Aβ pathology (CSF/PET Aβ‐positive group; Fig. 3)

The rest of plasma biomarker rates‐of‐change did not significantly increase, some were even deaccelerating (plasma Aβ42/40 and p‐tau231), as Aβ accumulated (Fig. 2 and 3).

Conclusion

Plasma biomarkers rate‐of‐change throughout the preclinical AD continuum differ. Plasma NfL rate‐of‐change accelerates in the later stage of preclinical AD, when overt Aβ pathology is present. The deceleration on the rate‐of‐change of plasma Aβ42/40 and p‐tau231 may explain why their early increase in the preclinical AD continuum tends to plateau in later stages.
Life course rural/urban place of residence, depression and cognitive impairment among older adults: Findings from the Longitudinal Aging Study in India
Authors: Muhammad T.
Published: December 2023

Background

Given the unique socioeconomic structures and rural/urban differentials in mental health outcomes in the country, this study aimed to explore the associations of childhood, adulthood and late‐life place of residence with mental health outcomes of depression and cognitive impairment among older adults in India. The study also examined the relationship between older individuals’ life‐course rural/urban place of residence and late‐life mental and cognitive health.

Method

Utilizing data from the Longitudinal Aging Study in India (n = 28,041 older adults age 60 years and above), I employed multivariable logistic and linear regression models to examine the association between urban/rural residential status, life‐course residence, depression and cognitive impairment among older adults.

Result

Childhood and adulthood place of residence was not associated with depression in older men and women. Current rural place of residence was positively associated with depression in older women [OR: 1.37, CI: 1.05‐ 1.80] but not men. Childhood [OR: 1.88, CI: 1.16‐ 3.04], adulthood [OR: 2.00, CI: 1.26‐ 3.16] and current rural residence [OR: 1.93, CI: 1.27‐ 2.91] was positively associated with cognitive impairment in men. Only current rural residence [OR: 1.71, CI: 1.29‐ 2.27] was associated with cognitive impairment in women. There was no significant association between life‐course place of residence and depression except in case of lifetime rural residence Respondents with urban‐urban‐urban place of residence were less likely to be depressed [Coef.: ‐0.14, CI: ‐0.21‐ ‐0.07] compared to those with rural‐rural‐rural place of residence. There were significant associations between life‐course residence and cognitive impairment except among rural‐urban‐rural and urban‐rural‐rural migrants, showing a urban advantage in cognitive function among older adults.

Conclusion

This study showed significant associations between life‐course residence and depression among permanent rural/urban residents. The study also showed significant associations between life‐course residence and cognitive impairment except among rural‐urban‐rural and urban‐rural‐rural migrants. Considering the rural disadvantage, the government should continue to support policies that can promote education among people residing in rural areas. The findings also urge social scientists and gerontologists, in particular, to consider the importance of lifetime historical context while evaluating mental and cognitive health of older persons.
Diffusion MRI track cortical microstructural changes over time during the early stages of the Alzheimer’s disease continuum
Authors: Spotorno Nicola , Strandberg Olof , Stomrud Erik , van Westen Danielle , Hansson Oskar
Published: December 2023

Background

Markers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Previous cross‐sectional investigations suggested that diffusion MRI (dMRI) can provide metrics sensitive to cortical microstructural alteration linked to multiple aspects of the AD pathological cascade including Aβ‐accumulation and astrocytic activity. However, currently little evidence is available regarding the ability of dMRI in tracking changes over time.

Methods

Mean diffusivity (MD) was computed from dMRI data acquired from 363 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐1 study. Each participant underwent multiple dMRI scan (range 2‐4 scans) and was classified as Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on CSF levels of Aβ42/40 and ptau‐181. Rates of changes in MD, cortical thickness and plasma level of GFAP were computed in a linear mixed effect framework. Cortical regional values of MD were compared across biomarkers‐defined groups as well as to rates of change of GFAP.

Results

Analyses of MD revealed widespread differences in rates of change already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation (fig.1). Further, analyses focusing on two composite ROIs, one encompassing regions that accumulate Aβ early in the disease process and a temporal meta‐ROI, confirmed that rates of change in MD significantly differed between groups even when cortical thickness was included in the model (Ps<0.05,fig.2). Regional MD rates of change in both neocortical temporal areas and key regions for Aβ‐accumulation, were also positively correlated with rates of change in GFAP (fig.3). Such result was supported by the analysis based on the two meta‐ROIs which confirmed the positive association between rates of change GFAP and MD.

