bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies
Authors: Diaz‐Galvan Patricia , Przybelski Scott A. , Algeciras‐Schimnich Alicia , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Jack Clifford R. , Min Paul H , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Ramanan Vijay K , Jones David T. , Botha Hugo , St. Louis Erik K , Knopman David S. , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , Kantarci Kejal
Published: December 2023

Background

Patients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aβ), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.

Method

We included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aβ40, Aβ42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aβ40/42. Lower Aβ40/42 indicates increased Aβ pathology. Plasma Aβ40, Aβ42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aβ and 18F‐Flortaucipir for tau.

Result

Higher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aβ40/42 did not correlate with amyloid or tau PET SUVr.

Conclusion

In the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.
Syzigium aromaticum may protect against paraquat mediated toxicity via p53 and Sestrin2 modulation
Authors: Rai Nitish , Dey Sharmistha
Published: December 2023

Background

Numerous environmental risk factors, particularly neurotoxins, have been linked to the development of sporadic Parkinson’s disease (PD), even though its exact cause is still unknown. The common spice Syzigium aromaticum has the greatest ORAC (Oxygen Radical Absorbance Capacity) value according to the National Institute on Aging. One of the three components of healthy ageing, vata, is calmed by Syzigium aromaticum while also stimulates nerves. The study investigated the rescue effect of Syzigium aromaticum ethanolic extract against paraquat (PQ) mediated PD type toxicity and elucidated the underlying molecular mechanism using the cell line.

Method

The cold extraction method was used to prepare the Syzigium aromaticum ethanolic extract by powdering, soaking in ethanol and stirring for 72 h. Then the supernatant was gradually aliquoted and filtered with Whatman filter paper no 1. Paraquat, at different doses, was used to generate PD type toxicity in SH‐SY5Y cells for 24, 48, and 72 hours, and MTT test was used to measure the cytotoxicity. The rescue effect was demonstrated by simultaneously treating cells with 100 mM PQ and various doses of Syzigium aromaticum and then performing MTT assay. The protein expression studies was done using western blot technique to elucidate the underlying mechanism.

Result

The toxicity experiment showed that PQ‐treated cells exhibited significant cell death, with the maximal toxicity occurring after 72 hours. However, the cells treated with Syzigium aromaticum were protected from the PQ‐induced cell death. Syzigium aromaticum exhibited rescue effect in proportion to its dose. The western blot analysis of PQ treated SH‐SY5Y cells demonstrated a dose‐dependent increase in the levels of p53, Setrin2, and phosphorylated AMPK (P‐AMPK). The levels of AMPK, mTOR and p70S6K remain unchanged, however, the phosphorylated p70S6K (P‐p70S6K) levels were declined. When cells were simultaneously treated with PQ and increasing dose of Syzigium aromaticum, the levels of p53, Sesn2, and P‐AMPK lowered similar to control. Further, there was an increase in the level of phosphorylated p70S6K (P‐p70S6K) in proportion to the dose of Syzigium aromaticum.

Conclusion

The current study showed that the Syzigium aromaticum ethanolic extract prevented PQ‐induced cell death in SH‐SY5Y by targeting p53 and sestrin2.
Prevalence of Dementia in a Diverse Cohort of Adults with Hip Fracture
Authors: Lee David R , Lo Joan C , Chandra Malini , Lee Catherine , Gilsanz Paola
Published: December 2023

Background

There is a 2.5‐fold increased risk of hip fracture for persons living with dementia compared to persons without dementia. Independently, the risk of hip fracture and Alzheimer’s Disease and Related Dementias (ADRD) increase with age and vary by sex and race and ethnicity. However, few studies have examined racial and ethnic variations in dementia prevalence among older US adults who experienced a hip fracture.

Method

This retrospective observational cohort study included adult health plan members aged ≥50y in a large Northern California healthcare system during 2000‐2019 who had a hip fracture event during follow‐up to 2021. ADRD diagnosis (ICD‐9/10) was obtained from clinical encounters within 5 years prior to and including the hip fracture hospitalization. Modified log‐Poisson regression models were performed with ADRD as the outcome and race and ethnicity as the primary predictor, adjusting for age and sex. Sensitivity analyses expanded the definition of prevalence of ADRD to include ADRD diagnoses up to 3 months after hip fracture.

Result

Among 46,622 adults with hip fracture (mean age 80.6 ± 9.9y, 69.7% female, 78.8% non‐Hispanic White (NHW) race), ADRD prevalence was 21.0% based on diagnoses prior to and during hip fracture hospitalization, increasing to 24.2% when including diagnoses within 3 months post‐hip fracture. ADRD prevalence was significantly higher in Black (29.2%), Hispanic (22.5%), and Asian (22.0%) adults compared to NHW (20.3%) adults. Expanding the definition found similar observations except no significant differences for Hispanic and Asian adults (see Figure). Adjusting for age and sex, Black (RR = 1.47, 95%CI 1.35‐1.59), Hispanic (RR = 1.15, 95%CI 1.07‐1.24) and Asian adults (RR = 1.12, 95% CI 1.04‐1.21) had greater risk of prevalent ADRD compared to NHW adults. Sensitivity analysis results were similar.

