bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Hypothyroidism and its Impact on Cognitive Function in Older Adults: A Cross Sectional Study
Authors: Jessy S Angeline , G Sandhya , S Monisha , Issac Thomas Gregor
Published: January 2025

Background

Thyroid disorders is one of the most common endocrine disorders. It is estimated that 42 million people suffer from thyroid disorders in India. The imbalance in thyroid hormone levels can significantly impact cognitive health of older population. This study aims at emphasizing the prevalence of hypothyroidism and its association with cognition.

Method

A cross‐sectional design, the study enrolled 1,181 participants from the TLSA cohort, focusing on individuals with complete data for sociodemographic characteristics and thyroid‐related blood parameters. Comprehensive clinical assessments, including medical history, physical examinations, and cognitive tests namely COGNITO battery (Computerized Assessment of Adult information processing), HMSE (Hindi Mental State Examination) and ACE‐III (Addenbrooke’s Cognition Examination) were conducted. Biochemical tests quantified plasma levels of thyroid‐stimulating hormones (TSH), triiodothyronine (T3), and thyroxine (T4). Participants were classified based on medication history and thyroid hormone levels.

Result

The study identified a 17.69% prevalence of hypothyroidism, among which 6.22% overt and 93.78% subclinical cases. Females exhibited a significantly higher prevalence (p=0.043). People with hypothyroidism are more frequently diagnosed with mild cognitive impairment than the people with euthyroid (p=0.008). Patients managed suboptimally performed poorer in auditory attention (p<0.001) compared to those on adequate treatment. In the domain of visual attention, the inadequately treated group performed significantly worse than the adequately treated group (p=0.018)

Conclusion

Previous studies suggest a direct association between hypothyroidism and cognitive impairment. This study concludes that hypothyroidism has a significant relationship with cognitive functioning in the attention domain in older adults. Hence, hypothyroidism should be treated as a priority to maintain cognition in an ageing population.
Is FDG‐PET metabolism associated with cognitive performance in long‐Covid patients?
Authors: Hernández Micaela A , Machado Luiza Santos , Bastiani Marco De , Schlickmann Thomas Hugentobler , Ferrari‐Souza João Pedro , Carello Agostina , Helou Belén , Crivelli Lucia , Sanz Emilia Osa , Bérgamo Yanina , Vazquez Silvia , Sevlever Gustavo , Allegri Ricardo , Zimmer Eduardo R. , Calandri Ismael Luis
Published: January 2025

Background

Current evidence indicates that COVID‐19 infection can lead to neurological complications that persist beyond 12 weeks of infection (long‐COVID), often associated with cognitive decline. However, the underlying mechanisms remain unclear. Our aim is to study the brain metabolism of patients with long‐COVID and its association with cognitive performance.

Method

Individuals with cognitive complaints for at least a month after COVID‐19 infection from an Argentine cohort of long‐COVID. Their brain glucose metabolism was assessed by FDG‐PET imaging, and the cognitive symptoms were monitored using cognitive evaluation. The FDG‐PET images were normalized using the individuals’ global mean value, and regions of interest mean signal was extracted using ICBM152 atlas. After applying Principal Components Analysis (PCA) to reduce dimensionality, we conducted clustering using K‐means with the two primary components extracted to create groups with similar metabolism patterns. With the neuropsychological data, we generated seven composites covering cognitive domains based on z‐scored data relative to the normal Argentine population. We conducted pairwise T‐tests to compare cognitive performance of metabolic clusters.

Result

Forty‐one subjects were recruited, 27 were female. Mean age of 55 years (±12) with an average of 15 years of education (±2.3). In PC1, key contributing regions included the right medial temporal lobe, right hippocampus and bilateral amygdala, exhibiting hypometabolism, and bilateral frontal lobe, displaying preserved metabolism (Figure 1). PC2 was characterized by hypometabolism in bilateral frontal lobe and right occipital lobe (Figure 2). Three distinct clusters were identified: Cluster 1 and 2, differentiated by PC1 and Cluster 3, distinguished from Cluster 1 and 2 by PC2 (Figure 3). Regarding cognitive assessments, we observed statistically significant differences between Cluster 1 and 2 in executive composite (p=0.049) and global composite (p=0.025).

Conclusion

Our study identified three distinct clusters based on brain metabolism, with differences in executive functions between the two of them. We consider that FDG‐PET only partially explains cognitive performance, mood and neural networks are probably relevant contributing factors to cognition.
Building consensus on the utility of central and peripheral physiological markers for neuropsychiatric symptoms of dementia: a Delphi Study
Authors: Lai Ka Sing Paris , Choudhury Samira , Kumar Sanjeev , Burhan Amer M.
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) of dementia are a heterogenous group of non‐cognitive symptoms and behaviors that occur in up to 90% of individuals with the condition. Characterizing NPS is a major issue and current methods are unreliable as they rely on subjective observations. Automatic identification of behaviors using central and peripheral physiological markers may be helpful to detect behaviors, allow for early intervention, and prevent critical incidents in patients with dementia.

