bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifiable dementia risk and protective factors in persons with subjective cognitive decline or mild cognitive impairment: a systematic literature review and Delphi study
Authors: Truin Lotte S. , Heger Irene , Deckers Kay , de Vugt Marjolein , Köhler Sebastian
Published: December 2023

Background

Many studies showed that addressing modifiable risk factors has an impact on dementia prevalence and incidence. Most studies have focussed on universal prevention, irrespective of individual risk stage, with risk factors for dementia mainly identified in the general population. Less is known about the most important target risk factors in persons with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), and hence, whether they have a similar potential for risk reduction as the general population. Therefore, this study aims to identify modifiable risk and protective factors for cognitive deterioration and dementia in persons with SCD or MCI.

Method

We use a mixed‐methods approach combining findings from a systematic literature review and an online Delphi study. Four electronic databases (PubMed, EMBASE, PsycINFO, Web of Science) were searched to review relevant literature. A broad search term was developed in consultation with an experienced librarian and consisted of terms linked to SCD, MCI, dementia, modifiable risk factors and disease progression. Observational studies with at least 50 participants and 1 year of follow‐up were considered for inclusion. Twenty international dementia prevention experts were invited to participate in the online Delphi study. In two rounds, experts were asked to spontaneously name, rank and weigh modifiable risk and protective factors in order of importance for the target population.

Result

Our search yielded 19,128 abstracts in total. After removal of duplicates, 9,862 abstracts were considered for inclusion and 203 full‐texts were read, of which 69 were included in our review. Several risk and protective factors were encountered including somatic, lifestyle and neuropsychiatric factors, and they are further scrutinized. Eighteen experts named 31 risk and protective factors in the first Delphi study round, of which physical activity, social isolation and hypertension were ranked highest. Results of round two are being collected.

Conclusion

Findings from the current study will result in an inventory of relevant modifiable risk and protective factors linked with clinical progression in persons with SCD or MCI. Results will serve as the basis for the development and testing of an online dementia risk reduction tool for use in clinical populations with SCD and MCI.
Pooling trial data to identify heterogeneity and characteristics of patients most likely to respond to treatment: a causal forest approach
Authors: Dubbelman Mark A. , Vromen Eleonora M. , Tijms Betty M. , Ottenhoff Lois , Vijverberg Everard G.B. , Prins Niels D. , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: December 2023

Background

A potential explanation for the limited success of past therapeutic trials for Alzheimer’s disease (AD) lies in disease heterogeneity. We set out to pool and jointly analyze data from completed trials using a hypothesis‐free machine learning approach, aiming to identify participant characteristics related to increased responsiveness to treatment. Considering methodological difficulties, we also aim to describe the pooling and analytical process.

Method

We requested data from fifteen completed phase I–III trials investigating several compounds in AD individuals and were granted access to six trial datasets using compounds LY450139 (semagacestat), GSK933776, and BI409306 (with donepezil) with 2,397 participants (73.3±7.8 years old, 55% female, Table 1), through the Vivli platform. Causal Forest analyses, a machine learning technique that extracts a minimal subset of patient characteristics that can explain heterogeneity in outcomes, were used with change on (1) ADAS‐Cog and (2) MMSE as outcome, accounting for treatment group (placebo vs. compound).

Result

The included trial datasets showed considerable differences in available variables and data structure, constraining the amount of data that may be used in joint analysis. We were able to pool and analyze twenty‐seven characteristics shared across trial datasets in the model, covering demographics, vital signs, MRI volumetrics, baseline cognitive and functional performance, apolipoprotein ε4‐carriership and drug compound. Causal forest analyses did not reveal heterogeneity in pooled treatment effects on ADAS‐Cog (estimate for differential forest prediction: ‐2.25, p = 0.96) or MMSE (‐2.97, p = 0.98), indicating that these patient characteristics were not predictive for increased responsiveness to treatment. Stratifying by compound, similar results were found.

Conclusion

We took an innovative approach and provided a methodological basis to examine heterogeneity in treatment effects by pooling existing trial datasets. Our results imply that responsiveness to treatment may not be well‐explained by the patient characteristics to our disposal, or that different compounds should be investigated. More research into other factors possibly related to treatment response is needed, e.g., fluid biomarkers and genetics. Based on our experience, we recommend that trial sponsors improve collaboration and data access, as we work towards personalized medicine by identifying which therapeutic approach works best for whom.
AMYPAD: Correlation of Amyloid PET results with anxiety and depressive symptoms in SCD+, MCI and dementia patients
Authors: Zeyen Philip , Sannemann Lena , Escher Claus , Maier Franziska , Rostamzadeh Ayda , Drzezga Alexander , Giehl Kathrin , Bischof Gerard N , Hönig Merle C. , Altomare Daniele , Garibotto Valentina , Barkhof Frederik , Scheltens Philip , van Berckel Bart N.M. , Collij Lyduine E. , Molinuevo Jose Luis , Grau‐Rivera Oriol , Gispert Juan Domingo , Delrieu Julien , Payoux Pierre , Nordberg Agneta K , Savitcheva Irina , Walker Zuzana , Edison Paul , Demonet Jean‐François , Stephens Andrew W. , Gismondi Rossella , Farrar Gill , Frisoni Giovanni B , Jessen Frank
Published: December 2023