Conclusion

At least 1 in 5 adults with hip fracture had diagnosed ADRD, with higher prevalence among racial and ethnic minority populations. Age‐ and sex‐adjusted risk was highest in Black adults and modestly higher in Hispanic and Asian adults. Hip fractures and ADRD are serious public health concerns leading to increased morbidity and mortality, and understanding differences among high risk groups will aid in the development of socially appropriate patient and caregiver interventions.
APOE E4 as a moderator for gait speed and executive function
Authors: Soo See Ann , Sandhu Gurveen Kaur , Zailan Fatin Zahra , Leow Yi Jin , Lee Faith Phemie Hui En , Ghildiyal Smriti , Koh Chen Ling , Kandiah Nagaendran
Published: December 2023

Background

Gait speed has been found to be associated with cognitive function (Liu, 2022) with slower walking speed related to poorer cognition (Hoogendijik, 2020). Slower gait speed was found to be associated with poorer global cognitive function, verbal memory and executive function (Watson, 2010). Additionally, APOE E4 carriers with slow gait speed have been found to perform worse on the MMSE than APOE E4 carriers without slow gait and APOE E4 non‐carriers with slow gait (Sakurai, 2017).

We aim to evaluate the moderating effects of APOE E4 status on gait speed and cognition in a pre‐dementia community population in Singapore.

Method

We recruited 534 participants from the community who completed a detailed neuropsychological assessment and APOE genotyping. To test for the moderating effects of APOE E4 with gait speed and cognition, we performed a multiple generalized linear model controlling for covariates of age, sex and education.

Result

The cohort included 186 subjects with subjective cognitive decline and 348 mild cognitive impairment subjects from Dementia Research Centre (Singapore). Mean age of the cohort was 62.55, SD = 9.55, mean education years was 13.97, SD = 3.45 and majority were women (57.1%). The presence of slow gait speed among our cohort was 4.7% and there were 12.6% APOE E4 carriers. There were no significant differences in walking gait between APOE E4 carriers and non‐carriers (p = 0.235). APOE E4 moderated the effect of slow gait speed on executive function. APOE E4 non‐carrier interacted with slow gait speed, resulting in worse performance on the trail making task B (β = 71.97, p = 0.003), digit span backwards (β = ‐2.23, p = 0.037), and colour trails 2 (β = 64.01, p<0.001).

Conclusion

APOE E4 status moderates the effect of slow gait speed on executive function. APOE E4 non‐carriers with slow gait speed are at risk for poorer executive function.
Prevalence of dementia screen positive among older adults in rural Kenya: results from a dementia screening program
Authors: Muyela Levi A. , Musyimi Christine W. , Farina Nicolas , Mutunga Elizabeth Kasimu , Masila Joe , Ndetei David
Published: December 2023

Background

Sub‐Saharan African countries have the fastest growing rates of older people, yet little is known about the number of cases of dementia. In Kenya, the little we know about dementia is derived from studies involving the few individuals who receive a diagnosis, but typically in the more advanced stages of the condition when carers have reached a crisis point. Effective and routine data screening is important for the early detection of dementia, but also provides insights into the number of people living with cognitive and functional impairment associated with dementia. We aimed to describe the number of people screening positive for dementia within rural Kenya, and identify factors associated with screening positive.

Method

Community Health Workers conducted an opportunistic household survey among community‐dwelling residents aged 60 and above in rural Kenya. The brief Community Screening Instrument for Dementia (CSID), which allows for potential cases of dementia to be identified without the need for specialist tools or intensive training was used to identify number of people living with dementia and socio‐demographic information collected. This is an interim analysis of the data.

Result

672 older adults (M = 71.0 years old; SD = 8.96) were screened for dementia. Participants were predominantly Kamba (n = 664, 98.8%) and from Makueni county (n = 617, 91.8%). 209 people screened positive for dementia (31.1% (95%CIs 27.6 to 34.8). Males (OR = 0.67, 95%CIs 0.52 to 0.87) and people who were literate (OR = 0.51, 95%CIs 0.41 to 0.64) were less likely to screen positive for dementia. Screening positive for dementia was also associated with old age, with the oldest age group (90 years+) being 3.7 times more likely to screen positive for dementia than the youngest group (60‐64 years) (OR = 3.67, 95%CIs 2.54 to 5.37).

