bluuebunny/crossref_metadata_2025 huggingface dataset:
In‐vivo Braak Stage Distribution of Screened and Randomized Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Saad Ziad S. , Cohen Julie S , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Kolb Hartmuth C.
Published: December 2023

Background

Tau PET is the gold standard for in‐vivo quantification of tau neurofibrillary tangles (NFT) which, along with amyloid plaques and neurodegeneration, constitute the pathological hallmarks of Alzheimer’s Disease (AD). The ongoing Auτonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia who are tau PET positive. The Janssen plasma p217+tau assay is being used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date, we report on the in‐vivo PET‐based Braak stage distribution and compare the outcomes to published, histology‐based Braak staging.

Method

NFT levels were quantified using 18F‐MK‐6240 SUVR in Braak Regions Of Interest (ROI)[1] using cerebellar gray as the reference region. In‐vivo Braak staging (Braakiv) was implemented following the approach by Biel et al.[2], with 18F‐flortaucipir to 18F‐MK‐6240 SUVR threshold conversion from Gogola et al.[3]. Participants with atypical[2] stages were reassigned to the Braak stage corresponding to the highest Braak ROI with average SUVR > 1.4. The screening results reported herein are from the first 355 participants with available biomarker screening data.

Result

Of 355 screened participants, 90% were assigned to typical Braakiv stages. Of the 10% atypical stages, 94% were lacking elevated uptake in Braak 2 ROI. When using the coerced stage assignment, the average Braakiv stage was 3.7 across all screened participants and 3.6 in randomized participants (Figure 1). For the 221 randomized participants, 59% were Braakiv stage 4 or less, and 40% were Braakiv stage 3 or less.

Conclusion

In early Alzheimer’s disease participants who were screened with tau PET in the ongoing Auτonomy trial, the average Braakiv stage was consistent with the average histology‐based Braak stage in MCI patients of 3.57 [4]. These results further support the use of tau PET‐based in‐vivo staging[5] as a proxy for histology‐based Braak staging.

[1] Schöll et al. Neuron 2016.

[2] Biel, D., et al. Alz Res Therapy 2021.

[3] Gogola A. et al. J Nucl Med. 2022. [4] Markesbery WR. J Alzheimers Dis. 2010.

[5] Therriault, J. et al. Nat Aging 2022
Dementia in multimorbidity: scoping review and priorities for research and care
Authors: Stirland Lucy E
Published: December 2023

Background

Most people with clinical dementia have at least two other conditions. This co‐occurrence of multiple conditions, known as multimorbidity, is associated with worse quality of life, increased mortality and greater healthcare costs. However, there is limited research on the bidirectional interaction of physical multimorbidity and all‐cause dementia.

We aimed to review and summarize key themes in this area, especially in the context of recent pharmacological advances.

Method

We searched PubMed and Google Scholar, updating the search strategy of a 2014 review of comorbidity and dementia. We added new key words reflecting recent trends in Alzheimer’s disease research, including: “amyloid”, “biomarker” and “disease‐modifying”. We searched the resulting papers’ references and citations and generated a narrative review of the literature grouped by research methodology.

Result

Several key themes emerged from the published literature. Epidemiological studies confirmed that most people with dementia have multimorbidity. They additionally identified multimorbidity as a risk factor for dementia or cognitive impairment and found it to be associated with dementia progression and worse quality of life.

Studies on the association between multimorbidity and biomarkers of neurodegeneration were either negative or found an inverse relationship. People with multimorbidity were found to be significantly under‐represented in clinical trials, especially those of dementia drugs.

Qualitative research on healthcare delivery highlighted the importance of family carers and communication between providers, and a review of care coordination interventions identified important factors that optimize transitions of care.

There was also recognition of the need to address racial and ethnic disparities in people with multimorbidity and dementia. Several papers called for a comprehensive understanding of dementia in relation to the whole person and society.

Conclusion

Having multiple conditions alongside dementia poses challenges for patients, caregivers and clinicians. Multimorbidity is an important consideration for those designing representative clinical trials, and it may be more difficult to treat dementia in people with several comorbid conditions.

This work highlights the need for specific research into the relative contributions of multimorbidity and other person‐centered characteristics on clinically meaningful outcomes. In the context of new and costly therapies, this will inform equitable allocation of research and healthcare resources.
Plasma Alzheimer’s Disease Biomarkers and Brain Amyloid in a Multi‐Ethnic Aging Cohort
Authors: Asken Breton M. , Wang Wei‐en , McFarland Karen , Arias Franchesca , Fiala Jacob , Mayrand Robin P. , Sawada Luana Okino , Freytes Christian , Adeyosoye Michael , DeKosky Steven T , Velez‐Uribe Idaly , Rosselli Monica , Curiel Rosie E , Loewenstein David A. , Marsiske Michael , Armstrong Melissa J , Smith Glenn E. , Adjouadi Malek , Vaillancourt David , Duara Ranjan
Published: December 2023

Background

Dementia diagnoses are more common among Hispanic (HW) than non‐Hispanic white (NHW) older adults. Alzheimer’s disease (AD) is the most common neuropathological finding in patients with dementia. Plasma AD biomarkers have accelerated efforts towards increasing access to timely diagnosis, but existing data often come from cohorts lacking ethnic diversity. Clinical translation of plasma AD biomarkers requires continued evaluation in study cohorts that reflect the growing ethnic diversity of the population.