Methods

This study will use a modified Delphi methodology to develop a guide for the use of central and peripheral markers that can be used for the detection, assessment, and monitoring of treatment response for persons with dementia exhibiting NPS in institutions. Experts including clinicians, educators, and researchers will be recruited internationally to participate as expert panellists. This study will review the current literature regarding the use of central and peripheral markers and NPS (e.g. wearable devices, mobile tracking devices, heart rate variability, skin conductance, and electroencephalography). A list of survey items will be developed and presented to the expert panellists for review and feedback. Survey items will also be refined accordingly based on panellist feedback. It is anticipated that there will be a total of 3 rounds of the modified Delphi process.

Implications

NPS can cause distress to patients and caregivers and increase the risk of injuries to the patients themselves and those in their vicinity. It is difficult for caregivers in care facilities or at home to continuously monitor the persons with dementia. If expert recommendations can be achieved about the use of markers for the detection, assessment, and monitoring of treatment response for NPS, clinicians will be able to better provide early intervention and deliver personalized treatment plans for persons with dementia exhibiting NPS.
Sharing Roles in Home Care: Family Care Partners and Paid Caregivers
Authors: Fabius Chanee D , Gallo Joseph J , Wolff Jennifer L
Published: January 2025

Background

Little is known about the prevalence and nature of role‐sharing among family care partners and paid caregivers.

Method

We studied 440 participants in the 2015 National Health and Aging Trends Study (NHATS) receiving paid help with self‐care, mobility, or medical care. Guided by Litwak’s task specificity model, we focus on frequency of receiving paid help only, help from care partners only, and role‐sharing by task. We examine whether role sharing and reliance on paid help only differs by older adults’ Medicaid‐enrollment and dementia status.

Result

Older adults whose helping arrangements did (versus did not) involve role‐sharing were more often living with dementia (48.7% vs. 25.6%, p<0.001) but less often Medicaid‐enrolled (32.1% vs. 49.4%, p<0.01). Those living with (versus without) dementia more often experienced role‐sharing in eating (OR 3.9 [95% CI 1.20, 8.50]), bathing (OR 2.7, [95% CI 1.50, 4.96]), dressing (OR 2.1 [95% CI 1.14, 3.86]), toileting (OR 2.9 [95% CI 1.23, 6.74]), and indoor mobility (OR 2.8 [95% CI 1.42, 5.56]), and less often received help solely from paid helpers with medication administration (OR 0.24, [95% CI 0.12, 0.46]). Those who were (versus not) enrolled in Medicaid more often received paid help only in dressing (OR 2.0 [95% CI 1.12, 3.74]), getting around outside (OR 2.4 [95% CI 1.28, 4.36]), and inside (OR 4.3 [95% CI 2.41, 7.62]), as well as with doctor visits (OR 2.8 [95% CI 1.29, 5.94]).

Conclusion

Findings highlight heterogeneity and the high prevalence of role‐sharing in paid care, particularly for older adults living with dementia and not enrolled in Medicaid. Findings lay the foundation for interventions that align with national recommendations to increase understanding of and strengthen relationships between family caregivers and paid caregivers.
Substantia nigra iron deposition in Lewy body disease: an MRI quantitative susceptibility mapping and neuropathology study
Authors: Diaz‐Galvan Patricia , Przybelski Scott A. , Lesnick Timothy G. , Nguyen Aivi T. , Murray Melissa E. , Reichard Ross R. , Dickson Dennis W. , Ono Daisuke , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Lowe Val J. , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Ramanan Vijay K. , Jones David T. , Botha Hugo , St. Louis Erik K , Knopman David S. , Day Gregory S , Graff‐Radford Neill R , Petersen Ronald C. , Jack Clifford R. , Ferman Tanis J , Boeve Brad F. , Kantarci Kejal
Published: January 2025

Background

Parkinson’s disease and dementia with Lewy bodies are characterized by abnormal iron deposition in the substantia nigra, which can be measured with quantitative susceptibility mapping (QSM) on MRI. However, neuropathologic validation of the increased QSM in the substantia nigra associated with Lewy body disease (LBD) is lacking. We compared substantia nigra QSM on antemortem MRI between patients with and without Lewy‐related pathology which was confirmed by autopsy in all cases.

Method

We studied cases with antemortem QSM who underwent autopsy from the Mayo Clinic Alzheimer’s Disease Research Center and Mayo Clinic Study of Aging (n=54). Immunohistochemistry was performed with rabbit NACP antibody against the amino acids 98‐115 of the α‐synuclein protein to detect Lewy‐related pathology. After neuropathologic evaluation, cases were classified as LBD‐present (n=13) if they had Lewy‐related pathology and LBD‐absent (n=42) if they did not have Lewy‐related pathology. Alzheimer’s disease co‐pathology was present in 9 of the LBD‐present cohort (70%). QSM was calculated for the whole substantia nigra and the two sub‐regions: pars compacta and pars reticulata. Non‐parametric Wilcoxon rank‐sum test was used to compare substantia nigra QSM values between LBD‐present and LBD‐absent cases. Area under the curve (AUC) analyses tested the accuracy of QSM to distinguish the two groups.

Results

LBD‐present group had higher QSM values in the substantia nigra than LBD‐absent group. Furthermore, sub‐regional analyses showed that the LBD‐present group had higher QSM in the substantia nigra pars compacta (p=0.008) but not in the pars reticulata than the LBD‐absent group (Figure 1). QSM of the substantia nigra pars compacta distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC=0.74; p=0.006; Figure 2).