Conclusion

These findings form the first‐ever dementia screening programme in rural Kenya and highlight the numbers of people living with cognitive and functional impairment, potentially indicating dementia. Although such cases need to be clinically confirmed, these data can support the planning, policy development and inclusion of dementia care within policy discussions.
Circulating Endocannabinoids and Early Markers of Alzheimer’s Disease: Considering the Role of Sex
Authors: Vered Shiraz , Beiser Alexa S. , Sulimani Liron , Sznitman Sharon , Gonzales Mitzi M. , Aparicio Hugo J , Lewitus Gil M , Meiri David (Dedi) , Seshadri Sudha , Weinstein Galit
Published: December 2023

Background

Endogenous cannabinoids (i.e. endocannabinoids; eCBs) have an essential role in multiple physiological processes including energy homeostasis, sleep patterns and mood. Moreover, preclinical studies highlight the implication of eCBs in neurodegeneration and Alzheimer’s disease pathogenesis. Yet, observational studies are scarce and limited by small sample sizes and assessment of limited numbers of eCBs. We assessed the relationship of multiple circulating eCBs with cognitive and brain MRI measures and tested for effect‐modification by sex.

Method

We measured serum levels of 44 eCBs and eCB‐like compounds from 237 cognitively healthy participants aged ≥65 years who attended the ninth examination cycle of the Framingham Heart Study Offspring cohort. Linear regressions were used to examine the associations of eCB levels with cognitive and brain MRI, adjusting for age, age2, sex and time between blood draw and cognitive/MRI examination. Bonferroni correction for multiple comparisons was applied, and interactions with sex were assessed by including interaction terms in the models and stratification.

Result

Mean age was 73.3±6.2 years and 95 (40%) were men. Overall, higher levels of N‐Linolenoyl amide and N‐Linoleoyl amide were associated with poorer performance on Logical Memory (β = ‐1.535±0.442; p = 0.0006; β = ‐0.171±0.045; p = 0.0002, respectively) and Trails‐making A (β = ‐0.127±0.036; p = 0.0005; β = ‐0.014±0.004, p = 0.0003, respectively). Higher levels of Linolenic acid and N‐Oleoyl alanine were associated with poorer performance on Trails‐making B‐A (β = ‐0.001±0.0001; p = 0.0007; β = ‐0.787±0.237; p = 0.001; respectively) (Figure 1). Our results further pointed to a potentially important interaction between sex and eCB signaling with regard to cognitive and brain MRI measures. Specifically, significant interactions between eCBs and sex were observed in relation to all the study outcomes except for total cerebral brain volume. Moreover, most associations that differed by sex were in the opposite directions comparing men to women (Figure 2 and 3). The aforementioned associations between specific eCBs and cognitive performance in the total sample were apparent in women but not men.

Conclusion

We identified a wide range of sex‐specific associations between novel eCB compounds and early AD markers among dementia‐free older adults. These findings suggest putative molecular pathways underlying AD pathophysiology, and highlight potential mechanisms behind sex differences in AD susceptibility that need to be further investigated.
Regional Brain Structure Mediates Age‐Related Decline in Eye Movement Control
Authors: Etteldorf Rika , Coors Annabell , Ettinger Ulrich , Breteler Monique M.B.
Published: December 2023

Background

Eye movements (EM) are considered potential biomarkers of neurodegeneration because they are altered in patients with neurodegenerative disease, including Alzheimer’s disease (AD). Alterations in EM control have also been observed in old age, with particularly strong age effects on saccadic latency, inhibitory errors in the antisaccade task, and smooth pursuit accuracy. The goal of our study was to characterize the neural pathways of age‐related changes in these EM outcomes.

Method

The analysis was based on 8,318 participants (aged 30 to 95 years) from the population‐based Rhineland Study. EMs were recorded using video‐based infrared oculography at 1,000 Hz. Volumes and thickness measures of selected brain structures were obtained using FreeSurfer from 3 Tesla T1‐weighted MR images. Relations of brain structure with EM outcomes were quantified using multivariable linear regression models. Brain structure variables were also analyzed as potential mediators in the relation between age and EM outcomes using causal mediation analysis under a counterfactual framework.

Result

In women, higher volume of the right thalamus and right globus pallidus was associated with lower antisaccade latency, whereas higher cortical thickness in the anterior cingulate cortex was associated with higher antisaccade latency. Higher cortical thickness in right supramarginal gyrus and right paracentral lobule and sulcus was associated with fewer antisaccade errors in women. There were no significant associations between regional brain structure and antisaccade performance in men. Higher cortical thickness in the right calcarine sulcus was associated with higher smooth pursuit velocity gain in both men and women. Additionally, individual brain structures mediated up to 11% of the age‐related decline in EM performance.