Method

We studied 379 older adults (age 71.9±7.8 years old, 60.2% female) from the 1Florida Alzheimer’s Disease Research Center who underwent blood draw and analysis for P‐tau181 (Quanterix). Of these, 240 completed Aβ‐PET (converted to Centiloids). Over half (57%) self‐identified as HW (32% Cuba, 18% South American, 7% other). Analyses included 1) comparing plasma biomarker concentrations between clinically normal (CN), amnestic MCI (amnMCI), amnestic dementia (amnDEM), and nonamnestic MCI/dementia (ANCOVA controlling for age), 2) evaluating P‐tau181 correlations with Aβ burden (Spearman’s rho), and 3) determining discriminability (AUC) of Aβ‐PET[+] from Aβ‐PET[‐]. Interactions between independent variables and ethnicity were evaluated to inform whether observed relationships differed between HW and non‐Hispanic white (NHW). Lastly, using a cutoff derived from the PET sub‐cohort, we investigated rates of P‐tau181‐defined “AD positivity” (plasmaAD[+]) between HW and NHW diagnosed with amnMCI. Additional data for plasma GFAP and NfL will also be presented.

Results

Plasma P‐tau181 was higher in amnMCI (p = .004, d = 0.53) and amnDEM (p<.001, d = 0.97) than CN. Higher P‐tau181 related to greater Aβ burden (ρ = .59 [.50‐.67], p<.001) and had good discriminability between Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86 [0.81‐0.91], Youden’s Index = 2.39 pg/mL). There were no significant interactions with ethnicity. Applying the P‐tau181 cutoff (2.39 pg/mL) to all amnMCI participants, HW diagnosed with amnMCI had lower odds of being plasmaAD[+] than NHW (36.5% vs. 58.5%; OR = 0.41 [0.21‐0.78], p = .006).

Conclusion

Plasma P‐tau181 may aid etiological diagnosis of cognitively impaired older adults from Hispanic and non‐Hispanic ethnic origins. Hispanic ethnicity alone does not significantly influence the interpretation of how plasma P‐tau181 relates to Aβ‐PET, but may be linked to greater likelihood of non‐AD causes of memory loss. Blood‐based biomarkers could help reduce barriers to clinical diagnosis and research participation that disproportionately impact underrepresented groups.
Frequency of repetitive head impacts and influence on clinical variability among male patients with Alzheimer’s disease and frontotemporal dementia
Authors: Asken Breton M. , Tanner Jeremy A. , Soleimani‐Meigooni David N. , Knudtson Marguerite V. , Grinberg Lea T. , Miller Bruce L , Kramer Joel H. , Mez Jesse B. , Alosco Michael L , Rabinovici Gil D.
Published: December 2023

Background

Repetitive head impacts (RHI) occur routinely in sports like American football (AmFootball) and are the most well‐established risk factor for chronic traumatic encephalopathy, a neurodegenerative tauopathy. However, RHI is not routinely evaluated in older adults with other suspected neurodegenerative diseases. The prevalence of RHI among older adults with neurodegenerative diseases and the influence on clinical symptoms is unknown.

Methods

RHI was defined by AmFootball participation and analyzed based on frequency of any and “substantial” exposure (> 4 years). The Boston University Head Impact Exposure Assessment was administered to 195 older adult males at the UCSF Memory and Aging Center. Of these 106 (54%) were clinically normal (CN) participants in the Brain Aging Network for Cognitive Health (BRANCH) study and 89 (46%) were cognitively impaired participants from the Alzheimer’s Disease Research Center. Diagnostic groups included AD‐related phenotypes (“clinAD”; amnestic‐predominant MCI/dementia, logopenic PPA; N = 26) and frontotemporal dementia spectrum conditions (“FTD”; behavioral variant FTD, semantic PPA, nonfluent PPA; N = 46). Our aims were: 1) investigate frequency of prior RHI between diagnostic groups (chi square), 2) compare age of symptom onset between participants with and without prior RHI (ANOVA), and 3) evaluate associations between RHI and cognition within the largest single diagnostic group (bvFTD N = 20; ANCOVA adjusted for age and education). Cohen’s d effect sizes are reported.

Results

Males with clinAD (27%; χ2 = 8.3, p = .009; d = 0.53) and FTD (21%; χ2 = 5.6, p = .02, d = 0.40) were more likely than CN (7%) to have had substantial prior RHI. Prior RHI was associated with younger age of symptom onset (62.1±7.6 vs. 56.7±7.7 years old; p = .001, d = 0.69). This effect was stronger within clinAD (63.1±7.2 vs. 53.3±7.5; d = 1.3) than FTD (60.1±7.0 vs. 55.9±6.0; d = 0.54). In participants with bvFTD, those with prior RHI scored significantly worse on memory testing (w‐scores ‐2.6±1.1 vs. ‐1.1±1.2, p = .02, d = 1.4).

Conclusions

RHI through AmFootball is more common in AD and FTD than healthy controls. Prior RHI may contribute to variability in age of symptom onset in both AD and FTD. Exposure to RHI may also partly explain why some participants with bvFTD, a classically nonamnestic syndrome, develop memory decline. Prior RHI should be routinely evaluated in neurodegenerative disease workups.
Building Stakeholder Consensus Regarding Disclosure of Individual Research Results in ADRD Research: A Delphi Study Protocol
Authors: Sankary Lauren R , Zelinsky Megan , Lerner Alan J. , Martinez Kathryn , Miller Justin B , Leverenz James B
Published: December 2023

Background

Informed decisions to enroll in clinical investigations of Alzheimer’s disease and related dementias (ADRD) require careful consideration of complex risks and uncertain benefits. Decisions regarding scope of research participation and whether to receive information about biomarker status are complicated by lack of scientific consensus regarding biomarkers as surrogate end points for Alzheimer’s disease. This Delphi protocol aims to establish stakeholder consensus regarding the content and features of ethically optimal informed consent support for ADRD research.