Conclusion

Mean diffusivity from dMRI is able to track cortical microstructural changes over time and to differentiate trajectories even during the early stages of the AD pathological cascade. The association between rates of change of MD and rates of change of GFAP suggested dMRI might reflect microstructural changes related to the astrocytic response to AD pathology. dMRI might help monitoring the effects of disease‐modifying therapies (e.g. Ab immunotherapies) in clinical trials.
Challenges with phenotyping dementia in a low resource setting; Frontotemporal dementias (FTDs) as a case study in Nigeria
Authors: Elugbadebo Olufisayo Oluyinka , Olawuyi Cynthia Olapeju , Farombi Temitope Hannah , Baiyewu Olusegun
Published: December 2023

Background

Phenotyping dementia is a major problem in low resource settings like Nigeria and it has implication for research and management of people with dementia. Challenges associated with phenotyping dementia are embedded in poor health financing and lack of health personnel. This study aimed at scoping studies on dementia in Nigeria to identify those related to frontotemporal dementia (FTD) and describe the pattern of its presentation in a memory clinic as a means of highlighting challenges of phenotyping.

Method

A literature search of studies on dementia that reported FTDs as a phenotype and or described profile or pattern of FTDs in Nigeria was conducted. In addition, a review of hospital records of all persons clinically diagnosed with dementia (PWD) using the ICD 10 criteria was conducted. Those with FTD phenotypes were identified. The cohort comes from a memory clinic in University College Hospital, Ibadan, Nigeria. Records of these individuals with FTDs were reviewed and data (including sociodemographic details, clinical profile and pattern of presentation) extracted for case series report.

Results

Literature search yielded 2 studies; a retrospective study that reported dementia phenotypes including FTD and a case report. From a total of 216 PWD, we identified and included 14 persons with FTDs (6.5%) in this case series. Initially, 32 records of tentative diagnosis of FTD were identified, however, 18 persons with incomplete evaluation after the initial assessment were excluded. The mean age (±S.D) of those included (n = 14) is 67.7(±8.4). The main presenting complaints were behavioral with 57.1% presenting to the hospital at least a year after onset of symptoms. The most common behavioral problem identified was personality change accompanied with disinhibition in 9 persons (64.3%). Symptoms started before age 60 years in only one person. Two of the 14 persons had an initial diagnosis of schizophrenia until subsequent review with neuroimaging. Delay in carrying out neuroimaging due to financial constraint was a major challenge in making a diagnosis.

Conclusion

There is paucity of data on FTDs in Nigeria. Out‐of‐pocket payment for assessment is a major setback in phenotyping dementia and it has implication on both clinical practice and research.
Development of a targeted proteomic assay for the quantitation of neurofilament light in cerebrospinal fluid: Correlation with Simoa‐based quantitation across neurodegenerative diseases and centres
Authors: Leckey Claire A. , Coulton John , Barthélemy Nicolas R. , He Yingxin , Laban Rhiannon , Heslegrave Amanda , Giovannucci Tatiana A. , Byrne Lauren M , Swift Imogen J , Esteve Aitana Sogorb , Rohrer Jonathan D. , Schott Jonathan M , Wild Edward J , Zetterberg Henrik , Wray Selina , Mills Kevin , Bateman Randall J. , Paterson Ross W.
Published: December 2023

Background

Cerebrospinal fluid (CSF) neurofilament light (NfL) is a dynamic biomarker of neurodegeneration that is used for supporting clinical diagnosis and monitoring disease‐modifying therapies. Development of new analytical tests has been limited, with quantitation of NfL in biomarker studies largely restricted to immunoassay methods. Targeted mass spectrometry is a highly specific technique that can be easily translated into existing proteomic and clinical pathology laboratories. In this multi‐centre study, we have developed two targeted mass spectrometry assays which were compared to Simoa, the gold standard method for NfL quantitation. The developed methods included immunocapture of intact NfL protein or specific peptides (immune‐peptide capture) prior to targeted proteomic analyses. We discuss the development, validation and merits of each technology to quantitate NfL in CSF from healthy controls and several neurodegenerative diseases.