Conclusion

Our results support that EMs indeed reflect neurodegenerative processes as changes in brain structure partly account for age‐related decline in oculomotor performance. Relevant brain regions include both brain regions vulnerable to AD pathology and brain regions that are typically spared, suggesting that both “normal” age‐related and pathological mechanisms may be causative for decline in EM control. Our results highlight the importance of taking into account normal age‐related changes when considering EMs as early biomarkers for AD. Further work is needed to better distinguish normal age‐related changes from pathological change.
Perspectives of General Practitioners on signaling and diagnosing dementia
Authors: Visser Fleur C.W. , van Eersel Marlise E.A. , van der Zaag Hester J. , van Munster Barbara C.
Published: December 2023

Background

Although a timely diagnosis of dementia is beneficial for patients, their relatives, and society, people with dementia often remain undiagnosed or receive a diagnosis at a relatively late stage (Lang 2017). General practitioners (GPs) have a prominent role in the detection of dementia, yet GPs experience several barriers in diagnosing dementia in primary care (Koch 2010). This study aims to explore the experiences and perspectives of GPs in diagnosing dementia in primary care.

Method

A qualitative study was conducted consisting of semi‐structured interviews with 10 Dutch GPs purposively selected using maximum variation sampling. The study was an initiative of Alzheimer Center Groningen as part of ABOARD (A Personalized Medicine Approach for Alzheimer’s Disease). Overall topics included: experiences in signaling dementia; thoughts about the decision to wait in diagnosing dementia, to perform diagnostics, or to refer to a medical specialist for diagnosing dementia; and the needs of GPs in the diagnostic process of dementia. Interview transcripts were analyzed in multiple rounds by a multidisciplinary research team using thematic analysis with a phenomenological approach.

Result

Overarching themes were ‘initiation of the diagnostic trajectory’, ‘timing of diagnosis’, ‘relevance of a formal diagnosis’, ‘division of roles and responsibilities, ‘patient denial’, ‘patient‐physician relationship’, ‘crisis’, and ‘arranging care after diagnosis’. Key findings within the ‘initiation of the diagnostic trajectory’ theme were that observations from people around patients (family, community nurse, practice nurse, pharmacist, or medical specialist) were often signals for GPs to start a conversation about dementia and diagnostic possibilities. The diagnostic trajectory rarely started with a request for help from the patient. Patient denial was described as a major obstacle in diagnosing dementia and arranging appropriate care subsequently. A proactive practice policy to detect and monitor cognitive impairment was a key facilitator to achieve a timely diagnosis and prevent crises in dementia. For example, GPs favored regular home visits by a practice nurse and low‐threshold cognitive examination; a long‐term physician‐patient relationship; and successful interdisciplinary collaboration with local care providers, especially consultation of an elderly care physician.

Conclusion

Patient denial and surrounding people are important barriers and facilitators, respectively, to the diagnostic process of dementia.
Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort
Authors: Grazia Alice , Dyrba Martin , Nunzio Pomara , Teipel Stefan
Published: December 2023

Background

Imaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.

Method

We analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.

Result

We found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.

Conclusion

Our findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.
Exploring the relationship between cognitive frailty and cognitive reserve in SCD and MCI
Authors: Facal David , Lojo‐Seoane Cristina , Campos‐Magdaleno Maria , Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Stern Yaakov , Pereiro Arturo X
Published: December 2023

Background

Cognitive frailty (CF) has been defined as the simultaneous presence of physical frailty (PF) and subjective or objective cognitive impairment, with current definitions differentiating, respectively, between reversible and potentially reversible CF. The former is indicated by subjective cognitive decline (SCD) and the latter by Mild Cognitive Impairment (MCI). Although CF is an emerging topic in the study of cognitive ageing, its relationship with cognitive reserve (CR) proxies have not been established.

Method

The prevalence of CF and the characterization of the sample in terms of its level of CR was studied in the second cohort of the Compostela Ageing Study (CompAS). 150 participants of the second follow‐up of this cohort who completed the PF assessment were studied. The frailty phenotype was used to operationalize the level of PF of the participants. Weakness was measured by 3 measurements of the grip strength (GS) in the dominant hand. Slow gait speed was measured through a timed‐up and go (TUG) task. Low physical activity was measured with the Spanish version of the Minnesota Physical Activity Questionnaire (VREM). MCI and SCD were diagnosed using the current criteria. The level of CR was established using the scores of the Cognitive Reserve Index questionnaire (CRIq). Bivariate correlations were made between CRIq subscales scores and the results in GS, TUG and VREM.

Results

A higher percentage of high CR was observed in participants without frailty, and a higher percentage of participants with medium level of CR showed pre‐frailty (c2 = 27,96 p<.05). Significant moderate correlations were obtained between GS and CRI‐q working activity (r = .47), and between TUG and CRI‐q leisure time (r = ‐.35).