Background

Depression and anxiety are two frequent neuropsychiatric symptoms in Alzheimer’s disease (AD). Moreover, depressive symptoms and anxiety are frequently associated with greater amyloid deposition and risk of Alzheimer’s dementia. The aim of the present study is to assess the association between anxiety and depression and amyloid burden.

Method

In the AMPYAD study, participants with subjective cognitive decline (SCD+, n = 244), mild cognitive impairment (MCI, n = 341) and dementia (n = 255) were enrolled in eight European memory clinics between 2018 and 2020. They underwent three study visits (baseline, six months, thirteen months) with collection of cognitive data and symptoms of depression and anxiety (Hospital Anxiety and Depression Scale, HADS) as well as measures of quality of life and coping strategies. Amyloid burden was obtained as the standardized centiloid values (CL). Correlation analyses were carried out for HADS‐Scores and CL. We analyzed the progression of depressive and anxiety symptoms over time between patients with and without presence of amyloid (CL≥21) using mixed‐model‐ANOVA. All analyses were corrected for time of PET result disclosure.

Result

A total of 840 patients (46.2% female; mean age of 70.9 (SD = 7.8)) were included. Among SCD+ patients, CL values were positively correlated with baseline anxiety scores (r(216) = .14, p = .038). In contrast, MCI and dementia patients showed a negative correlation between CL and depressive symptoms (r(296) = ‐.16, p = .005; r(209) = ‐.23, p<.001). In SCD+, there was no significant interaction between time and CL status for anxiety (p = .512), but a significant main effect of time (F(2,302) = 3.4, p = .036, η² = .02), indicating a decline in anxiety symptoms over time. A trend indicated higher anxiety for amyloid positive participants, but the effect missed statistical significance (p = .068). For depressive symptoms, we found no main effects and no significant interaction of time and CL status.

Conclusion

The AMYPAD study contains a large amyloid‐PET data set of patients from eight European memory clinics. We observed an association of increased anxiety scores with amyloid load in SCD+, but reduced symptoms of depression with higher amyloid load in the MCI and dementia group. These findings and their longitudinal development over time will be put into a broader context of patient characteristics.
Discriminative power of multi‐PET tracer approach targeting reactive astrogliosis, tau pathology, and dopaminergic impairment in 4R primary tauopathies
Authors: Malarte Mona‐Lisa , Gillberg Per‐Göran , Kumar Amit , Nordberg Agneta K
Published: December 2023

Background

The 4R tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are described as dementias with parkinsonian syndrome. Even if they are proven to represent clinically different entities, their complex neuropathology and common hallmarks often make the differential clinical diagnosis of CBD and PSP challenging. The highly entangled astrocytic and tau pathologies observed in these diseases are however displaying unique disparities which might unravel specific neuropathological profiles for each disease. The multi‐PET tracer approach applied in the present study in postmortem brain tissue might provide new mechanistic insights. We recently demonstrated that the second‐generation tau PET tracer, 3H‐PI2620 had a discriminative potential in CBD, PSP, and Alzheimer’s disease (AD) brains (Malarte et al. Mol. Psychiatry. 2022). To further understand the interaction between tau spatial distribution and its potential effects on astrocytic reactivity, we conducted a comparative multi‐tracer investigation in CBD, PSP, AD, and control brains using novel tau and astrocytic tracers. To gain a deeper insight into the relationship between tau, astrogliosis, and concomitant motor impairments, we also studied the interaction with the dopaminergic system.

Method

We performed autoradiography studies on large frozen hemispherical brain tissue of CBD, PSP, AD, and control cases using the tau PET tracer 3H‐PI2620, in comparison to astrocytic tracers (3H‐BU99008 and 3H‐Deprenyl) and dopaminergic tracers (3H‐Raclopride and 3H‐FE‐PE2I). We also analyzed the regional distribution of these tracers in small adjacent frozen brain sections of pathologically specific brain regions (globus pallidus, putamen, caudate, frontal cortex, medulla oblongata). We also performed saturation studies with 3H‐BU99008 and 3H‐Deprenyl on CBD and PSP brain homogenates

Result

Our preliminary results are promising and suggest high astrogliosis measured by 3H‐BU99008 and 3H‐Deprenyl in large frozen autoradiography in CBD and PSP brains, and with different binding intensities in different brain regions comparable with regional 3H‐PI2620 binding. 3H‐BU99008 and 3H‐Deprenyl both highlighted two binding sites in the putamen of CBD cases, but only one site in PSP.