Method

CSF was collected from patients with a range of neurological diseases at the National Hospital for Neurology and Neurosurgery (London, UK). Clinical diagnosis was determined by their treating clinician according to consensus clinical criteria. NfL concentrations were measured by Simoa (Quanterix, USA) and two immunoprecipitation‐targeted mass spectrometry (IP‐MS) assays developed by a collaboration between UCL and Washington University in St Louis. To evaluate replication of results across centres and mass spectrometry approaches, results were compared using Spearman’s correlation analysis and Bland‐Altman testing.

Results

A high correlation was observed for CSF NfL levels between Simoa and both IP‐MS assays (immune‐peptide capture, r = 0.90, P<0.0001 and immune‐protein capture, r = 0.88, P<0.0001). Relative differences in mean NfL concentration between clinical groups remained the same across the analytical methods, with the highest and lowest NfL concentrations observed in the Huntington’s disease and the healthy control groups respectively. Interestingly, differences in the extent of correlation between Simoa and IP‐MS were observed between the different clinical groups (r = 0.37 ‐ 0.94).

Conclusion

Immunoprecipitation‐targeted mass spectrometry quantitation of NfL correlates highly with NfL Simoa measures across a range of neurodegenerative and neuroinflammatory diseases, and is replicable between laboratories using different immunoprecipitation‐targeted mass spectrometry approaches.
CSF synapse marker changes in predementia Alzheimer´s Disease: AMPA receptor modulators NPTX2 and NPTXR mediate cognition within A/T/N stages
Authors: Kirsebom Bjørn‐Eivind , Nilsson Johanna , Vromen Eleonora M. , Jarholm Jonas Alexander , Tecelao Sandra , Selnes Per , Aarsland Dag , Grøntvedt Gøril Rolfseng , Rongve Arvid , Skogseth Ragnhild E , Visser Pieter Jelle , Brinkmalm Ann , Blennow Kaj , Fladby Tormod
Published: December 2023

Background

Synapse pathology has been linked to excitotoxicity and glutamate receptor dysregulation (such as AMPAR) in Alzheimer´s Disease (AD) progression. Of the core cerebrospinal fluid (CSF) AD biomarkers for amyloid, tau pathology and neurodegeneration (A/T/N), T/N status is proposed to reflect levels of neuronal plasticity, but fluid biomarkers for precision interventions in subgroups with increased excitotoxicity are lacking. Herein, we assess group differences of 19 CSF synapse markers including the AMPAR‐modulating NPTX, in both cognitively normal (CN) and Mild Cognitive Impairment (MCI) with either A+/T‐/N‐ and A+/T or N+ (A+/T/N+) as compared to CN A‐/T‐/N‐ and assess relationships with verbal memory recall and hippocampal volume.

Methods

A/T/N was determined using the CSF Aβ42/40 ratio, p‐tau181 and total‐tau in predementia AD cases (n = 194) and CN participants with normal AD biomarkers (n = 145) in the Dementia Disease Initiation cohort. CSF synapse marker concentrations were determined using mass‐spectrometry (table 1) and ELISA for GAP‐43. Adjusted for age and sex, we compared marker concentrations between CN cases (A+/T‐/N‐ n = 20; A+/T/N+ n = 40) and MCI cases (A+/T‐/N‐ n = 25;A+/T/N+ n = 109) with CN A‐/T‐/N‐ (n = 145) as the reference group. Associations to verbal memory recall and brain imaging were performed in the total sample and respective A/T/N groups adjusted for covariates. Results p<.01 were considered significant.

Results

Top markers based on between‐group results are reported (Table 1 & figure 1‐2 for all markers). Compared to CN A‐/T‐/N‐, 14‐3‐3 ζ/δ concentrations were higher in all A+/T/N+ groups (p<.001), but unaltered in A+/T‐/N‐ groups. In A+/T‐/N‐, NPTX2 concentrations were lower in MCI (p<.001) but not in CN. In A+/T/N+, NPTX2 was higher in CN (p<.001) but not in MCI. 14‐3‐3 ζ/δ was associated with worse memory in the total sample (p<.001) but not in the A+ groups. Lower NPTX2 was associated with worse memory in the total sample (p<.001) and in both A+ groups (p<.01; p<001). Neither 14‐3‐3 ζ/δ nor NPTX2 were significantly associated with hippocampal volume (figure 2).