Conclusion

This study provides neuropathologic insight into the relevance of QSM of substantia nigra pars compacta as an in‐vivo biomarker of autopsy‐confirmed LBD. These findings indicate that imaging evidence of abnormal iron deposition in the substantia nigra may serve as a biomarker of Lewy‐related pathology in patients with primary LBD (i.e., Parkinson disease, dementia with Lewy bodies) and patients with potential LBD co‐pathology (e.g., patients with Alzheimer disease).
CSF SNAP‐25 and Neuronal pentraxin 2 associations with cognitive decline in the presence of CSF ptau181/Aβ42 in an at‐risk cohort
Authors: Planalp Beth M. , Langhough Rebecca E. , Valentino De'Karlos , Ealy Denise , Quijano‐Rubio Clara , Kollmorgen Gwendlyn , Blennow Kaj , Zetterberg Henrik , Jonaitis Erin M. , Johnson Sterling C.
Published: January 2025

Background

Alzheimer's disease (AD) is identified by the accumulation of amyloid β (Aβ) and tau proteins in the brain. The NeuroToolKit offers automated cerebrospinal fluid (CSF) immunoassays of core AD biomarkers and biomarkers of neurodegeneration and synaptic function, including neurofilament light (NfL), SNAP‐25, and neuronal pentraxin 2 (NPTX2). This work explores whether these three markers predict pre‐dementia cognitive decline synergistically with or after accounting for CSF ptau181/Aβ42.

Method

Participants included N=360 baseline dementia‐free adults (45—85 years) with complete CSF biomarker and cognitive data from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (on‐going, longitudinal preclinical AD studies). We assessed CSF biomarkers using the NeuroToolKit (NTK), a panel of robust prototype biomarker assays (Roche Diagnostics International, Switzerland). Mixed models examined separately whether NfL, SNAP‐25, or NPTX2 biomarkers further modified Preclinical Alzheimer’s Cognitive Composite (PACC3) trajectories beyond Aβ+ effects. Biomarker*ptau181/Aβ42*age (linear and quadratic) interactions were examined, and non‐significant higher order interactions removed sequentially before interpreting NfL, SNAP‐25, and NPTX2 effects.

Result

Sample characteristics are shown in Table 1, and show significant correlations among all biomarker pair except NPTX2 and ptau181/Aβ42. Table 2 and Figure 1 depict PACC3 model outputs and biomarker associations; Aβ+ performed worse or declined faster than Aβ‐ across all models. Compared to a base “amyloid‐only” model, NfL, SNAP‐25, and NPTX2 “biomarker” models showed an improved model fit (Table 2). The best‐fitting model included the NPTX2* ptau181/Aβ42*age2 interaction (Table 2) which showed greatest average PACC3 decline in those with higher amyloid and lower NPTX2 (Figure 1d). SNAP‐25 also related to cognition such that individuals with lower amyloid and higher SNAP‐25 had the highest PACC3 average (interactions with age were non‐significant), and individuals with higher NfL showed steeper PACC3 decline than those with lower NfL.

Conclusion

In addition to known effects of NfL, recently developed NTK immunoassays for SNAP‐25 and NPTX2 accounted for additional variability on AD‐related pre‐dementia PACC3 performance. Future work may identify clinically useful cutpoints for SNAP‐25 and NPTX2 and explore relations with other biomarkers common to neurodegeneration and AD. We will also examine associations with other outcomes including clinical progression of AD.
A diffusion kurtosis MRI signature of subjective cognitive decline
Authors: Flaherty Ryn , Sui Yu Veronica , Li Mu , Ardelean Ana , Rusinek Henry , Masurkar Arjun V. , Lazar Mariana
Published: January 2025

Background

Diffusion weighted imaging (DWI) of brain white matter is better at predicting future cognitive decline and medial temporal lobe atrophy than cerebrospinal fluid biomarkers in subjective cognitive decline (SCD)1. However, few studies have investigated gray matter DWI in SCD, despite the importance of regional gray matter changes as a biomarker for Alzheimer’s Disease and related dementias.

Method

316 cognitively normal participants from Cam‐CAN2 (123 SCD) older than 55 were included in the analysis. Participants were placed in the SCD group if they endorsed problems with their memory. Imaging data was collected on a 3T Siemens Trio scanner2. Diffusion imaging included 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions, and were processed using MrTrix3, PyDesigner, and AMICO to apply diffusion tensor (DTI), diffusion kurtosis (DKI), and neurite orientation density and dispersion (NODDI) models. FreeSurfer with T1w and T2w images was used to segment subcortical and cortical regions (Figure 1B&C), then calculate regional volume and cortical thickness. Segmentations were also registered to diffusion images to generate regional averages of the diffusion metrics. Uncorrected p<0.05 according to Wilcoxon tests were considered significant.

Result

The metric with the most regional group differences was kurtosis fractional anisotropy (KFA) from DKI, an indicator of structural complexity. KFA was significantly lower in SCD in 17 of 84 gray matter regions, including hippocampus (Figure 2‐3B). DTI showed reduced fractional anisotropy (Figure 2‐3C) and increased mean diffusivity (Figure 2‐3D) in SCD, but for fewer regions than KFA. NODDI showed increased free water (Figure 2‐3E), increased orientation dispersion (Figure 2‐3F), and increased neurite density (Figure 3G) in SCD. Volume and thickness were higher in SCD in 5 regions, but lower in 3 regions (Figure 2‐3A). Only KFA showed group differences in hippocampus.