Conclusion

As expected for a risk factor for dementia, there were significant relationships between CF and several domains of CR. Future longitudinal analysis should analyze the capacity of the CR to attenuate or delay the onset of cognitive frailty.
Deterioration of true resting state electroencephalographic alpha rhythms in patients with mild cognitive impairment due to Alzheimer’s disease at a 6‐Month follow‐Up
Authors: Jakhar Dharmendra , Noce Giuseppe , Tucci Federico , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Soricelli Andrea , Ferri Raffaele , Arnaldi Dario , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Marizzoni Moira , Frisoni Giovanni B , Babiloni Claudio
Published: December 2023

Background

Previous studies have shown that patients with Mild Cognitive Impairment due to Alzheimer’s disease (ADMCI) were characterized by reduced posterior rsEEG alpha rhythms after a 12‐month follow‐up (Babiloni et al., 2013). However, none of them have found an alpha deterioration considering a shorter follow‐up.

A promising neurophysiological biomarker of the quiet vigilance alteration is the measurement of the posterior rsEEG alpha rhythms reduction in amplitude (reactivity) in the transition from the eyes‐closed to the eyes‐open condition (Babiloni et al., 2022).

Here we tested the exploratory hypothesis that ADMCI reactive patients may display a deterioration of rsEEG alpha rhythms at a 6‐month follow‐up as a sign of disease progression (a relevant feature for intervention clinical trials).

Method

Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 matched healthy elderly (Healthy) seniors were available from an international archive (www.pdwaves.eu). The rsEEG frequency bands were individual delta, theta, and alpha (defined based on its posterior topography and “reactivity” to the eyes‐open condition) or background frequency (BGF), as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz). Cortical source estimation was performed by eLORETA freeware.

Result

A substantial (> ‐10%) reduction in the posterior alpha source activities during the eyes‐open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI participants (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition predicted the global cognitive status at 6‐month follow‐up. In all younger ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes‐closed condition reduced in magnitude at that follow‐up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD.

Conclusion

These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation.
CSF proteome profiling identifies novel biomarkers for Frontotemporal Dementia and its pathological subtypes
Authors: Hok‐A‐Hin Yanaika S. , Vermunt Lisa , Peeters Carel F.W. , van der Ende Emma L. , de Boer Sterre C.M. , Meeter Lieke H. , van Swieten John C. , Hu William T. , Lleó Alberto , Alcolea Daniel , Engelborghs Sebastiaan , Sieben Anne , Chen‐Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , del Campo Marta
Published: December 2023

Background

Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and the most common forms are characterized by either tau (FTLD‐Tau) or TDP43 (FTLD‐TDP) brain aggregates. However, FTD‐specific fluid biomarkers are lacking. Furthermore, the pathological subtypes are not distinct in their presentation, hampering accurate subtyping at clinical diagnosis. Therefore, there is a strong need to identify fluid biomarkers that could aid in FTD diagnosis and to discriminate the pathological subtypes.

Method

We employed an antibody‐based proteomic technology to analyze >600 proteins in a large multicenter cohort including cerebrospinal fluid (CSF) samples from FTD (n = 189), AD (n = 235) and cognitively unimpaired individuals (n = 196). For a subset of cases the underlying neuropathology was known or could be predicted (FTLD‐Tau = 85 and FTLD‐TDP = 57). Differences in protein expression profiles were analyzed by nested linear models. Penalized generalized linear modeling was used to identify classification protein panels. Protein panels were then validated in independent clinical cohorts (cohort 1: n = 157; cohort 2: n = 165) and a neuropathology cohort (n = 100) using customized assays.

Result

We observed 65 differentially regulated proteins in FTD versus controls and AD patients, associated with axonogenesis, synapse assembly, or locomotory behavior pathways. We identified panels of 14 and 13 proteins that could discriminate FTD from controls (AUC = 0.96, 95%CI:0.91‐0.99) and AD patients (AUC = 0.91, 95%CI:0.85‐0.96), respectively. Most of these proteins (21 out of 27) were translated into customized panels, which discriminated between groups with high accuracy for all three cohorts (FTDvsCon: AUCs > 0.96, FTDvsAD: AUCs > 0.88). When comparing the FTLD‐Tau and FTLD‐TDP subtypes, we observed that 86 proteins were increased in FTLD‐Tau, and associated with developmental and cellular processes and locomotion pathways. A panel of 8 proteins could discriminate between the pathological subtypes (AUC = 0.82, 95%CI:0.66‐0.95), which was however not stable during cross‐validation.

Conclusion

We identified and validated CSF panels to discriminate FTD from controls and AD with high accuracy. The identification of a biomarker panel to discriminate between the FTLD pathological subtypes likely requires larger and more homogeneous groups. The panels developed within this study might be useful for diagnosis and trial inclusion of FTD patients.
Effect of neuroinflammation markers on the relation between A, T and N: sex‐specific resilience or vulnerability?
Authors: Akinci Muge , Vila‐Castelar Clara , Palpatzis Eleni , Argiris Georgette , Kollmorgen Gwendlyn , Carboni Margherita , Blennow Kaj , Zetterberg Henrik , Falcon Carles , Gispert Juan Domingo , Suarez‐Calvet Marc , Arenaza‐Urquijo Eider M
Published: December 2023

Background

Sex‐specific vulnerability and resilience along the amyloid cascade may be partly explained by neuroinflammatory processes. Microglial activation may play a more important role in the development of Alzheimer’s disease (AD) in women than in men. We investigated the effect of sex and biomarkers of microglia and astrocytic activation on amyloid (A) and tau (T) burden, and neurodegeneration (N) in cognitively unimpaired (CU) older adults at increased AD risk.