Conclusion

Overall, increased 14‐3‐3 ζ/δ was most closely associated with worse memory recall. Lower NPTX2 was linked to poorer cognitive status within A+ groups, suggesting links to AMPAR dysregulation and excitotoxicity.
Angiotensin receptor blockers reduced the risk of post stroke cognitive impairment among first‐ever ischemic stroke patients
Authors: Vidyanti Amelia Nur , Prodjohardjono Astuti , Hardhantyo Muhammad
Published: December 2023

Background

The effect of antihypertensive drug classes in reducing the risk of post‐stroke cognitive impairment (PSCI) remains elusive. We aimed to investigate the association between antihypertensive drug classes and the risk of PSCI among ischemic stroke patients using data collected from a tertiary hospital in Indonesia.

Methods

We carried out a retrospective analysis of data from a medical database in Sardjito General Hospital Yogyakarta, Indonesia. We identified the first‐ever ischemic stroke patients hospitalized between June 2018 to May 2019 and whose serial measurements of cognitive function were available up to 90 days after stroke. The effect of antihypertensive drug classes on PSCI was measured by using multivariate logistic regression analysis.

Results

We found 71.11% patients developed PSCI at 90 days after stroke. Forty‐one patients (44.09%) received no antihypertensive drugs, 14 (15.05%) with angiotensin receptor blockers (ARB), 20 (21.50%) with calcium channel blockers (CCB), and 18 (19.35%) with combination of ARB and CCB. After controlling covariates, we found that ARB reduced the risk of PSCI by 64% (aOR 0.364, 95% CI = 0.14‐0.91, p<0.05), with improvement of total MoCA‐INA score by 3.113 points (p<0.05).

Conclusions

Among first‐ever ischemic stroke patients, ARB showed more favorable outcome on reducing the risk of PSCI and improving cognitive performance at 90 days after stroke. These findings may contribute to assist clinicians for selecting antihypertensive drug classes in PSCI prevention.
Blood‐based biomarkers for Alzheimer’s Disease in Down Syndrome
Authors: Jacob Charlotte , Heylen Annelies , Tollenaere Marleen , De Deyn Peter Paul , Van Dam Debby
Published: December 2023

Background

People with DS are at high risk to develop Alzheimer’s disease dementia (AD) (Lott & Head, 2001). Predicting and monitoring decline and onset of dementia is a diagnostic challenge and of essence in daily care and support for people with DS. Behavioral and Psychological Symptoms of Dementia (BPSD) are an easily accessible tool for the prediction of dementia onset in the DS population. The BPSD‐DS II scale was developed and validated by our team to identify behavioral changes linked to AD between the last six months and pre‐existing behavior in an individual with DS (Dekker et al., 2021). This project is based on a cohort of DS individuals without AD (n = 94), with AD (n = 43), or with questionable AD (qAD) (n = 54) aged >35 years. At inclusion, the BPSD‐DS II was applied to assess AD‐linked behavioral changes, and biofluid sampling was performed as well. Changes in cerebrospinal fluid (CSF) levels of monoaminergic neurotransmitters and metabolites have been associated with BPSD in AD (Dekker et al., 2015). However, CSF sampling procedures remain difficult in DS, illustrating the need for blood biomarkers. BPSD‐DS II results will be correlated with the serum levels of monoaminergic and classical AD biomarkers. Three years post‐inclusion, a follow‐up study was conducted to assess the evolution of possible AD dementia within this group and to determine the predictive values of the BPSD‐DS II scale and the different analytes.

Method

We will use reversed‐phase ultra‐high performance liquid chromatography with electrochemical detection to determine the levels of (nor)epinephrine, dopamine, serotonin and their metabolic products in serum. We will use the Simoaâ platform on the serum of clients with DS without or with (q)AD to detect the levels of Ab40, Ab42, total tau, phosphorylated tau, Glial Fibrillary Acidic Protein and Neurofilament Light chain.