Conclusion

KFA was more sensitive to SCD and more consistent than regional gray matter volume, cortical thickness, and all other diffusion metrics. This may indicate KFA is a biomarker signature of SCD across the whole brain gray matter.

Selnes P, Aarsland D, Bjornerud A, et al. J Alzheimers Dis. 2013;33(3):723‐36.

Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1‐25.
Interplay of inflammatory, vascular, and Alzheimer’s disease biomarkers in cognitively unimpaired older adults
Authors: Rizvi Batool , Adams Jenna N. , Bamford Alison , Sathishkumar Mithra , Kim Soyun , McMillan Liv , Brickman Adam M. , Mapstone Mark , Thomas Elizabeth A. , Yassa Michael A.
Published: January 2025

Background

Neuroinflammatory processes, assessed by cytokines such as interleukins, are implicated in vascular disease and amyloid‐β (Aβ) burden. White matter hyperintensities (WMH), markers of small vessel cerebrovascular disease, are associated with memory impairment and Alzheimer’s disease (AD)‐related cortical atrophy. Here, we used structural equation modeling (SEM) to test whether inflammatory markers are related to markers of AD pathology and neurodegeneration through their impact on WMH.

Method

A sample of 118 older adults without dementia (mean age (SD) = 70.8 (6.22) years, age range: 59.8‐86.4 years, 77 (65%) women) were included. Regional WMH volumes were derived from T2‐FLAIR images using ANTs, parcellated by a vascular territory atlas. Aβ was assessed with 18F‐florbetapir‐PET, with SUVR was extracted from composite ROIs reflecting early, intermediate, and late regions of deposition. Medial temporal lobe (MTL) volume/thickness measures including averaged bilateral hippocampal volumes, entorhinal cortex thickness, and parahippocampal cortex thickness, were derived using FreeSurfer v.6.0. A set of inflammatory markers (IL‐2, IL‐4. IL‐6, IL‐8, IL‐10, IL‐12, IL‐13) and phosphorylated tau (P‐tau217, P‐tau181) were measured in plasma. We tested the relationships among inflammation, amyloid‐β, WMH, P‐tau, and MTL gray matter using structural equation modeling (SEM) and confirmatory factory analysis (CFA).

Result

Model fit indices demonstrated acceptable model fit: χ2 (84) = 104.328, p = 0.066; comparative fit index (CFI) = 0.982; Tucker‐Lewis index (TLI) = 0.977; Root Mean Squared Error of Approximation (RMSEA) = 0.070 (90% CI: 0.021, 0.104); and Standardized Root Mean Square Residual (SRMR) = 0.107. Inflammation was associated with WMH (b=0.430, β=0.403, p=0.031), but not with amyloid‐β burden (b=0.099, β=0.099, p=0.549). Only amyloid‐β was related to phosphorylated tau (b=0.535, β=0.462, p<0.001). Both WMH and phosphorylated tau burden were associated with reduced MTL gray matter (WMH: b=‐0.228, β=‐0.231, p=0.049; P‐tau: b=‐0.233, β=‐0.251, p=0.031).

Conclusion

Our study suggests that inflammation promotes AD‐related neurodegeneration through its impact on vascular disease whereas amyloid appears to operate through tau in its effect on atrophy. The study highlights the possible ways in which inflammatory and vascular pathways converge with amyloid pathways to drive AD‐related neurodegeneration.
Longitudinal assessment of neuronal calcium, glutamate, and hemodynamic changes in aging APP‐PS1 mice
Authors: Cover Christopher G , Peretin Jenna M , Poplawsky Alexander , Vazquez Alberto L
Published: January 2025

Background

Preclinical Alzheimer’s disease research has gained traction as a potential point of intervention, though it is relatively unknown how early stages of the disease impact cortical health. The following study utilizes optical imaging methods (Figure 1) to characterize changes in neuronal, glutamate, and hemodynamic activities in a preclinical amyloidosis mouse model of the disease.

Method

Five (n = 5; 2 females & 3 males) APPswe/PS1dE9 x Thy1‐jRGECO1a double transgenic mice were breed for whole‐brain fluorescent imaging of neuronal activity. At two months of age, mice were injected with a fluorescent glutamate sensor in the right barrel cortex (BC), primary motor cortex (PMC) and retrosplenial cortex (RSP), then implanted with a 5mm cranial window. From 3‐12 months of age, mice were imaged monthly in the awake state using both wide‐field optical and two‐photon microscopy (2PM) to investigate both systems‐level and cellular/synaptic activities, respectively. Imaging sessions consisted of spontaneous resting‐state activity and evoked responses from a single, repeated whisker puff to the left whisker pad. Nonparametric statistical analysis was performed due to the small sample size.

Result

Peak amplitudes progressively declined from baseline levels (i.e., 3 months of age) at the systems level in the aging mice and reached significance by 10 months of age (p < 0.05; Figure 2B). Additionally, a trend towards excitatory imbalances were seen from 5‐7 months of age. Interestingly, impairments in glutamate clearance trended towards significance only at 6 months of age, but not at other times. See Figure 3 for example 2PM in response to a single whisker puff.