Method

We included 397 CU participants (49‐73 years, 61.5% women) with the following available CSF biomarker data: Aβ42/40, p‐tau181, sTREM2, GFAP, and YKL40 measured with Roche NeuroToolKit or Elecsys® immunoassays. A subsample (n = 299) also had MRI‐based hippocampal volume data (ASHS segmentation). The outcomes of interest were A: Aβ42/40, T: p‐tau181, and N: hippocampal volume. Predictors included demographics and neuroinflammation markers. First, we tested the effect of sex and neuroinflammation markers on A, T, and N in the whole sample. Then, we tested the neuroinflammation*Aβ42/40 and neuroinflammation*p‐tau interactions on p‐tau and hippocampal volume, respectively. Finally, we looked at sex‐stratified models.

Result

Men were older, more often APOE‐ε4 carriers and showed higher GFAP levels (men>women). In the whole sample, neither sex nor neuroinflammation markers were associated with Aβ42/40. However, sex (women>men), higher sTREM2 and higher YKL40 were associated with higher p‐tau181 levels, and sex (women<men), lower sTREM2, and higher YKL40 were associated with lower hippocampal volume. Models including interaction terms showed a sex‐independent interaction of GFAP with Aβ42/40 and p‐tau181 on p‐tau181 and hippocampal volume, respectively, suggesting a role of astrocytic activation along the ATN pathway. Sex‐stratified analyses showed (1) in women only, a YKL40*Aβ42/40 interaction on p‐tau181 and an association of higher sTREM2 levels with greater hippocampal volume (p = .030), suggesting a protective effect, and (2) in men only, a p‐tau181*sTREM2 and p‐tau181*YKL40 interaction on hippocampal volume. Statistics are provided in Table 1.

Conclusion

Pending replication with longitudinal measurements, our results suggest that microglial and astrocytic activation may play a sex‐specific role in downstream amyloid. While astrocytic activation moderates the associations between A, T and N in men and women, microglial activation might provide resilience to neurodegeneration only in women (Figure 1).
Sex differential effects on the joint contribution of air pollution and biological aging on cognitive performance in individuals at risk of Alzheimer’s disease
Authors: Rodríguez‐Fernández Blanca , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Cirach Marta , Nieuwenhuijsen Mark , Sunyer Jordi , Fauria Karine , Molinuevo Jose Luis , De Vivo Immaculata , Navarro Arcadi , Gispert Juan Domingo , Sala‐Vila Aleix , Crous‐Bou Marta , Vilor‐Tejedor Natalia ,   for the ALFA study
Published: December 2023

Background

Air pollution is associated with cognitive performance, risk for AD and may accelerate biological aging. Biological aging due to telomere shortening has been associated with cognitive impairment. However, few studies have looked at the link between air pollution, telomere length, and cognitive performance among sexes. In this study, we investigated the joint effect of sex, air pollution, and leukocyte telomere length (LTL), on cognitive performance in cognitively unimpaired (CU) individuals at risk of AD.

Method

The study included 1,472 middle‐aged CU adults with increased risk of AD from the ALFA study [Table 1]. Residential exposure to air pollutants including nitrogen dioxide (NO2) and particulate matter (PM2.5, PM10) was estimated by land use regression models. LTL was determined by qPCR from DNA extracted from peripheral blood leukocytes. LTL was residualized against chronological age and sex (rLTL). A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing and executive function. Further, episodic memory (EM), executive function and Preclinical Alzheimer Cognitive Composite (PACC) composites were calculated by averaging normalized raw scores of the subtests. Models were corrected by chronological age, years of education and APOE‐ε4 status. Sex‐specific effects were investigated by adjusting interaction models.

Result

There was no overall effect of neither rLTL nor air pollution on cognitive performance, but crossover interactions with sex were found. Exposure to higher levels of NO2 and PM2.5 were associated with worse EM only in men [Figure 1]. Three‐way interaction models revealed longer rLTL and lower levels of air pollution were associated with better performance on PACC (for PM2.5, PM10 and NO2) and EM (for PM10 and NO2) among men. In women, these associations were only observed at higher exposure levels of air pollution [Figure 2].