Method

This consensus‐building Delphi protocol consists of three rounds of online surveys conducted with three stakeholder groups: Alzheimer’s disease research experts (including ethicists, research oversight specialists, and clinical trialists), Alzheimer’s disease research participants, and study partners of individuals enrolled in ADRD research. Participants will be administered questionnaires developed from a synthesis of researcher‐ and participant‐endorsed decisional needs identified in published literature and a decisional needs assessment conducted with support from an Alzheimer’s Association Research Grant. Participants will also be asked their views on the design, content, and implementation of a decision support tool. ≥70% agreement will be required to achieve consensus. Response rates, level of agreement, medians, interquartile ranges, and group rankings will be analyzed. Following each round of data collection, our research team will undertake qualitative content analysis of open‐ended responses and forum interactions.

Result

This protocol will develop consensus regarding priorities for decision support for ADRD research participants and the key features and content of ethically optimal informed consent support interventions. The Delphi technique is appropriate to develop consensus between diverse stakeholders because of its ability to offer anonymity to other participants and minimize bias.

Conclusion

Findings will contribute to the development of a digital health research infrastructure that is inclusive of diverse individuals and attentive to the needs of cognitively vulnerable patient populations and their caregivers.
Predicting of β‐amyloid Positivity Using Integer‐based Risk Scores with Blood‐based Biomarkers
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Grober Ellen , Lipton Richard B. , Davatzikos Christos , Ezzati Ali
Published: December 2023

Background

β‐amyloid (Aβ), a pathologic hallmark of Alzheimer’s disease (AD) is the target of recently FDA‐approved drugs. In trials and in practice, identifying individuals likely to be β‐amyloid positive (Aβ+) with accessible and affordable tests will be increasingly important. Blood‐based biomarkers (BBMs) have shown early promise in determining amyloid status. We aimed to develop machine learning‐based integer risk scores using BBMs and other accessible measures to predict Aβ positivity by PET in older, non‐demented (cognitively unimpaired or mild cognitive impairment) adults.

Methods

We used data from 722 individuals (72.1 ± 7.0 years old) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to develop integer risk scores for predicting Aβ positivity. The sample was divided into training (75%) and test (25%) sets. Variables were categorized as demographics (D: age, sex, and education), genetic information (G: APOE4 status), cognitive measures (C: ADAS‐Cog‐13 and MMSE), and plasma biomarkers of p‐Tau181(T) and neurofilament light (N: NfL). Feature‐sets were formed as hierarchically constructed combinations of these categorized variables (see Figure 1). Using the AutoScore algorithm, variables were ordered according to their Random Forest Gini Index and were iteratively included in the construction of logistic regression‐derived risk score models. Variables were included based on increases in Area Under the ROC Curves (AUCs).

Results

Four models were developed based on four feature‐sets. All models utilized age and APOE4 status and, when considered, all models retained ADAS‐Cog‐13, p‐Tau, and NfL. The best performing model corresponded to the DGCTN feature‐set with performance on the dedicated test set of AUC = 0.810 (C.I.: 0.745‐0.876). Using the DGCTN model on the test set, 97% of individuals with scores in the top quartile of possible risk score points were correctly identified as Aβ+.

Conclusions

We developed risk score models utilizing accessible and affordable measures to predict Aβ positivity. Plasma biomarkers improve performance of risk scores indicating their value. Applications include screening in clinical settings for therapeutic care and enrichment of clinical trials. These data can be used to optimize the efficient use of PET in determining eligibility for clinical trials and amyloid targeted therapies in practice.
Cross‐sectional investigation of synaptic markers Neurogranin and BACE1 in CSF from the AIBL study
Authors: Fowler Christopher J , Stoops Erik , Vanmechelen Eugeen , Vanbrabant Jeroen , Dewit Nele , Mauroo Kimberley , Rowe Christopher C , Fripp Jurgen , Li Qiao‐Xin , Bourgeat Pierrick , Collins Steven J , Martins Ralph N , Masters Colin L , Maruff Paul , Vanderstichele Hugo Marcel , Doecke James D
Published: December 2023

Background

Synaptic disfunction is a feature of Alzheimer’s disease. Recent studies show both pre‐ and post‐synaptic termini proteins change in concentration in the CSF across the A/T/N framework. Here we investigate BACE1, neurogranin (Ng) and alpha‐synuclein, along with total‐tau (t‐tau) and amyloid‐β 1‐42 (Aβ42), in relation to PET‐amyloid status.

Method

Participants (n = 105) with CSF and matching PET‐amyloid scans from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were analysed for CSF synaptic markers BACE1, Ng and alpha‐synuclein using commercially available antibody assays (EUROIMMUN). BACE1 used ADx401 (5G7) and ADx402 (10B8) antibodies, Neurogranin trunc p75 used monoclonal ADx403 (ADxNGCI2) and ADx451 (ADxNGCT1) antibodies, and alpha‐synuclein used ADx301 and ADx302 antibodies. Total‐tau and Aβ42 were measured using the Roche Elecsys®. PET‐amyloid status was defined using a Centiloid of <25 as negative, and 25 or greater positive.