Conclusion

Longitudinal decline in stimulus‐evoked neuronal calcium, glutamate, and hemodynamic activities were seen in young, aging AD mice. Future directions will consist of 1) increasing the sample size, 2) analysis of resting‐state data at the systems and cellular levels, and 3) analysis of 2PM data with the whisker stimulus.
Impaired Complex Activities of Daily Living Correlated with Altered EEG Oscillations in the Dementia Spectrum Disorder
Authors: Chen Poyu , Wu Chin‐Yi , Huang Yu‐hua , Hsu Jung‐Lung , Chuang I‐Ching , Sikkes Sietske A.M
Published: January 2025

Background

Literature on biomarker studies suggests that pathological changes begin approximately 10 to 20 years before the first cognitive symptom appears in dementia populations. It is an emerging era for developing methods to detect the early signs of progressive cognitive decline. Recently, the instrumental activity of living (IADL) capacity has been regarded as a functional biomarker to predict the progression from MCI to dementia. EEG, combined with cognitive performance, such as IADL performance, might be able to provide a more sophisticated biomarker candidate. Thus, the present study aimed to adopt EEG combined with the Amsterdam Instrument of Daily Living Questionnaire‐Short Version Traditional Chinese (A‐IADL‐SQ‐TC) to early detect cognitive decline in the preclinical stages.

Method

We recruited 76 participants, including those with normal cognition (n=25), SCD (n=21), MCI (n=17), and dementia (n=13) in both community and memory clinics. All of the participants were measured with the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and eye‐closed EEG recording. Furthermore, all proxies of the participants filled out the A‐IADL‐SQ‐TC.

Result

Individuals with MCI and dementia exhibited larger relative power in the low‐frequency bands, specifically the delta (0.5‐4 Hz) and theta bands (4‐8 Hz), and smaller relative power in the high‐frequency band, specifically the alpha (8‐13 Hz) and beta bands (13‐20Hz). These findings are consistent with previous research. Additionally, we discovered that the A‐IDAL‐Q‐SV‐TC T‐score negatively correlated with theta relative power across the scalp (r = ‐.55 to ‐.62, all p**<.001), while positively correlated with beta relative power across the scalp (r =.35 to ‐.46, all p<**.001). Regarding the global theta relative power, the one‐way ANOVA showed significant group differences, F (3,72) = 19.768, p<.001. However, the post‐hoc effect revealed only the dementia group showed a significantly higher relative power than the other groups.

Conclusion

We have discovered that the resting‐state EEG oscillations exhibited different patterns across different stages of dementia. Furthermore, A‐IADL‐SQ‐TC was associated with the spectral intensity of the resting‐state EEG oscillations, and together they provide more sensitive indicators for early detection.
Direct comparisons of the associations between the tau PET tracers [18F]Flortaucipir and [18F]MK6240 with tests of general cognitive performance ‐ The HEAD study
Authors: Amaral Livia , Povala Guilherme , Bellaver Bruna , Bauer‐Negrini Guilherme , Lussier Firoza Z , Ferreira Pamela C.L. , Cehula Juli , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A.
Published: January 2025

Background

Tau PET tracers are employed to measure the accumulation of tau in vivo in the brain. Each tau tracer possesses unique characteristics, including binding affinity, sensitivity, and specificity to tau aggregates. This study leverages the HEAD study dataset, which is currently performing baseline tau PET tracers and conducting multiple clinical and cognitive assessments. The objective of this study is to elucidate the relationship between tau PET tracers [18F]Flortaucipir and [18F]MK6240 and commonly used tests of general cognitive performance.

Methods

We assessed 170 individuals (107 cognitively unimpaired, and 63 cognitively impaired) with available PET [18F]Flortaucipir [18F]MK6240 and cognitive assessments (MoCA, MMSE, and CDR‐SB). We calculated tau PET SUVR for [18F]Flortaucipir and [18F]MK6240 using the inferior cerebellar grey matter as a reference. Pearson correlations were performed between SUVR values for each Braak region and MoCA, MMSE, and CDR‐SB. In addition, linear regression models accounting for age, sex, years of education, HEAD site, and diagnosis were used to estimate the relationships. The Akaike Information Criterion (AIC) was utilized to evaluate the models, with smaller AIC values signifying better performance.

Results

Person correlation coefficients (r), which were calculated without considering any covariates, demonstrated higher numerical values between [18F]MK6240 and the scores of MoCA, MMSE, and CDR‐SB across the Braak regions (Figure 1). Similarly, when we performed linear regressions that accounted for relevant covariates, we found that the [18F]MK6240 SUVR in Braak 1 and Braak 4 regions exhibited a stronger association with cognitive tests than in other Braak regions or any region with [18F]Flortaucipir SUVR (Figure 2).

Conclusions

Both [18F]Flortaucipir and [18F]MK6240 SUVR demonstrated a robust association with tests of general cognitive performance commonly used in AD research and clinical practice. Generally, Braak regions 1 and 4 exhibited a stronger association with general cognitive performance using all tests, whereas Braak regions 5‐6 showed the weakest association.
Clinical use of tau PET in Aβ PET positive individuals: a case series
Authors: Machado Vitor Hugo , Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Amaral Livia , Bauer‐Negrini Guilherme , Lussier Firoza Z , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A.
Published: January 2025

Background

Identifying individuals’ levels of tau PET pathology could prove to be beneficial in clinical settings, given that emerging therapies aimed reducing Aβ seem to be most effective in these individuals. Here, we present the cases of four patients who visited the memory clinic at the University of Pittsburgh Medical Center between June and December 2023 and underwent both Aβ and tau‐PET scans.