Conclusion

Ongoing multi‐PET tracer studies targeting different pathological hallmarks of CBD and PSP tauopathies will improve differentiation and provide new knowledge regarding the spatial distribution of tau and its correlation with astrogliosis and the dopaminergic system in primary tauopathies.
Correlations in hippocampal subfield volume and pathological hallmarks in Alzheimer’s and Parkinson’s disease
Authors: Bouwman Maud M.A. , Frigerio Irene , Reijner Niels , Lin Chen‐Pei , Bouwman Femke H. , Berg Wilma D.J. , Jonkman Laura E.
Published: December 2023

Background

The hippocampus is highly vulnerable to protein aggregations and often severly atrophic in Alzheimer’s disease (AD) and related neurodegenerative disoders such as Parkinsons’ disease (PD) with dementia (PDD). This study aims to define the association between MRI‐measured hippocampal subfield volumes and pathology load using a cross‐disease and within‐subject post‐mortem MRI‐pathology approach in clinically‐defined and pathologically‐confirmed AD and PD brain‐donors.

Method

We included 17 typical (amnestic) and 13 atypical (non‐amnestic) AD, 10 PD, 9 PDD and 14 age‐matched control donors. 3T in‐situ MRI 3D‐T1 images were obtained for FreeSurfer‐based subfield segmentation. Hippocampus tissue sections were immunostained for amyloid‐beta (Aβ), p‐tau, and pSer129‐α‐synuclein. Immunoreactivity in manually segmented subfields (DG, CA1 to CA4, (para)subiculum and entorhinal cortex) was quantified as area% load. Clinical Dementia Rating (CDR) scores were obtained from clinical reports. Group differences were analysed with general linear models and regional assocations with partial correlations, corrected for age, sex, postmortem delay and intracranial volume.

Result

Total hippocampal, CA1 and subiculum MRI‐volumes were lower in typical AD compared to all other groups (p<0.03). PD and PDD showed higher volumes in all subregions compared to typical AD, except for CA2/3 and parasubiculum (Fig.1).

Typical and atypical AD showed similar p‐tau burden, which was higher compared to other groups in most subfields. CA1 and entorhinal cortex showed the highest Aβ pathology load in AD compared to controls and PD. No significant differences in pSer129‐α‐synuclein pathology were seen between PD and PDD (Fig.2).

Cross‐disease, p‐tau negatively correlated with volume in total hippocampus and all subfields (all r←0.30, p<0.025) (Fig.3). In typical AD, no disease‐specific correlations between pathology and volume could be observed. In PD(D), pSer129‐α‐synuclein was negatively associated with volume in CA4, whereas p‐tau negatively correlated with volume in total hippocampus, DG and CA4 in PDD.

CDR scores correlated negatively with volume in total hippocampus, subiculum and entorhinal cortex cross‐disease, and in typical AD with p‐tau in total hippocampus, CA1 and CA2.

Conclusion

Although similar pathological burden is observed in typical and atypical AD, typical AD showed more severe hippocampal MRI‐atrophy. Furthermore, p‐tau load is associated with MRI‐atrophy of hippocampal subfields cross‐disease, and is regionally associated with impaired cognition.
Identifying modifiable psychosocial outcomes to maintain physical ACTIVity and promote independence in DEMentia: the ActivDem study
Authors: Ardle Ríona Mc , Din Silvia Del , Hicks Ben , Kingston Andrew , Banerjee Sube , Thomas Alan J , Robinson Louise , Rochester Lynn
Published: December 2023

Background

Promoting habitual physical activity (HPA; e.g. walking) may help decelerate dependency and disability in people with dementia (PwD). HPA refers to any movement the skeletal muscles make which requires energy expenditure, including daily tasks (e.g. gardening/housework). Research regarding physical activity in PwD mainly focuses on exercise‐based activities, which may not be feasible for people with chronic health conditions or frailty, or who cannot afford or travel to exercise classes. Promoting participation in HPA may be an inclusive, accessible strategy to support PwD to remain physically active and mobile. PwD participate in less HPA than recommended and disease‐specific factors (e.g. cognition) do not sufficiently explain this. In healthy ageing, HPA participation is associated with multiple socio‐ecological factors (e.g. psychosocial wellbeing/social support/environment) but this has not been explored in dementia. The ActivDem study aims to identify key socio‐ecological influences on HPA change over time in community‐dwellers with dementia. Figure 1 presents ActivDem’s core objectives.