Result

Cross‐sectional changes in biomarker values between the PET‐amyloid negative and positive groups were seen for Ng (p<0.05), but not for BACE1 or alpha‐syn. The ratio of Ng/BACE1 improved separation between groups (p<0.001). Total‐tau displayed the greatest differentiation of a single biomarker (p = 2.7×10−10) and this separation was improved using a ratio of t‐tau/BACE1 (p = 3.2×10−12). For predicting PET‐amyloid status (adjusting for age, APOE e4 and gender), t‐tau (AUC: 0.87 [95%CI: 0.80‐0.95]) was slightly improved using the ratio of t‐tau/BACE1 (AUC: 0.90 [95%CI: 0.82‐0.97]) to the same degree as using t‐tau/Aβ42 (AUC: 0.90 [95%CI: 0.82‐0.97]), although this was not significant (p>0.05).

Conclusion

This study saw within a PET‐amyloid positive subpopulation of AIBL an increase in neurogranin, a post‐synaptic marker. The presynaptic marker BACE1 alone was not changed in concentration, but when BACE1 was used in a ratio with t‐tau, a marker of neuronal degradation, the differentiation between amyloid negative and positive groups increased. The predictive ability between t‐tau/BACE1 and t‐tau/Aβ42 to estimate PET‐amyloid load is comparable and measurements incorporating BACE1 may provide an alternative to Aβ42‐based assays and the inherent variability associated with Aβ42 measurement between testing sites.
Neuropsychological assessment of financial skills in mild cognitive impairment, Alzheimer’s disease and frontotemporal dementia
Authors: Wong Stephanie , Rawson Georgina , Dixon Ann , Wei Grace , Piguet Olivier , Kumfor Fiona
Published: December 2023

Background

The capacity to handle money and personal finances is crucial for living independently. Cognitive decline can lead to financial mismanagement (e.g., forgetting to pay bills, overspending) and exploitation (e.g., falling for financial scams). While greater susceptibility to financial mismanagement and exploitation is commonly reported by carers of people with dementia, objective neuropsychological measures of these financial skills are scarce. It is also unclear whether profiles of change in financial skills vary across different stages and subtypes of dementia.

Method

A normative sample of 112 healthy controls and individuals with mild cognitive impairment (MCI; n = 16), Alzheimer’s disease (AD; n = 7) or behavioural‐variant frontotemporal dementia (bvFTD; n = 18) completed a novel neuropsychological Test of Financial Skills (TOFS), which assessed performance across three key areas: everyday financial tasks, susceptibility to financial scams and financial goal planning. For all patients and controls, measures of dementia severity (Clinical Dementia Rating Scale) and general cognition (Addenbrooke’s Cognitive Examination, 3rd Ed.) were also collected.

Result

Relative to controls, AD and bvFTD patients showed lower overall performance on the TOFS, whereas MCI patients did not differ significantly from controls. While AD and bvFTD patients showed similar levels of impairment on everyday financial tasks and financial goal planning, bvFTD patients performed significantly worse on the financial scams subtest. Across all participants, lower TOFS performance was associated with greater dementia severity and cognitive impairment.

Conclusion

Our results are consistent with previous studies of carer‐reported changes in financial mismanagement and exploitation in people with dementia. Notably, we found important differences in the areas of financial skills impacted by different stages and subtypes of dementia. These findings provide novel insights into the different factors that contribute to deficits in financial skills in people with dementia, highlight the importance of objective neuropsychological assessments in this area, and open avenues for targeted financial support strategies.
Levels of TDP‐43 from Plasma‐Derived Astrocyte Exosomes Accurately Differentiates Autopsy Verified LATE from AD
Authors: Rissman Robert A , Winston Charisse N. , Sukreet Sonal , Lynch Haley M , Lee Virginia M. M.‐Y. , Wilcock Donna M. , Nelson Peter T.
Published: December 2023

Background

Limbic predominant age related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a neurodegenerative disease characterized brain disease that mimics Alzheimer’s disease (AD) clinically. LATE‐NC is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of extracellular vesicle (EVs) protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. We developed a high throughout bioassay to detect TDP‐43 in plasma derived exosomes for identification of LATE and AD.

Method

TDP‐43 was isolated from neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs) using antemortem plasma from participants with autopsy‐confirmed diagnoses, including many with LATE (n = 22). Quantified TDP‐43 concentrations were compared to the cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia (n = 42).

Result

TDP‐43 was significantly elevated in plasma ADEVs derived from LATE‐NC subjects, with or without comorbid AD pathology. Measurable levels of TDP‐43 were also detected in EV‐depleted plasma; however, TDP‐43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE‐NC. No correlation was observed between EV TDP‐43 levels with cognition‐based variables, sex, and APOE carrier status.

Conclusion

Our recently developed bioassay and levels of TDP‐43 in ADEVs may serve as a potential diagnostic tool to rapidly identify subjects with LATE‐NC for screening into clinical trials.
Dementia Burden in India and the Research Challenges
Authors: Ravindranath Vijayalakshmi , Sundarakumar Jonas S.
Published: December 2023

Longer lifespan has led to increase in number of older persons in LMICs including India. By 2050, people older than 60 years will account for 19.1% of total population (∼360 million) in India. South Asian region would be a major contributor to new dementia cases in the world.

Owing to their vast burden, public health efforts have focused on communicable diseases and reduced the burden. However, with growing incidence of cardiovascular diseases, diabetes and hypertension along with increasing longevity, there has been an epidemiological transition towards NCDs in terms of the overall disease burden. Increased prevalence of vascular risks and differential (yet to be identified) genetic susceptibility will impact dementia prevalence. Vast disparity exists between urban middle‐class and two‐thirds of India that live in villages. This disparity is seen in socio‐economic status, lifestyle, literacy as well as access to health care and modern technology. Well‐planned, harmonized, large‐scale studies are needed to identify risk and protective factors. As the impact of vascular risk factors in dementia is evident, understanding their complex interplay with diverse environment will help in devising public health measures to reduce risks through lifestyle interventions earlier in life course.