Method

These individuals had standard clinical and cognitive outcomes, typical blood tests order in patients with memory impairment, MRI, and, as part of the HEAD study, PET PIB Aβ and two tau PET tracers (MK6240 and Flortaucipir).

Result

All patients presented a primary complaint of progressive memory decline. The results of their blood count, metabolic panel, TSH, and vitamin B12 tests were unremarkable. Patient 1 had a normal MRI, while Patients 2‐4 exhibited mild ischemic changes (Table 1). All patients tested positive for amyloid PET, supporting the diagnosis of AD. However, their tau PET results varied. Patients 1 (MOCA = 6) and 3 (MOCA =19), who were demented with impaired Instrumental Activities of Daily Living (IADL), tested positive for tau PET with Braak stages V‐VI using both tau PET tracers. Conversely, the mild cognitive impairment (MCI) Patients 2 (MOCA = 19) and 5 (MOCA = 29, neuropsych evaluation indicating MCI), who exhibited low tau levels, tested positive for MK6240 but negative for FTP.

Conclusion

All four patients exhibited symptoms and signs consistent with typical amnestic AD presentation, which were confirmed using Aβ PET. Aβ PET presented a similar pattern across all individuals (Figure 1). Tau PET demonstrated greater variability, with lower levels in less cognitively impaired patients. Although tau PET can potentially be useful in identifying individuals in the earliest stages that would benefit from Aβ‐lowering therapies, this small series did not exclude that a low MOCA score combined with Aβ PET could achieve a similar outcome. Larger samples in real‐world clinical contexts are necessary to identify individuals with discrepancies between tau PET uptake and cognitive tests. This would reinforce the need for tau PET markers as complementary tests, singularly capable of identifying individuals across various biological stages to indicate therapies in clinical practice.
Will a Culturally Adapted Training Material for Caregivers Improve Dementia Care in Ghana?
Authors: Yalley Sally , Manu Kwaku Sarfo , Romero‐Ortuno Roman
Published: January 2025

The World Health Organization (WHO) emphasizes the need to provide support to caregivers of people living with dementia, as one of seven action areas. This is especially crucial in Ghana, where, similar to other Lower Middle‐Income Countries (LMICs), the majority of people with dementia reside in the community and are cared for by informal caregivers, often family members. These caregivers usually do not have any training in dementia care and may have limited understanding of the disease and its potential symptoms. This increases the physical and psychological burden on caregivers, highlighting the urgent need for education and training of informal caregivers in Ghana (Ayisi‐Boateng et al. 2022).

The Alzheimer’s and Related Disorders Association of Ghana operates a caregiver support platform that has expanded since its inception. This aims to provide individualized support and education for caregivers, primarily utilizing freely available or open‐source educational resources such as the WHO iSupport manual, as well as educational materials from organizations like the Alzheimer’s Society UK, Alzheimer’s Association of the USA, and Alzheimer’s Disease International.

While the currently available materials offer a much‐needed foundational understanding, addressing translational and cultural differences is essential. Ghanaian cultural practices, marked by its heterogeneity and distinctions from Western culture, presents unique challenges in dementia care. Moreover, considering varying levels of literacy, particularly among older adults, the adaptation of resources to include tailored video content could be beneficial for a more inclusive and effective approach.

The WHO’s iSupport manual has been successfully translated and adapted into several languages and cultural settings around the world. Replicating this adaptation in the Ghanaian cultural context would be a momentous step in developing bespoke and culturally relevant dementia care resources in Africa.
Improve Statistical Efficacy Inference: Global Reduction Rate in Disease Progression
Authors: Wang Guoqiao , Jin Kun
Published: January 2025

Background

In AD trials, the treatment effect is typically evaluated by estimating the absolute difference in change from baseline to the end‐of‐study visit (e.g., 18 months) between treatment arms using the MMRM model. To enhance clinical interpretability, this absolute difference is often converted into a percentage slowing relative to the placebo decline (e.g., 27% of CDR‐SB in lecanemab trial). We propose to model this percentage directly as a global reduction rate (GRR) in disease progression using multivariate proportional MMRM models (MpMMRM). MpMMRM estimates GRR across all multiple longitudinal and/or survival endpoints, either at the last study visit or for all post‐baseline visits. For example, donanemab lead to 35.9% reduction in iADRS, 36.0% in CDR‐SB, and 38.6% reduction in progression to more advanced disease stages as measured by CDR global, which can be model simultaneously to estimate a GRR. The objective of this presentation is to evaluate the advantages of utilizing GRR as an inference tool for treatment efficacy.

Method

We will compare the global reduction rate (GRR) with three other statistical efficacy inference methods. These methods include: (i) Traditional MMRM inference using a single endpoint. (ii) Global statistics test (GST): GST combines z‐test statistics across multiple endpoints. (iii) Composite analysis utilizing a composite score derived from multiple endpoints. To evaluate these methods, we utilized simulated data that mimicked successful early Alzheimer’s disease trials.