Result

We expect a correlation between the results of the BPSD‐DS II and the levels of the monoamines and classical biomarkers in patients with DS without or with (q)AD.

Conclusion

The diagnosis predicted by the results of the BPSD‐DS II correlates with the levels of monoamines and classical biomarkers in individuals with DS without or with (q)AD.
Plasma biomarkers of Alzheimer’s disease in a biracial, community‐based sample
Authors: Ramanan Vijay K , Graff‐Radford Jonathan , Syrjanen Jeremy A. , Shir Dror , Algeciras‐Schimnich Alicia , Lucas John A. , Martens Yuka A , Carrasquillo Minerva M. , Day Gregory S. , Ertekin‐Taner Nilufer , Lachner Christian , Willis Floyd B. , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Vemuri Prashanthi , Graff‐Radford Neill R , Mielke Michelle M.
Published: December 2023

Background

For blood‐based biomarkers to fulfill their potential to revolutionize diagnosis and management of Alzheimer’s disease (AD), additional research in diverse populations remains critical. Here, we analyzed a biracial sample to assess the profiles of blood‐based AD biomarkers and their relationships to cognition and medical comorbidities.

Methods

Self‐reported African‐American (AA; n = 267) and non‐Hispanic White (NHW; n = 268) participants evaluated through the Mayo Jacksonville Alzheimer’s Disease Research Center were matched on age, sex, and clinical diagnosis. Plasma AD biomarkers (Aβ42/40, p‐tau181, GFAP, NfL) were measured using the Quanterix SiMoA HD‐X analyzer. Cognition was assessed with the Mini Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels, covarying for age and sex. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition, further covarying for education.

Results

The sample included adults aged 43‐100 years, with 69% women. Education was higher in NHW participants (median 16 vs. 12 years, p<0.001). APOE (apolipoprotein E) ε4 positivity was higher in AA participants (43% vs. 34%; p = 0.04). There were no differences in plasma AD biomarker levels between AA and NHW participants. These findings were unchanged after stratifying by cognitive status (unimpaired versus impaired). Although the association between p‐tau181 and cognition appeared stronger in NHW participants while the association between Aβ42/40 and cognition appeared stronger in AA participants, these findings did not survive after excluding individuals with CKD. Women displayed higher GFAP (p = 0.002) and lower p‐tau181 (p = 0.001) levels than men. Diabetes was inversely associated with GFAP levels (p<0.001).

Conclusions

In a biracial, community‐based sample, we observed that sex differences, CKD, and vascular risk factors contributed to variation in plasma AD biomarkers, while self‐reported race did not. Our results reinforce the critical need to account for sex and systemic medical comorbidities in equitably deploying blood‐based AD biomarkers in the general population.
Evaluation of Gestational Alcohol Intake on the Hippocampus of an Adult Wistar Rats
Authors: Ojo Mayokun Afolabi
Published: December 2023

Background

Chronic consumption of alcohol is a leading cause of death worldwide due to it effect on differs organs of the body. The need to better understand the impact of alcohol intake on Hippocampus was the motivation behind this study.

Method

The study was performed on (20) twenty pregnant wistar rats weighing between 142‐181g which were divided into two (2) groups of ten animals each; A (Control), B (Treated). Group A (control) were administered normal saline orally on a daily basis for seven (7) consecutive days while the Group B (treated) were administered 12% Acetone orally for seven (7) consecutive days. The animals went through neurobehavioral tests for fear and anxiety with the aid of an elevated plus maze. The Hippocampus tissues gotten after the study were determined for histological analysis (H&E, Silver Stains).

Result

There was observable reduction on the body weight on administration of Alcohol and a drastic reduction in the mean cell count and size of animals in group B (treated) compared to group A (control) showing a significant effect of alcohol on the hippocampal cell count of the animals. Histo‐architectural analysis of the hippocampus showed distortion of the dentate gyrus, disorientated molecular layer, scattered granule and glail cells in the treated groups (B) indicating the effect of the administered alcohol.