Method

PwD and their carers will be recruited from the ongoing cohort study, DETERMIND, they will participate in a continuous seven‐day HPA assessment. This involves wearing an inertial measurement unit on their lower back at baseline and one‐year follow up. Digital mobility outcomes relating to volume (e.g. steps per day), pattern (e.g. mean ambulatory bout length), and variability (i.e. of bout length) will be derived via validated algorithms. PwD will also complete the LASA Physical Activity Questionnaire and Falls Efficacy Scale. Carers will complete the Dementia Management Strategies Scale. Demographic, clinical and psychosocial characteristics and information on care support will be assessed as part of the DETERMIND study (1).

Result

Longitudinal statistical methods will identify key predictors of HPA change in PwD, and examine the relationship between HPA and independence

Conclusion

The ActivDem study will identify key socio‐ecological predictors of HPA change, these will inform key interventional components to support PwD to remain physically active and mobile following diagnosis of dementia.

References

1. Farina et al., 2020. DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND): A protocol paper. Int. J. Geriatr.
Blood‐brain barrier disruption measured by dynamic contrast‐enhanced MRI in Alzheimer’s disease
Authors: Rauchmann Boris‐Stephan , Toth Hannah , Üstün Guersel Selim , Schirge Philine , Schweiger Meike , Brendel Matthias , Franzmeier Nicolai , Lamby Niclas , Burow Lena , Kurz Carolin Isabella , Koriath Carolin , Tato Maia , Papazov Boris , Moussiopoulou Joanna , Pogarell Oliver Michael , Keeser Daniel , Dietrich Olaf , Stöcklein Sophia , Seelos Klaus , Perneczky Robert
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Blood‐brain barrier (BBB) dysfunction has been associated with AD. Aβ‐plaques have been found to disrupt the BBB, leading to increased permeability and invasion of immune cells into the CNS and triggering an inflammatory response, and contributing to neurodegeneration. In this study, we investigated BBB disruption in Alzheimer’s disease and its associations with amyloid deposition and clinical severity, and cognitive decline.

Method

In this cross‐sectional study, n = 16 AD patients were included. AD patients were defined as amyloid positive by CSF amyloid‐β42/amyloid‐β40 ratio < 5,5% and a Mini‐Mental‐State Examination (MMSE) score < 27. Dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI), a non‐invasive imaging technique that uses intravenously injected gadolinium to quantify the permeability of the BBB has been acquired. DCE‐MRI quantification was quantified using the Patlak method. To analyse the regional degree of BBB disruption the AAL atlas was warped onto the Patlak maps and the median of each ROI was calculated. The cortical amyloid deposition has been quantified using 18F]flutemetamol β‐amyloid‐PET and cognitive performance was assessed using the Alzheimer’s Disease neuropsychological battery (CERAD‐NB). Associations were tested using linear regression models adjusted for age and sex in SPSS.

Result

The highest Ktrans values were measured in the orbitofrontal cortex (mean: 1,6×10−3 min−1). BBB dysfunction in median Ktrans values in the bilateral temporal lobe and particularly the right hippocampus were associated with decreases in the CSF amyloid‐β ratio. Furthermore, BBB dysfunction was negatively associated with cognitive decline measured by the CERAD‐NB. BBB dysfunction overlapped with amyloid PET accumulation in the parietal and temporal brain regions.

Conclusion

DCE MRI shows spatially localized BBB dysfunction in AD. The BBB dysfunction seems to be more severe in regions of the brain that are affected by Aβ plaques. This could support the idea that Aβ plaque contributes to BBB dysfunction in AD. BBB dysfunction also tends to be pronounced in patients with more severe cognitive impairment, suggesting that it may play a role in the progression of AD.
CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

Cerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.

Method

The first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.

Result

Table 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.

Conclusion

In CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.
Prediction of continuous amyloid PET values by CSF tau measures
Authors: Wisch Julie K. , Gordon Brian A. , Barthélemy Nicolas R. , Horie Kanta , Henson Rachel L. , He Yingxin , Flores Shaney , Benzinger Tammie L.S. , Morris John C , Bateman Randall J. , Schindler Suzanne E. , Ances Beau
Published: December 2023

Background

Alzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden.

Method

CSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1).

Result

Combining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids).

Conclusion

CSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures.
The gut microbiome as an early biomarker of preclinical Alzheimer disease
Authors: Ances Beau , Ferreiro Aura L. , Choi JooHee , Ryou Jian , Newcomer Erin , Stark Susan L. , Benzinger Tammie L.S. , Holtzman David M. , Fagan Anne M. , Schindler Suzanne E. , Cruchaga Carlos , Butt Omar Hameed , Morris John C , Tarr Philip , Dantas Gautam
Published: December 2023

Background

The current paradigm of Alzheimer disease (AD) pathology teaches that people progress from cognitive normality, to cognitive normality with biomarker evidence of disease (preclinical AD), and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiomes of symptomatic AD patients have distinct taxonomic compositions compared to healthy cognitively normal controls. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited.