Result

Our preliminary simulation results showed that utilizing GRR across multiple longitudinal endpoints shows power advantages compared to the other methods, including GST. These advantages can be observed when considering the GRR at the last visit or overall post‐baseline visits. Additionally, estimating the GRR based on combined longitudinal and survival endpoints also demonstrates power advantages. Importantly, we also demonstrated that Type I errors are well‐controlled for all the methods considered in our simulations.

Conclusion

GRR evaluates the totality of evidence of a treatment effect. It can be estimated using a one‐step approach based on well‐established SAS procedures. GRR does not require any additional assumptions and offers greater interpretability and power compared to traditional methods like GST and the composite method.
Pilot study of Myocardial MIBG Scintigraphy with 123I‐FP‐CIT SPECT in Isolated REM Sleep Behavior Disorder
Authors: Miyagawa Toji , Vernon Cynthia , Przybelski Scott A. , Min Hoon‐Ki , Fields Julie A. , Forsberg Leah K. , St. Louis Erik K , Kantarci Kejal , Lowe Val J. , Boeve Brad F.
Published: January 2025

Background

Autopsy studies in Lewy Body Disease (LBD) indicate that cardiac sympathetic denervation precedes Lewy body pathology and neuronal loss in the brain. Myocardial 123I‐metaiodobenzylguanidine (MIBG) scintigraphy noninvasively assesses postganglionic cardiac sympathetic denervation in LBD and is considered an important biomarker in the international diagnostic criteria of Dementia with Lewy Bodies and Parkinson’s Disease (PD). Despite the internationally recognized importance of MIBG scintigraphy in LBD, its use in neurodegenerative disorders is not FDA approved for this indication and is rarely used in the US for neurological research. We sought to add MIBG scintigraphy to our multimodal imaging research in prodromal LBD. We launched pilot MIBG scintigraphy study in isolated REM Sleep Behavior Disorder (iRBD) individuals, who are typically regarded as representing evolving LBD.

Method

We conducted MIBG scintigraphy and 123I‐FP‐CIT SPECT in seven individuals with iRBD including two RBD with mild cognitive impairment (MCI), one with PD, and one healthy control (mean age of 71.5±8.3). Heart‐to‐mediastinum (H/M) ratio of the MIBG uptake on delayed image (3‐4 hours after Adreview® injection) was calculated with MIM. Cutoff value of 1.68 was used for determining abnormal H/M ratio (Yoshita et al, 2006). Nigrostriatal dopamine transporter uptake was evaluated with DaTQUANT 2.0 software.

Result

Four iRBD participants including two RBD with MCI had abnormal MIBG scintigraphy (mean age 73.5±8.6, delayed H/M ratio 1.25±0.29)) and three iRBD participants had a normal scan (mean age 67.8±4.5, delayed H/M ratio 2.57±0.25). Delayed H/M ratio was 1.00 for the PD participant and 2.60 for healthy control participant. Among the four iRBD participants with abnormal MIBG scintigraphy, one participant had 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score <‐2.0 and three participants had z‐score in the range of ‐1.5 and ‐1.0. All iRBD participants with normal MIBG scintigraphy had normal 123I‐FP‐CIT SPECT with DaTQUANT putamen z‐score >‐1.0.

Conclusion

MIBG scintigraphy was abnormal in half of this small cohort. Our preliminary data suggests its utility in detecting early signs of evolving LBD. Increasing the number of the MIBG scintigraphy in iRBD participants and controls are planned to determine if MIBG scintigraphy can facilitate early detection of progression for use in clinical trials targeting LBD.
Alzheimer's disease staging with [18F]MK6240 and [18F]Flortaucipir ‐ the HEAD study
Authors: Soares Carolina , Povala Guilherme , Bauer‐Negrini Guilherme , Lussier Firoza Z , Ferreira Pamela C.L. , Bellaver Bruna , Amaral Livia , Zalzale Hussein , Madeiros Marina Scop , Cehula Juli , Bloomquist Madeleine , Oliveira Markley , Felix Cynthia , Rodrigues Matheus Scarpatto , Ruppert Emma Patrice , Abbas Sarah , Zimmer Eduardo R. , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Rosa‐Neto Pedro , Tudorascu Dana , Jagust William J. , Klunk William E , Baker Suzanne L. , Pascoal Tharick A.
Published: January 2025

Background

Utilizing PET amyloid‐beta (Aβ) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aβ PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.

Method

We evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aβ‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aβ positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).

Results

We found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).

Conclusion

Our findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.
Investigating the association between cholinergic integrity and amyloid burden using cholinergic anatomy and [18F]‐FEOBV PET in individuals with Down Syndrome from the ABC‐DS and TRC‐DS cohorts
Authors: Russell Jason K , Conley Alexander C , Boyd Brian , Schlossberg Rachel , Stranick Allison , Rosenberg Adam J , Acosta Lealani Mae Y. , Rafii Michael , Shokouhi Sepideh , Newhouse Paul A
Published: January 2025

Background

Adults with Down Syndrome (DS) have the highest risk of developing Alzheimer’s disease (AD) worldwide. Triplication of the amyloid precursor protein gene on chromosome 21 results in early amyloid accumulation and Alzheimer’s pathology. The cholinergic system is known to decline early in the development of AD and plays a fundamental role in observed cognitive deficits. In the present work, we assess the association between amyloid accumulation and cholinergic integrity.