South Asian countries, including India, that have recently invested in dementia research would benefit from joining global ADRD consortia providing access to technology and bi‐directional data sharing. Data sharing across the world is important to gain insights, which will in turn help in developing strategies to prevent or delay the onset of dementia.
Self‐reported physical activity levels do not predict brain beta amyloid levels in older cognitively normal adults over time
Authors: Slee Michael , Rainey‐Smith Stephanie R , Villemagne Victor L , Sohrabi Hamid R , Taddei Kevin , Ames David , Dore Vincent , Maruff Paul , Laws Simon M , Masters Colin L , Rowe Christopher C , Martins Ralph N , Erickson Kirk I. , Brown Belinda M
Published: December 2023

Background

Animal studies have consistently shown that physical activity reduces brain levels of beta‐amyloid (Aβ). However, human studies of physical activity and Alzheimer’s disease (AD)‐related brain biomarkers have produced somewhat inconsistent findings. To date, most human studies examining physical activity and Aβ have utilised cross‐sectional analyses and relatively small sample sizes. As brain Aβ is detectable decades prior to the onset of clinical symptoms, examination using longitudinal brain imaging is vital to provide insight into how ongoing physical activity levels impact the progression of AD. In addition, the causal direction of these relationships requires further investigation; some research suggests physical activity levels may decline prior to dementia diagnosis.

Method

Habitual physical activity and Aβ measures were collected over 15 years from 731 cognitively normal older adults (60 years and over) participating in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Physical activity was assessed via the self‐reported International Physical Activity Questionnaire and brain Aβ measures obtained via PET imaging. Regression modelling examined the cross‐sectional and longitudinal relationships between physical activity and brain Aβ. Moderation analyses examined the impact of apolipoprotein (APOE) ε4 carriage on the physical activity‐Aβ relationship. To further examine the causal nature of this relationship, the trajectory of physical activity levels for individuals as a predictor of either high or low Aβ brain load was also examined.

Result

Physical activity was not associated with brain Aβ at baseline (β = ‐0.001, p = 0.131) or over time (β = ‐0.101, p = 0.571). APOE ε4 status did not moderate the relationship between physical activity and brain Aβ over time (β = 0.04, p = 0.917). Brain Aβ levels were not associated with physical activity trajectory (β = ‐54.26, p = 0.590).

Conclusion

Our study did not identify a relationship between habitual physical activity and brain Aβ levels. Future longitudinal studies should examine middle‐aged participants to assess whether physical activity influences Aβ accumulation earlier in life.
Predictive Value of CSF Inflammatory Biomarkers in Alzheimer’s disease
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Grober Ellen , Lipton Richard B. , Ezzati Ali
Published: December 2023

Background

A growing body of evidence suggests that neuroinflammation contributes actively to pathophysiology Alzheimer’s disease (AD) and promotes AD progression. The predictive value of neuroinflammatory biomarkers for disease‐staging or estimating disease progression is not well understood. In this study, we investigate the diagnostic (i.e., differentiating clinical stages of disease) and prognostic (estimating probability of cognitive decline) ability of inflammatory biomarkers in combination with conventional AD biomarkers.

Methods

We included 242 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had CSF biomarkers of Aβ, tau, and inflammation. Outcome of interest was clinically meaningful cognitive decline (CMCD) as defined by an increase of ≥4 on the Alzheimer’s Disease Assessment Scale Cognitive Subscore 11 (ADAS‐11, scores 0‐70, higher scores indicate worse cognition). Predictor variables were categorized as demographics (D; age, sex, and education), genetic information such as APOE4 status (G), inflammatory biomarkers (I; see Table 1 for details), and cerebrospinal fluid (CSF) biomarkers of β‐amyloid (A), p‐Tau (P), and total Tau (T). Logistic regression was performed to investigate if grouped inclusion of eleven CSF inflammatory biomarkers as covariates in the models improved classification of baseline clinical diagnosis (CN, cognitively normal; MCI, mild cognitive impairment; Dementia) as well as classification of individuals with and without CMCD one year after baseline.

Results

At 1‐year follow up, 25.6% experienced CMCD. Inclusion of inflammatory biomarkers improved classification of MCI vs Dementia for models base on DG (p = 0.039) and DGAPT (p = 0.016) feature‐sets. Addition of inflammatory biomarkers to model with DGAPT features, but not the DG model, improved predictive performance for CMCD in CN (p = 0.021) and MCI (p < 0.001) participants.

Conclusions

Addition of CSF Inflammatory biomarkers to AD biomarkers can improve diagnostic accuracy of clinical disease stage. Furthermore, inflammatory biomarkers add incremental value to AD biomarkers for prediction of clinical course and cognitive decline.
Multi‐modal MR and synaptic PET changes in dementia with Lewy bodies
Authors: Mak Elijah , Carter Stephen F , Savulich George , Holland Negin , Swann Peter , McKiernan Elizabeth , Chouliaras Leonidas , Malpetti Maura , Su Li , Jones P Simon , Rowe James B. , O'Brien John T
Published: December 2023

Background

Novel, validated imaging biomarkers for assessing disease severity and progression in dementia with Lewy Bodies (DLB) are needed as standard neuroimaging changes such as atrophy are not pronounced. Both multi‐modal MR and PET offer opportunities, for example cortical microstructure and dendritic imaging can be assessed using advanced MR diffusion weighted imaging (DWI) methods such as neurite orientation dispersion and density imaging (NODDI) and PET with UCB‐J can assess synaptic density. We applied these and other markers to people with DLB and controls.