Method

In this cross‐sectional study we compared the taxonomic composition, microbial functional potential, and metagenome‐assembled genomes (MAGs) abundances in a cohort of 93 cognitively normal individuals, 43 of whom had biomarker evidence of preclinical AD.

Result

Preclinical AD individuals have distinct gut microbial taxonomic profiles compared to their healthy controls. Observed microbiome features correlated with amyloid, but not tau or neurodegeneration biomarkers, suggesting that the gut microbial community changes early in the disease process. We identified specific taxa and microbial pathways that were associated with preclinical AD; inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for preclinical AD status.

Conclusion

Gut microbiome correlates of preclinical AD neuropathology have the potential to improve our understanding of AD etiology, enable the identification of gut‐derived biomarkers of AD or AD risk, and guide development of novel therapeutic interventions.
Mutation in presynaptic protein Bassoon induces tauopathy in vivo
Authors: Patel Henika , Martinez Pablo , You Yanwen , Kouri Naomi , Rothberg Darren M. , Yaguchi Hiroaki , Tanaka Shinya , Wakabayashi Koichi , Yabe Ichiro , Murray Melissa E. , Reeves Cristian A Lasagna
Published: December 2023

Background

Tau aggregation is the underlying cause of several neurodegenerative tauopathies. Formation of tau aggregates with seeding activity involves interactions with other proteins, but with unknown effects on tau‐seed properties. Our previous study found that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity in vivo. Bsn downregulation reduced tau spreading and overall pathology. A previous study also linked missense mutations in BSN to the aggregation of 3‐ and 4‐repeat tau in patients. However, it is unknown how genetic mutations in BSN influence tau pathology in vivo.

Method

We developed a knock‐in mouse model harboring a mutation in endogenous BSN (p.Pro3882Ala), equivalent to p.Pro3866Ala BSN mutation identified in patients. We evaluated the cognitive and motor abilities of aged heterozygous and homozygous BSNKI mice and also we analyzed BSN and tau patterns in the brains of these mice. Additionally, we examined BSN and tau patterns in the BSN mutation carrier.

Result

At 10 months, BSNKI mice did not exhibit anxiety‐related behavior and had similar activity as WT littermates. They also displayed similar cognitive abilities as the WT mice. Interestingly, the BSNKI mice displayed lower latency to fall off the rotarod and reduced grip strength compared to the WT mice. We also observed an increase in the accumulation of pathological tau and BSN deposits in the brains of the BSNKI mice. The BSN mutation carrier displayed inclusions of BSN and tau pathology.

Conclusion

We developed a mouse model with a knock‐in mutation in the Bassoon gene, allowing us to evaluate the effects of this disease‐associated mutation in vivo. Our results have shown that the mice with Bsn mutation have impairments in motor coordination, and postural instability, similar to BSN mutation carriers and show pathological tau and BSN deposits in the brain. We found inclusions of BSN and tau pathology in BSN mutation the carrier that resembled certain pathological features of AD and PSP. These findings suggest that BSN plays a role in tau pathology and targeting it may represent a promising therapeutic strategy for tauopathies. Further research is needed to fully understand our findings' underlying mechanisms and potential therapeutic implications.
Plasma biomarkers as a diagnostic tool for amyloid status: factors affecting the frequency of false positive and false negative results
Authors: Rousset Rebecca Z. , Verberk Inge M.W. , van Harten Argonde C. , van der Flier Wiesje M. , Lemstra Afina W. , Pijnenburg Yolande A.L. , Wilson David , den Braber Anouk , Teunissen Charlotte E.
Published: December 2023

Background

Amyloid Positron Emission Tomography (PET) and Cerebrospinal fluid (CSF) analysis are used to diagnose Alzheimer’s Disease (AD). Plasma biomarkers have been proposed as a cost‐effective and less invasive AD diagnostic tool. The main diagnostic markers of interest are Amyloid‐beta1‐42/1‐40 (Abeta1‐42/1‐40), phosphorylated Tau‐181 (pTau181), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light chain (NfL). These markers have good predictive potential for AD diagnosis, but there is also disagreements between plasma analysis and amyloid status through PET/CSF analysis for a significant number of patients. We aim to identify factors that could account for discordancy of plasma and PET/CSF results.