Conclusion

The results show that lower levels of air pollution allow for the protective effect of rLTL on cognitive performance only in men for whom air pollution had a stronger negative impact. In women, the results show different mechanisms through which air pollution and rLTL affect cognitive performance. Further analyses will be conducted to gain insight into the observed effects.
Cognitively Unimpaired Multiparous Women Have Higher CSF p‐tau181 Levels Which Have More Deleterious Effects on Neurodegeneration and Executive Function
Authors: Brugulat‐Serrat Anna , Escalante Armand González , Sánchez‐Benavides Gonzalo , Milà‐Alomà Marta , Shekari Mahnaz , Ashton Nicholas J. , Karikari Thomas K , Kollmorgen Gwendlyn , Carmona Susana , Falcon Carles , Cacciaglia Raffaele , Anastasi Federica , Grau‐Rivera Oriol , Carboni Margherita , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   for the ALFA Study
Published: December 2023

Background

Epidemiologic studies show that multiparity (≥3 children) is associated with a higher risk of clincal AD in cognitively unimpaired (CU) women. However, studies exploring the impact of parity on AD biomarkers are scarce. We explored the association between number of children and imaging and fluid AD biomarkers, and the related interaction with neurodegeneration and cognition.

Method

We included 210 CU parous women from the ALFA+ cohort with 34 nulliparous women and 152 men with children as controls. The number of children was dichotomized as <3 children vs ≥3 children. All CSF biomarkers were measured using the Roche NeuroToolKit and Elecsys® immunoassays (both Roche Diagnostics International Ltd), except p‐tau231 and GAP‐43 (ELISA). All plasma biomarkers were measured using the Simoa HD‐X (Quanterix Corp) except sICAM1 (MSD). Jack’s cortical thickness AD signature was used as a marker of neurodegeneration. Cognitive change (3‐year follow‐up) was measured with a PACC‐like composite as well as for individual cognitive domains. Biomarkers differences between parity groups were analyzed with ANCOVA adjusted by age. Independent linear models with biomarkers, AD signature and cognitive change as dependent variable were constructed. The number of children was set as predictor, and age, APOE‐ε4, and age at first birth as covariates in all models. Interaction terms between number of children and biomarkers were modeled. p‐values <0.05 were considered as significant.

Result

Several biomarkers were significantly higher in grand multiparours women (Table 1). Linear regression results (Table 2, Fig. 1A) showed that multiparity was associated with higher CSF p‐tau181 levels. Moreover, multiparity interacted with CSF p‐tau181 to predict thinner cortical thickness in AD‐sensitive regions and a steeper decline in executive function (Table 2, Fig. 1B & 1C). No significant associations in men and nulliparous women were found.

Conclusion

Having ≥3 children increases the risk of higher CSF p‐tau181 levels in CU middle‐aged women, with CSF p‐tau181 having a more deleterious effect on cortical thickness and change on executive function performance. These findings contribute to our understanding of the higher risk for AD observed in CU multiparous women, who show higher susceptibility and more adverse downstream consequences to tau pathology.
The mismatch negativity as an index of cognitive impairment in adults with Down syndrome
Authors: Saini Fedal , Masina Fabio , Wells Jasmine , Rosch Richard , Startin Carla , Hamburg Sarah , Strydom Andre
Published: December 2023

Background

People with Down syndrome (DS) have a high risk of developing Alzheimer’s disease (AD; Zis and Strydom 2018). The mismatch negativity (MMN) is an event‐related potential that can be used to index cognitive decline (Näätänen et al., 2011). Given its relative independence from attentional processes (Naatanen and Näätänen 1992), the MMN may be particularly useful when studying populations with intellectual disability, who may find sustained attention tasks challenging. We therefore investigated the MMN in people with DS and its association with cognitive abilities.

Methods

MMN responses to a passive auditory oddball task were recorded from 27 adults with DS (aged 18 to 59) without any hearing impairments. Associations between MMN and age, as well as memory, language, IQ, and attention scores were examined.

Results

The MMN was present only in young adults up to the age of 40 and the latency was prolonged. Attenuation of MMN amplitude was associated with poorer memory scores. Finally, longer MMN latencies were associated with increased inter‐individual performance variability and worse performance on memory, verbal, and general IQ tasks.

Conclusion

Overall, our results indicate that MMN amplitude may be associated with AD‐related memory loss, while increased MMN latency seems to reflect verbal abilities in people with DS. Furthermore, the association between MMN latency and inter‐individual performance variability may suggest the presence of AD‐driven white matter degenerations affecting the brian’s frontal lobe. Therefore, the MMN may represent a valuable tool for studying cognitive abilities and AD pathology in DS.

References

:

Naatanen R, Näätänen R. 1992. Attention and brain function. Psychology Press.

Näätänen R, Kujala T, Kreegipuu K, Carlson S, Escera C, Baldeweg T, Ponton C. 2011. The mismatch negativity: an index of cognitive decline in neuropsychiatric and neurological diseases and in ageing. Brain 134(12):3435‐3453.