Method

In linked studies, people with probable DLB and similarly aged controls (n = 10‐30 per group depending on study) underwent multimodal 3T‐MRI (including structural, multi‐shell DWI and arterial spin labelling imaging) and PET imaging with AV1451 (for assessment of tau), PiB (for amyloid status) and [11C]UCB‐J PET/MR. For MR, T1‐MRI and DWI datasets were processed using FreeSurfer 7.2 and FSL 6.0.4 respectively with whole‐brain ODI derived from the Microstructure Diffusion Toolbox. The [11C]UCB‐J and [18F]AV1451 binding potentials (BPND) were assessed using a simplified reference tissue model (reference centrum semiovale for UCBJ and cerebellum for AV1451). Group differences in ODI, UCB‐J and AV1451 BPND were examined and correlated with structural changes and clinical and cognitive variables (ACE‐R score).

Result

Compared to controls, people with DLB showed significantly thinner neocortex (T = ‐2.8, p = 0.01) in temporo‐parietal regions but more widespread reductions in cortical microstructure (ODI, T = ‐3.9, p < 0.001)(Figure 1). Within the DLB group, hippocampal ODI was positively correlated with cognitive performance (robust linear regression: p < 0.001)(Figure 2). Reduced synaptic density (UCB‐J BPND) was found for the DLB group in posterior regions (p<0.05, FWE corrected)(Figure 3), with a trend for greater reductions in those who were amyloid positive. ACE‐R scores significantly correlated with synaptic density (p<0.05, FWE corrected). There were no significant differences in AV1451 binding between DLB and controls.

Conclusion

Extensive reductions in ODI and reduced synaptic density, both associated with cognitive impairment and occurring in regions without significant atrophy or tau deposition, suggests that NODDI and synaptic PET imaging are promising biomarkers for DLB which merit further investigation, including in longitudinal studies.
Thalamocortical dysrhythmia in patients with delirium: an EEG possible marker of prodromal dementia with Lewy bodies
Authors: Bonanni Laura , Carrarini Claudia , Calisi Dario , De Rosa Matteo , Iorio Angelo Di , D'Ardes Damiano , Gazzina Stefano , Pilotto Andrea , Arighi Andrea , Carandini Tiziana , Cagnin Annachiara , Gallucci Maurizio , Costa Cinzia , D'Antonio Fabrizia , Bruno Giuseppe , Cipollone Francesco , Babiloni Claudio , Onofrj Marco , Padovani Alessandro
Published: December 2023

Background

EEG in DLB is characterized by pre‐alpha dominant frequency (DF) [6–7.5] Hz. The appearance of prealpha rhythm in the cortex is linked to a dysfunctional thalamocortical connection, the thalamocortical dysrhythmia (TCD). The hypothesis that TCD is implicated in DLB has been demonstrated by several structural, functional, and molecular imaging studies. TCD has been implicated in the appearance of altered conscious states, including fluctuating cognition and delirium, two clinical core features of DLB. Delirium can represent the onset of DLB and is listed among the symptoms of prodromal DLB. We aimed to assess specific QEEG abnormalities akin to those found in DLB, also in delirium, to detect a prodromal stage of DLB.

Method

Cross‐sectional multicentre cohort study and longitudinal prospective study, nested in the multicentre. rsEEG activity was compared in hospitalized patients with delirium vs. patients without delirium. In a subset of 23 patients, rsEEG was also recorded in patients with delirium at resolution of symptom and and at 1‐month follow‐up. DF and DF variability (DFV) were analysed.

Result

Cross‐sectional multicentre study: 65 subjects with acute delirium were matched for age/sex with 41 controls. Abnormal EEGs were found in 100% delirium patients vs. 34% no‐delirium patients. DF was lower in delirium group (p<0.001), which showed pre‐alpha DF; no‐delirium group had alpha DF. DFV was higher in delirium group (p<0.001). Single‐centre longitudinal study: After delirium resolution, 21 patients had EEG normalization and were cognitively unimpaired. 2 patients had abnormal EEG and were respectively diagnosed as DLB and MCI.

Conclusion

Acute delirium was characterized by pre‐alpha rhythm, expression of TCD. In most patients EEG normalized after resolution, making EEG a state marker of acute delirium, when the thalamocortical system becomes unstable, but it is still able to recover. TCD may become unrecoverable when the neurodegenerative process of DLB progresses.
Ultra‐processed food consumption and risk of dementia and Alzheimer’s disease: the Framingham Heart Study
Authors: Weinstein Galit , Koijs Daniel , Walker Maura , Beiser Alexa S. , Seshadri Sudha
Published: December 2023

Background

Ultra‐processed foods (UPFs) are industrialy‐processed formulations that constitute a large and increasing amount of the food supply in high and middle‐income countries. Accumulating evidence suggests that UPFs are related to increased risk of mortality and morbidity, including cardiovascular and metabolic health conditions, however its association with dementia risk has rarely been studied. We investigated the association of UPF sonsumption with risk of dementia and Alzheimer’s disease (AD) in the Framingham Heart Study.