Method

1183 participants were included from the Amsterdam Dementia Cohort (Table 1). Amyloid status was determined by Amyloid PET or CSF. Plasma Abeta1‐42/1‐40, pTau181, NfL and GFAP were measured and included of amyloid status in a multivariate logistic regression model. This logistic model was applied back in the cohort, returning a probability of amyloid positivity for each patient based on their plasma biomarkers concentrations. These probabilities were used to classify patients as plasma positive (≥ 0.5) or plasma negative (< 0.5). Analysis was carried out in 2 groups: patients with positive CSF/PET amyloid status and patients with negative CSF/PET amyloid status. Univariate logistic regression models were applied to identify demographic factors, comorbidities or medications associated with false negative (negative plasma status, positive CSF/PET amyloid status) and false positive (positive plasma status, negative CSF/PET amyloid status) cases.

Result

1183 patients had an amyloid status based on CSF or PET, of which 130 had false negative (10.99%), 106 had false positive (8.96%), 451 (38.12%) had true negative and 496 (41.93%) had true positive plasma results. Higher MMSE scores were associated with higher odds of having a false negative plasma status. Older age, having suffered a stroke, and impaired kidney function were associated with higher odds of false positive plasma results (Table 2).

Conclusion

We identified MMSE score to be associated with false negative plasma results, and age, stroke, and kidney function to be associated with false positive plasma results. Adjusting for these factors may improve predictive ability of plasma biomarkers and AD diagnostic accuracy.
Discovery of high‐affinity amyloid ligands using a ligand‐based virtual screening pipeline
Authors: Chisholm Timothy Stewart , Mackey Mark , Hunter Christopher A
Published: December 2023

Background

A ligand‐based virtual screening pipeline was developed to discover structurally novel ligands for Aβ(1‐42) fibrils.

Method

A database of ligands that bind to Aβ(1‐42) fibrils was used to develop a two‐step ligand‐based virtual screening pipeline. The first step involved developing machine learnings models that use relatively simple chemical descriptors to predict ligand dissociation constants (Kd
). The second step involved constructing 3D models based on field points that describe the surface, shape, and electronic properties of ligands. The combined pipeline was then used to screen 63 million compounds from the ZINC15 database.1 The most promising compounds were experimentally evaluated using binding assays.

Result

For the first chemical descriptor model, a support vector machine model was found to predict the ‐log(Kd
/M) of Aβ(1‐42) fibril ligands with a mean absolute error of only 0.41. An ensemble of four 3D models were then developed that each predicted ‐log(Kd
/M) with a cross‐validation regression coefficient of 0.48–0.56. The ZINC15 database compounds were screened through the first chemical descriptor model, and the 10,000 compounds with the highest predicted affinities were then screened through the 3D models. The 46 highest‐ranked ligands were then evaluated using Thioflavin T competition assays, resulting in five new Aβ(1‐42) ligands with novel structures that exhibited nanomolar binding.

Conclusion

A ligand‐based virtual screening pipeline has been developed to discover new fibril‐binding ligands. Using Aβ(1‐42) fibrils as a target, five new structurally diverse ligands were found that exhibit nanomolar binding affinities.

1. Sterling and J. J. Irwin, J. Chem. Inf. Model.
2015, 55, 2324‐2337.
Road to implementation: patient and healthcare professional’s perception of the blood test
Authors: Teunissen Charlotte E.
Published: December 2023

Background

Alzheimer’s disease blood‐based biomarkers show robust performance for discrimination of amyloid pathology and for monitoring disease progression, both on analytical and clinical level. Now it’s time to prepare for clinical implementation, beyond selected cohorts and in more diverse settings. We therefore started the CANTATE study, which aims to address clinical testing in academic and peripheral memory clinics and in primary care. We aim to elucidate differences between these settings, such as different a priori chances of being amyloid positive, and in test performances and requirements, for example exclusion versus inclusion. In addition, the context of use and perspectives on implementation in primary care are not yet known. We therefore aim to investigate and address attitudes and perspectives of patients and health care professionals on the current diagnostic process and blood‐based biomarker testing.

Methods

We surveyed perspectives of 111 people visiting the website of the Dutch Alzheimer’s association, which were mostly caregivers to persons with dementia, regarding blood‐based testing for a timely AD diagnosis.

Results

When presented with different scenarios, the majority of participants were interested in blood‐based testing for AD, independent of the severity of symptoms they might experience (71.2% if they would experience mild symptoms versus 64.0% if no symptoms). Trust in a negative outcome of a blood‐based test for AD, however, was influenced by symptom severity (78.4% would feel reassured if experiencing mild symptoms versus 48.6% upon severe symptoms). The availability of a treatment option increased interest in blood testing to 92.8%.