Zis P, Strydom A. 2018. Clinical aspects and biomarkers of Alzheimer’s disease in Down syndrome. Free Radical Biology and Medicine 114:3‐9.
Single nucleotide polymorphisms linked to Alzheimer’s disease are associated with distinct neuropathological phenotypes
Authors: Laureyssen Celeste , Gawor Klara , Van Dongen Jasper , Kucukali Fahri , Koper Marta J , Ronisz Alicja , Otto Markus , von Arnim Christine , Van Damme Philip , Vandenberghe Rik , Thal Dietmar Rudolf , Sleegers Kristel ,   Complex Genetics of Alzheimer’s Disease group
Published: December 2023

Background

Neurodegenerative brain diseases (NBDs) ultimately result in neuronal loss and subsequent cognitive decline. In Alzheimer’s disease, tau neurofibrillary tangles (NFT) and amyloid plaques are considered as the hallmark lesions, but there are a number of other distinct features that are not exclusive to AD and do occur to a certain extent in other NBDs.

Method

We extracted DNA from a cohort of 382 post‐mortem brains of NBD patients and controls with detailed neuropathological characterization. Genotyping of 85 genetic loci, previously found to be associated with AD, is ongoing using an in‐house developed oxford nanopore technologies (ONT) multiplex assay, allowing simultaneous sequencing of all variants on an ONT Flongle platform. Base‐ calling, alignment to Hg38 and variant calling were performed followed by QC on the data and regression analysis.

Result

Association testing has currently been performed for 59 of the total 85 SNPs in the assay using either linear or logistic regression. This revealed significant association for an AD risk variant in the SIGLEC11 locus and Braak NFT staging (p = 0.003) and NIA_AA score (p = 0.002). Significance was also found for a risk variant in the EPHA1 locus and Hirano body score (p = 0.008). Furthermore, we found numerous nominally significant associations between risk loci and TDP43 LATE, granulovacuolar degeneration, phases of amyloid plaque distribution and CAA severity.

Conclusion

These results possibly highlight biological pathways involved in generating these additional features. Our ongoing work is currently focusing on increasing our sample size to further validate the associations we discovered and optimizing our ONT assay.
Amyloid re‐accumulation after donanemab treatment: summary from 3 interventional trials
Authors: Shcherbinin Sergey , Gueorguieva Ivelina , Cheng Yun‐Ju , Evans Cynthia D. , Case Michael G. , Chidambaram Swathi , Collins Emily C. , Brooks Dawn A. , Sims John R. , Lu Ming
Published: December 2023

Background

In TRAILBLAZER‐ALZ, amyloid clearance (defined as reaching <24.1 centiloids, CL) (Navitsky, 2018) was achieved for 40% of participants (mean baseline 107.6 CL) after 6 months of donanemab treatment (Mintun, 2021). The estimated time course of natural amyloid plaque accumulation at the amyloid‐negative stage is approximately 3.3 CL/year (Jagust, 2021). Our objective was to examine the longer‐term effect of donanemab on brain amyloid deposition by evaluating the amyloid re‐accumulation observed in trial participants who reached clearance and were no longer receiving donanemab infusions, and compare it with amyloid accumulation for untreated amyloid‐negative participants.

Methods

In I5T‐MC‐AACD (NCT02624778) and TRAILBLAZER‐ALZ (NCT03367403), we identified N = 46 participants with ≥2 post‐treatment florbetapir scans conducted approximately 6 months after reaching amyloid clearance (Table 1). Part C of ongoing TRAILBLAZER‐EXT trial (NCT04640077) is evaluating participants from TRAILBLAZER‐ALZ at least 52 weeks after the participant’s last dose of donanemab. To examine re‐accumulation rate, a linear regression was used to analyze change in amyloid level during post‐treatment using follow‐up time (in years) as a covariate. Furthermore, an advanced exposure‐response model (ERM) with all available dosing, pharmacokinetic and florbetapir data, over treatment and post‐treatment periods was employed (N = 304).

Results

Among 46 participants who achieved amyloid clearance after donanemab treatment, a single participant (∼2%) became amyloid‐positive. The average amyloid level (mean±SD) changed from 4.4±8.9 to 3.9±11.4 CL during the observation period (mean 9.7±3.1 months) after stopping dosing. The rate of annualized change in amyloid level is approximately 3.4 CL/year. The rate of change in amyloid level was not significantly associated with amount of amyloid reduced over the treatment period or amyloid level achieved post‐treatment. ERM predicted an average rate of 3.4 CL/year for amyloid re‐accumulation in patients who reached clearance.

Conclusion

The post‐treatment florbetapir scans at 9.7±3.1 months for amyloid‐negative I5T‐MC‐AACD and TRAILBLAZER‐ALZ participants suggest that a re‐accumulation rate is comparable with the inherent amyloid accumulation rate. Additional analyses of TRAILBLAZER‐EXT data with the longer post‐treatment period will be presented at the conference. Treatment with donanemab not only reduces amyloid levels in early, symptomatic AD patients below the amyloid‐positive threshold but also places them on a plaque accumulation trajectory similar to untreated, amyloid‐negative patients.