Method

The sample for this cohort study included participants of the Offspring cohort who were ≥60y of age, completed a food‐frequency questionnaire (FFQ) and were dementia‐free at baseline. Food items included in the Harvard semi‐quantitative FFQ were classified as UPFs using the NOVA classification system. Participants were followed‐up for dementia incidence starting from exam 7 for a mean duration of 12.7±6.0 years. Cox regression models were used to assess the link of UPF levels with dementia and AD risk while adjusting for potential confounders, including diet quality and total calorie consumtion. Effect modification by age, BMI, diabetes and ApoEɛ4 genotype were additionally assessed.

Result

The study sample included 1,519 participants (mean age 68±6 years, 53% women). The average consumption of UPF at baseline was 6.1±3.4 servings per day. During the follow‐up, 253 and 196 were diagnosed with dementia and AD, respectively. Overall, no statistically significant associations were observed between UPF consumption and dementia or AD risk. However, an effect‐modification by age was identified (p‐for interaction = 0.016 and 0.007, for dementia and AD, respectively). Among participants younger, but not older than 68 years of age (i.e. median), the risk of dementia was increased comparing individuals at the top four quartiles to the bottom quartile (HR = 2.9; p‐value = 0.015). Each serving per week of UPF derived from low‐calorie soft drinks was significantly associated with 4% increase in risk of AD (HR = 1.04; p‐value = 0.012), but not all‐cause dementia (HR = 1.03; p = 0.074). However, the association of total UPF with dementia risk remained robust after omitting UPF from low‐calorie soft drinks (HR = 2.4; p‐value = 0.029).

Conclusion

Our findings suggest that UPF consumption in middle‐age and young‐old adulthood may be related to increased risk of all‐cause dementia.
Use of α‐synuclein seed amplification assays to assess how clinical features relate to the diagnosis of Dementia with Lewy Bodies
Authors: Middleton John , MacLeod Karen R , Bozoki Andrea , Galvin James E , Irwin David J , Lippa Carol , Litvan Irene , Lopez Oscar L. , Berman Sarah , Tsuang Debby W , Zabetian Cyrus P , Honig Lawrence S. , Marder Karen , Fleisher Jori E , Sabbagh Marwan , Wint Dylan , Taylor Angela , Bekris Lynn M. , Leverenz James B , Galasko Douglas R.
Published: December 2023

Background

Dementia with Lewy Bodies (DLB) is defined by abnormal deposits of alpha‐synuclein (Lewy bodies), in the brain. DLB may be accompanied by variable co‐pathology, especially Alzheimer’s Disease (AD). DLB is diagnosed clinically, with definitive diagnosis only possible at autopsy. Misdiagnosis may occur due to overlapping symptoms in different dementias.

The alpha‐synuclein (αSyn) seed amplification assay (SAA) is a qualitative test that detects misfolded aggregates of αSyn in synucleinopathies, including DLB, with high sensitivity and specificity. In autopsy‐confirmed AD with limbic or neocortical synuclein pathology, SAA was positive even when DLB phenotypic features were mild (Arnold et al., 2022).

We are now evaluating SAA in cerebrospinal fluid (CSF) samples and clinical features in patients with DLB followed through a multi‐Center DLB Consortium (NINDS U01NS100610), which is part of the NINDS Parkinson’s Disease Biomarkers Program (PDBP).

Method

CSF from 3 groups: 1) analytical controls: youngest available age, no neurological symptoms, normal neurological exam; 2) clinical controls: no symptoms/signs, age and gender match to DLB; 3) DLB. SAA will be run blind to diagnosis using standardized assay methods by Amprion. We will compare Core clinical features of DLB patients and SAA. We hypothesize that SAA‐ patients will have less clear clinical features for DLB, and will be likely to meet clinical and/or CSF biomarker criteria for other diagnoses, e.g., AD.

Core clinical features will be defined as strongly or weakly present, e.g., REM Sleep Behavior Disorder: PSG‐proven (strong); +questionnaire (weak); Parkinsonism: ≥ 2 cardinal features (strong); 1 feature (weak). Hallucinations and fluctuations are described in standardized rating scales/interviews. CSF AD biomarkers (Aβ42, t‐Tau and p‐Tau181) were analyzed for almost all DLB subjects.

Sensitivity and specificity of each Core clinical feature will be calculated in relation to SAA+ and SAA‐ results.

Result

Subjects were recruited at 8 clinical sites across the USA from 2017‐2021. Demographics of subjects with available CSF are shown in Table 1. Demographics, clinical features and CSF AD biomarker results will be presented in SAA+ and SAA‐ groups .

Conclusion

Results will inform how well different core clinical features predict pathological αSyn (CSF SAA+) in people diagnosed with DLB.
Genetic characterization of NOTCH2NLC repeat expansion in patients with neuronal intranuclear inclusion disease (NIID)
Authors: Fitrah Yusran Ady , Higuchi Yo , Hara Norikazu , Kasuga Kensaku , Miyashita Akinori , Ikeuchi Takeshi
Published: December 2023

Background

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative condition that which is caused by abnormal expansion of GGC repeat in NOTCH2NLC. Despite the increase of the reported patients with NIID, how the repeat sequence and length in NOTCH2NLC affect the development of NIID remains unclear. We report the genetic characterization of repeat expansion and sequence of NOTCH2NLC in Japanese patients with NIID.

Methods

Fifteen patients clinically diagnosed with adult‐onset NIID were genetically analyzed. Repeat expansion in NOTCH2NLC was examined by repeat‐primed PCR. Repeat length was determined by amplicon length PCR. Repeat length and sequence were analyzed by Nanopore long read sequence.