Conclusions

These results indicate that there is added value from a public perspective for blood‐based biomarker testing for AD.
Drug utilization among patients with mild cognitive impairment and Alzheimer’s disease in diverse populations: A large nationwide electronic health record cohort study
Authors: Sánchez‐Soliño Olga , Boroje Isabella , Yue Emma Xiaomeng , Vinikoor‐Imler Lisa C
Published: December 2023

Background

Cholinesterase inhibitors (ChE‐Is), such as donepezil, rivastigmine, and galantamine, and N‐methyl‐d‐aspartate receptor antagonists, such as memantine, are prescribed to decrease symptoms associated with cognitive impairment. Few studies have examined the initiation and utilization of these medications among diverse populations. This study’s objective was to characterize drug utilization among patients with mild cognitive impairment (MCI) and/or Alzheimer’s disease (AD) in the United States and stratify by gender, age and race/ethnicity.

Method

This retrospective cohort study was conducted using the Optum® Market Clarity database, which contains electronic health records and insurance claims. Cases of MCI and AD were identified utilizing the International Classification of Diseases, Ninth and Tenth Revisions diagnosis codes. Drug prescriptions were determined to occur before, on, or after the date of first diagnosis. All cases were required to have ≥12 months of enrollment in the database prior to first diagnosis. The study period was from January 2017 through September 2021. Descriptive statistics were calculated stratified by demographic groups.

Result

A large number of cases were identified (197,346 MCI and 144,321 AD cases). Approximately 6% of individuals with MCI had prescriptions for ChE‐Is prior to diagnosis and 14% after diagnosis. For memantine, the proportions with prescriptions before and after MCI diagnosis were 2% and 5%, respectively. Among individuals with AD, prescriptions for ChE‐Is occurred in 22% prior to diagnosis and 32% after diagnosis. Memantine prescriptions increased from 10% prior to AD diagnosis to 18% after. The results did not differ by gender. The highest proportions with ChE‐Is and memantine prescriptions were older age groups <85 years. When examining race/ethnic groups, the proportion of MCI and AD cases with these prescriptions was generally lowest among African Americans.

Conclusion

As expected, prescriptions for ChE‐Is and memantine increased after diagnosis. The proportion of MCI and/or AD cases with prescriptions were similar across genders. The proportion with prescriptions was generally lowest among African Americans. Future research into the discrepancy in the occurrence of prescriptions by race/ethnicity as well as the timing of certain prescriptions will be valuable in further understanding the patient population and their access to appropriate medications.
The Role of Alzheimer’s Disease Pathology in Cognition, Brain Volume, and Plasma Biomarker Concentrations in Traumatic Encephalopathy Syndrome
Authors: Asken Breton M. , Tanner Jeremy A. , VandeVrede Lawren , Mantyh William G , Casaletto Kaitlin B. , Staffaroni Adam M. , soleimani‐Meigooni David N. , Gaynor Leslie S , Fonseca Corrina S. , Shankar Ranjani , Grant Harli E. , Smith Karen , Lago Argentina Lario , Xu Haiyan , La Joie Renaud , Cobigo Yann , Rosen Howard J. , Perry David C. , Rojas Julio C. , Grinberg Lea T. , Miller Bruce L , Gardner Raquel C. , Wang Kevin K.W. , Kramer Joel H. , Rabinovici Gil D.
Published: December 2023

Background

Patients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer’s disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer’s neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES.

Methods

We studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ[+] or Aβ[‐] and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex).

Results

Cognitively, Aβ[+] RHI/TES performed worse than Aβ[‐] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing brain volume, Aβ[+] RHI/TES, but not Aβ[‐] RHI/TES, had lower parietal volume than HC (p = .003, d = 1.3). Conversely, Aβ[‐] RHI/TES had lower hippocampal volume than patients with AD (p = .03, d = 0.77). Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and similar GFAP levels to patients with AD (p = .26, d = 0.38). Conversely, Aβ[‐] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and a trend towards higher plasma NfL than Aβ[+] RHI/TES (p = .11; d = 0.61).

Conclusions

Patients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ[‐] RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ[‐] RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management.
Compensatory versus Rehabilitative Dysphagia Management Approaches are More Frequently Recommended in Hospitalized Persons with Alzheimer’s Disease and Related Dementias
Authors: Robison Raele Donetha , Broadfoot Courtney , Gustafson Sara , Yee Joanne P. , Burdick Ryan , Butz Nicole , Gilmore‐Bykovskyi Andrea L , Kind Amy J. , Rogus‐Pulia Nicole M.
Published: December 2023

Background

Persons with Alzheimer’s disease and Related Dementias (AD/ADRD) frequently develop difficulty swallowing (dysphagia). Two general categories of dysphagia management approaches are initiated by Speech‐Language Pathologists (SLP): compensatory (e.g., modifying fluid/food characteristics) and rehabilitative (exercise‐based). While compensations may improve swallowing safety (no airway invasion) and efficiency (no residue) in the short term, they do not actively target swallowing muscles (e.g. rehabilitative approaches) to induce lasting change in physiology. Additionally, compensatory recommendations are often based on clinical examinations (Desai, 2020) that do not permit visualization of swallowing possible with instrumental assessment (e.g. videofluoroscopic swallow study, ‘VFS’) which may lead to recommendations that are misaligned with swallowing physiology. This study aimed to elucidate whether the frequency of compensatory versus rehabilitative recommendations differs based on VFS findings. Specifically, we sought to characterize: 1) dysphagia management recommendations and 2) VFS findings contributing to these recommendations in a cohort of hospitalized patients with AD/ADRD.