Method

188 individuals from the ABC‐DS cohort (U01AG051406; U01AG051412; U19AG068054) were assessed cross‐sectionally. Basal forebrain volumes were calculated using the ScLimbic FreeSurfer pipeline for the basal forebrain (Ch1‐Ch4) and the DnSeg pipeline for Ch4 volumes. Linear regressions were performed between centiloid values, age, and basal forebrain volumes. Nine individuals recruited for a TRC‐DS sub‐study underwent a multimodal imaging assessment, including [11C]‐PiB PET and [18F]‐FEOBV PET imaging. Global centiloid values were calculated using PMOD, with regional SUVRs calculated using PetSurfer with GTM for partial volume corrections. Linear regressions were performed between global centiloid, regional [11C]‐PiB SUVR, and regional [18F]‐FEOBV SUVR.

Result

In ABC‐DS and the TRC‐DS sub‐study, global amyloid accumulation was positively associated with age (p<0.0001 and p=0.041). Age and global amyloid accumulation were negatively associated with Ch1‐Ch4 (p<0.005) and Ch4 (p<0.05) cholinergic basal forebrain volumes. In the TRC‐DS sub‐study, global amyloid accumulation negatively associated with [18F]‐FEOBV uptake in the amygdala (p<0.05), statistical trends were observed in the thalamus and left entorhinal cortex (p<0.08). Regional [11C]‐PiB uptake was negatively associated with [18F]‐FEOBV uptake in the left inferior temporal and right pericalcarine cortices (p<0.05), with statistical trends observed in the right amygdala, left pericalcarine, and left fusiform cortices (p<0.08).

Conclusion

Measures of cholinergic integrity were found to decline with increasing amyloid in individuals with DS across two cohorts, utilizing different methodologies. In the ABC‐DS cohort, we observed a reduction in basal forebrain nuclei volume with increasing age and amyloid accumulation. The basal forebrain contains cholinergic and noncholinergic neurons. To understand whether this volume reduction was from cholinergic loss, we assessed the integrity of cholinergic terminals using [18F]‐FEOBV PET and found regional cholinergic integrity negatively associated with both global and regional amyloid accumulation.
Increased Myeloid Progenitor Inhibitory Factor 1 and Dysbiosis in Mild COVID‐19 Patients With No Change in Alzheimer's Disease Markers
Authors: Giridharan Vijayasree V , Catumbela Celso , Kluwe‐Schiavon Bruno , Arent Camila O. , Borba Laura A. , Bagatini Margarete D. , Ignácio Zuleide M , Pedro Lucas C , Ceretta Luciane B , Quevedo João , Morales Rodrigo , Reus Gislaine Z , Barichello Tatiana
Published: January 2025

Background

The persistent neurological symptoms seen in long COVID survivors are attributed to immune system dysfunctions and changes in the microbiome induced by SARS‐CoV‐2 infection. In addition to the initial respiratory manifestations, a significant portion of COVID‐19 patients present with neurodegenerative symptoms. Our hypothesis suggests that disruptions in inflammatory signals and alterations in the gut microbiome post‐COVID‐19 play pivotal roles in the development of neurodegenerative complications among individuals experiencing prolonged effects of the disease.

Method

In our cross‐sectional study, we enrolled individuals with post‐COVID‐19 (n = 26) and age‐ and sex‐matched healthy controls (n = 57). Our objective was to conduct a comprehensive examination of neuropsychiatric symptoms, lipid profiles, oxidative stress markers, inflammatory signals, and Alzheimer's disease (AD) markers in plasma samples and gut microbiome status using feces samples from post‐COVID patients. Depressive and anxiety symptoms were evaluated using the Hamilton Rating Scale, while cognitive performance was assessed with standardized measures. The intricate details of the gut microbiome status were revealed through 16S rRNA sequencing.

Result

The investigation uncovered no statistically significant differences in anxiety or cognitive status however the depression was elevated in post‐COVID‐19 as compared to healthy subjects. Further, AD markers (Aβ42, Aβ40, t‐tau, and p‐tau) and oxidative stress markers displayed no discernible distinctions between the two groups. A noteworthy discovery was the significant increase in CCL23, the macrophage inhibitory protein‐3, among COVID‐19 patients. CCL23, known for its role in inflammation and host defense, has recently been linked to neuroinflammation in the early stages of AD. Furthermore, apoptosis markers Caspase‐3 and ‐8 were significantly elevated in COVID‐19 patients. While α‐diversity in the gut microbiome showed no significant differences, β‐diversity indicated a notable distinction between the control and post‐COVID‐19 groups. Furthermore, post‐COVID‐19 individuals displayed a decreased abundance of the phylum Verrucomicrobia and genus Akkermansia, a short‐chain fatty acid producer, and microbial group significantly associated with intestinal barrier permeability and cognitive improvement.

Conclusion

While longitudinal studies are essential for a comprehensive understanding of the behavioral trajectory of COVID‐19 individuals, the current results indicate that CCL23 levels and changes in microbiome status may function as early indicators of post‐COVID neurological and neuropsychiatric outcomes.