Conclusion

Measure should be taking in reducing the consumption of alcohol if abstinence is not possible
Amyloid‐β and tau accumulation in traumatic brain injury: A study of Vietnam war veterans
Authors: de Bruin Hannah , Groot Colin , Kamps Suzie , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , Ossenkoppele Rik , Franzmeier Nicolai
Published: December 2023

Background

Traumatic brain injury (TBI) is widely viewed as a risk factor for dementia. Since amyloid‐β and tau pathology have been reported in up to a third of individuals with TBI – even after a single TBI event – their accumulation could be a potential mechanism underlying this association. The aim of this study was to examine the relationship between TBI and amyloid‐β and tau pathology more closely and to assess whether the association between amyloid‐β and tau is influenced by TBI status.

Method

A total of 102 Vietnam war veterans (79% normal cognition, 21% mild cognitive impairment; 23% amyloid‐β positive) were included from the Alzheimer’s Disease Neuroimaging Initiative Department Of Defense study. Among these individuals, 65 had a history of TBI (42 mild and 23 moderate/severe TBI) whereas 37 did not. Amyloid‐PET ([18F]florbetapir) and tau‐PET ([18F]flortaucipir) SUVRs were assessed within regions from the Schaefer atlas. For both amyloid‐PET and tau‐PET ROI‐wise and global TBI group differences were determined by ANCOVAs. Moderating effects of TBI status on the association between ROI‐wise amyloid‐PET and tau‐PET SUVRs were tested using linear regression. Analyses were adjusted for age, sex, education, clinical diagnosis, and, where applicable, global amyloid‐PET and time lag between amyloid‐ and tau‐PET scans.

Result

TBI groups did not show significant increases in amyloid‐ or tau‐PET uptake compared to no‐TBI groups, neither globally nor on the ROI‐level (i.e. all p>0.05 after correcting for multiple comparisons, Fig. 1). However, we found that a history of (particularly moderate/severe) TBI was associated with a weaker relationship between amyloid‐PET and tau‐PET uptake in temporal and parietal brain regions compared to no history of TBI (Fig. 2). This effect seemed to be driven by the amyloid‐β positive group. TBI groups did not differ regarding age and APOE‐status.

Conclusion

While amyloid‐β is known to promote tau spreading in Alzheimer’s disease (AD), our results indicate that in TBI there might be a detachment of amyloid‐β and tau pathology in AD‐susceptible temporo‐parietal brain regions. This finding is supportive of the view that TBI could lead to distinct changes in the interplay of pathological proteins, potentially underlying the link between TBI and dementia.
High late‐life physical activities and reduced progression from MCI to Alzheimer’s dementia
Authors: Sohn Bo Kyung , Byun Min Soo , Yi Dahyun , Jeon So Yeon , Choe Young Min , Lee Dong Woo , Lee Jun‐Young , Kim Yu Kyeong , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2023

Background

Physical activity (PA) has been reported to reduce the risk of Alzheimer`s disease (AD) dementia and related cognitive decline. We aimed to investigate the influence of PA on the progression from cognitively normal (CN) status to mild cognitive impairment (MCI) or from MCI to AD dementia in non‐demented older adults.

Method

This study included 194 non‐demented (148 CN and 46 MCI) participants from the Korean Brain Aging Study for Early diagnosis and prediction of Alzheimer’s disease (KBASE), who completed both baseline and 2‐year follow‐up clinical evaluation. At baseline, the participants underwent comprehensive clinical and neuropsychological assessment, multimodal brain imaging including [11C] Pittsburgh Compound B positron emission tomography (PET), [18F] fluorodeoxyglucose PET and MRI, and current PA measured using the Lifetime Total Physical Activity Questionnaire.

Result

After 2 years, five CN and 22 MCI participants progressed to MCI and AD dementia, respectively. Logistic regression analyses showed that high current PA (above the median value) reduced the risk of the progression from MCI to AD dementia even after controlling age, sex, education, apolipoprotein E e4 positivity, baseline brain amyloid deposition, AD‐signature region glucose metabolism, and AD‐signature region cortical thickness (Bonferroni corrected p‐value = 0.028). In contrast, PA had no effect on the progression from CN to MCI.

Conclusion

The findings suggest that a physically active lifestyle in late‐life reduces the risk of conversion to AD dementia in MCI independently of AD‐related brain pathologies.