Method

The retrospective sample included all inpatients (n = 122) with AD/ADRD (≥50 years) referred for a VFS at an academic hospital in 2014. AD/ADRD was determined by a diagnosis in the EHR and/or if the patient was taking medication(s) prescribed for AD/ADRD. Dysphagia management recommendations and VFS outcomes including swallowing safety (Penetration‐Aspiration Scale (Rosenbek, 1995) ‘PAS’ scores), efficiency (oropharyngeal residue), and biomechanical impairments (as identified by the SLP) were abstracted from the EHR. The absence (PAS scores 1,2, or 4) or presence (PAS scores 3,5,6, 7, or 8) of airway invasion was further classified (Steele, 2017). Descriptive statistics were calculated to analyze the data.

Result

All recommendations were compensatory with no rehabilitative treatments offered (Table 1). Across recommendations, pharyngeal phase impairments (e.g., pharyngeal delay) and inefficiency (e.g., vallecular residue) on VFS were more common than oral phase impairments/inefficiency. While relatively infrequent, airway invasion was most observed in the pill, solid, and liquid modification groups (Table 2).

Conclusion

In this cohort, all dysphagia treatment recommendations were compensatory approaches focused on optimizing swallowing safety and efficiency. While these recommendations were aligned with VFS findings reflecting pharyngeal phase impairments/inefficiency, they highlight a missed opportunity to address swallowing impairments by directly targeting underlying physiology with a rehabilitative approach.
Implementing new technologies to enhance specimen quality and researcher value at the National Centralized Repository for Alzheimer’s Disease and Related Dementias
Authors: Edler Michael C. , Mitchell Colleen M. , Smith Samantha N. , Denton Michael A. , Sullen Katharina , Ayres Elizabeth , Shaffer Trent B. , Bantel Andrew P. , Bever Thomas , Case K. Rose , Schwantes‐An Tae‐Hwi , Nudelman Kelly N. H. , Hobbick Chris C. , Faber Kelley M. , Foroud Tatiana M.
Published: December 2023

Background

The National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) was established in 1990 at Indiana University with the mission to support research focused on the etiology, early detection, and development of therapeutics for ADRD. NCRAD has been funded by the National Institute on Aging (NIA) since 1990 and is an integral international resource for clinical information and biological materials. As ADRD research has advanced, NCRAD and the NIA have worked together to expand the number and type of biological specimens available to the research community. NCRAD currently houses DNA, RNA, CSF, plasma, serum, stool, brain tissue, LCLs, PBMCs, fibroblasts and iPSCs from individuals with ADRD and healthy controls. NCRAD and the NIA have invested in technologies to standardize specimen processing, enhance specimen quality, and increase specimen distribution to researchers. Paired with this, all data generated from NCRAD specimens must be made available to other researchers through approved data warehouses.

Method

DNA extractions are performed with standardized Chemagen chemistries on the Chemagic360 platform. Genotyping is performed with SNP Type™ assays on Juno™ and Biomark™ platforms. Automated specimen storage is executed by a Hamilton® BiOS M. Biofluid handling and sub‐aliquoting are carried out on Janus®, Biomek, and STARlet liquid‐handling platforms.

Result

DNA extraction quality, consistency, and throughput increased after adopting the Chemagic360 platform. Custom SNP fingerprint genotyping of DNA specimens upon intake and distribution ensured specimen identity was not lost due to collection site errors or specimen swaps during processing. Additionally, APOE and LRRK2 G2019S genotyping has provided researchers banking specimens with valuable ADRD‐related genetic information. Automated, high‐density storage has permitted the banking of more specimens, allowing for onboarding of additional studies. Storage automation reduced the handling of specimens that could introduce warming events, contributing to confounding preanalytical variables.

Conclusion

Recent investments in new technologies have allowed NCRAD to accelerate ADRD research by supporting a broader range of biological specimens, increasing the number of specimens banked, limiting the effects of preanalytical variables, and shortening the time to distribute specimens. The broad availability of NCRAD specimens and the data generated from these specimens, has resulted in over 700 peer‐reviewed publications.