Results

Repeat primed PCR analysis revealed a sawtooth pattern in 15 patients who were clinically suspected as having NIID. This suggests the presence of repeat expansion in NOTCH2NLC. Next, we performed amplicon‐length PCR to determine the repeat size. The mean repeat length of was 8.2±1.5 (range 7 to 10) in normal allele and 92.5±12.8 (range: 71 to 110) in expanded allele. To define the repeat length and sequence, we performed Nanopore long read sequencer. The repeat size was 138.6±69.0 (range: 95 to 361) in expanded allele. The GGC repeat length was 114.5±36.6 (range: 44 to 194). One patient carried pure GGC repeat expansion, and remaining patients carried others trinucleotide repeat including GGA, AGC, and GAC. Most frequent trinucleotide insertion was GGA at the end of GGC repeat, which is commonly observed in normal allele. We identified two patients who carried bi‐allelic GGC expansions.

Conclusion

Abnormal repeat expansion in NOTCH2NLC was identified as heterozygous or bi‐allelic state in patients with NIID. There was heterogeneity of length and sequence in expanded repeat expansion of NOTCH2NLC. The further study is required to understand how genetic heterogeneity correlates with clinical presentations of patients with NIID.
Suitability of Computerised and Pencil‐and‐Paper Neuropsychological Assessments in Healthy Older Culturally and Linguistically Diverse Australians: The CogSCAN Study
Authors: Page Zara A , Croot Karen , Brodaty Henry , Sachdev Perminder S. , Lam Ben C. P. , Kochan Nicole A.
Published: December 2023

Background

Computerised neuropsychological assessments (CNAs) are proposed as more accessible and culturally appropriate alternatives to traditional pencil‐and‐paper neuropsychological assessments (PnPAs) for diagnosing dementia in diverse populations. Whilst some PnPAs have demonstrated cultural and linguistic bias, research investigating the suitability of CNAs for culturally and linguistically diverse (CALD) individuals is limited, especially outside of the United States.

Method

This study compared cognitive performance in a heterogenous sample of older Australian CALD English‐speakers and an L1 English‐speaking background (ESB) sample. Cross‐sectional data were drawn from the ongoing CogSCAN Study. Participants were 212 community‐dwelling individuals aged 60‐95 years without a dementia diagnosis (159 ESB/53 CALD). Participants completed a PnPA and/or CNAs, sessions were counterbalanced accordingly. CNA sessions involved two of four commercially‐available CNAs in a randomised order. Differences in the level and pattern of cognitive performance between groups on two CNAs (CANTAB/Cogstate) and a comprehensive PnPA in English, controlling for sociodemographic and health factors, are reported here. Selection of key variables for examination were based on previous findings (PnPA) and test developer recommendations (CNAs).

Result

Sample characteristics are summarised in Table 1. CALD participants’ cognitive performance on individual tests (Figure 1) was largely comparable to ESB participants on PnPA and each CNA. Significant differences between groups, after Bonferroni correction for multiple comparisons, were observed for the Boston Naming Test (PnPA; a language test widely criticised for use with CALD populations due to culturally biased stimuli) and Rapid Visual Information Processing (CANTAB; a test of attention/processing speed). Among participants who completed PnPA and Cogstate, a significant interaction between group and assessment type on global cognitive performance was observed; ESB participants outperformed CALD participants on PnPA, but not on Cogstate (Figure 2). No significant main effects or interaction were observed in PnPA versus CANTAB.

Conclusion

These results showed fewer and smaller discrepancies across groups and assessment types than has been found in previous literature with other CALD samples, perhaps reflecting higher levels of English proficiency, acculturation, and education in English than previous cohorts. Work in progress is investigating the influence of linguistic and acculturation factors on cognitive performance in a larger and more diverse sample.
Usefulness of the Visual Cognitive Assessment Test (VCAT) in detecting mild cognitive impairment in the community
Authors: Soo See Ann , Kumar Dilip , Leow Yi Jin , Koh Chen Ling , Saffari Seyed Ehsan , Kandiah Nagaendran
Published: December 2023

Background

A delay in the detection of Mild Cognitive Impairment (MCI) in the community delays the opportunity for early intervention. Accurate tools to detect MCI in the community are lacking. The Visual Cognitive Assessment Test (VCAT) is a visual based cognitive test useful for multilingual populations without the need for translation. Here, we evaluate the usefulness of VCAT in detecting MCI in a community population in Singapore.

Method

We recruited 469 participants from the community who completed a detailed neuropsychological assessment and 261 of them completed a 3T Magnetic Resonance Imaging (MRI) brain scan. We performed a ROC analysis to test the diagnostic performance of VCAT compared to MoCA in distinguishing mild cognitive impairment (MCI) from cognitively normal (CN) by measuring area under the curve (AUC). To test for the association of VCAT with structural MRI, we performed a Pearson’s correlation analysis for VCAT and MRI variables.

Result

We recruited 39 CN, 168 subjective cognitive decline and 262 MCI participants from Dementia Research Centre (Singapore). Mean age of the cohort was 62.77, SD = 9.57, mean education years was 13.97, SD = 3.41 and majority were women (57.8%). VCAT was effective in detecting MCI from CN with an AUC of 0.794 (95% CI 0.723‐0.865) which was slightly higher than MOCA 0.699 (95% CI 0.621‐0.777). Among subjects with MCI, VCAT was associated with medial temporal lobe atrophy (MTA) (ρ = ‐0.265, p = 0.001).

Conclusion

The VCAT is useful in detecting MCI in the community in Singapore and may be an effective measure of neurodegeneration.