bluuebunny/crossref_metadata_2025 huggingface dataset:
Interstitial fluid as a proxy of glymphatic dysfunction in patients with cognitive impairment: The necessity of three‐directional intravoxel incoherent motion
Authors: Thiel Merel M. , Freeze Whitney M. , Jong Joost J. , Ramakers Inez H.G.B. , Backes Walter H. , Jansen Jacobus F.A.
Published: February 2022

Background

IntraVoxel Incoherent Motion (IVIM) MRI can detect an intermediate diffusion component, which is thought to be related to increased interstitial fluid (ISF). However, IVIM imaging with a proper estimation of the diffusion tensor requires a long acquisition time (∼10 min), which is not feasible in clinical practice. This study simultaneously examines the contribution of individual diffusion directions and the potential group differences between patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively normal controls (CN). We foresee to find a higher ISF‐fraction in patients compared with controls, as underlying pathologic processes, e.g. inflammation and oedema, would ultimately lead to loss of tissue structure and increase in ISF.

Method

Patients with AD dementia (n=15) and MCI (n=15), and 33 CNs underwent 3T MRI. IVIM images were acquired with a range of b‐values (10‐1000 s/mm2) in three orthogonal diffusion directions: M (left‐right), P (anterior‐posterior) and S (superior‐inferior) (Fig. 1).

The intermediate diffusion components (Dint) in the range 1.5<Diffusivity<4.0*10‐3 mm2/s, for each direction and average (trace) diffusion images were calculated with spectral analysis and the relative signal contribution of Dint was quantified by the ISF‐fraction (fint). The median values of the parenchymal diffusivity (Dpar), Dint and fint were extracted from the normal appearing white matter and corpus callosum.

Per brain region, the fint, Dpar and Dint values were compared between the subject groups using multivariate linear regression while correcting for age and sex.

Result

Group characteristics and descriptive statistics are shown in Table 1 and 2. Table 3 contains all significant group differences of fint, Dpar, and Dint, derived by the M, P, S and trace images, which shows a higher fint in patients than in CNs. Similar group differences in fint can be obtained from the M‐direction and the trace (Fig. 2)

Conclusion

A higher ISF‐fraction was found in AD patients as compared to CNs, which is expected to point out tissue degeneration. The ISF‐fraction assessed with spectral analysis in IVIM can be considered as a potential non‐invasive biomarker related to glymphatic alterations in brain disease. As the M‐direction was sufficiently sensitive to determine differences in ISF fraction, more clinically acceptable acquisition times can be achieved.
Baseline amyloid and tau PET imaging characteristics in the ongoing phase 2 study of tilavonemab in early Alzheimer’s disease
Authors: Wooten Dustin W. , Guo Qi , Jin Ziyi , Gladstein Scott , Stage Edwin , Hesterman Jacob , Fisseha Nahome , Florian Hana , Comley Robert A.
Published: February 2022

Background

Amyloid and tau are recognized hallmarks of Alzheimer’s disease (AD). Tilavonemab is a monoclonal antibody that binds to the N terminus of human tau and is being developed as a treatment for early AD. The goal of this work is to present the baseline amyloid and tau PET imaging characteristics of patients enrolled in the ongoing phase 2 study of tilavonemab.

Method

453 patients who met the clinical criteria for early AD and had a positive amyloid PET scan (by visual read) at screening were randomized into the study. Amyloid PET was quantified on the standard Centiloid (CL) scale utilizing a processing pipeline developed in‐house and validated using recommended procedures [Klunk, et al., 2015]. Tau PET imaging using 18F‐MK6240 was also performed in a subset of patients to assess presence of tau pathology, the target of tilavonemab, and to monitor disease progression and treatment effects. Here we report baseline tau PET data from 59 subjects randomized into the trial (out of 70 scans collected, not including screen fails or out of baseline window scans). Tau PET was quantified in Braak regions I‐VI using standardized uptake value ratio (SUVR), extent (percentage of voxels within a region above threshold) and load (extent * mean SUVR of voxels within a region above threshold) metrics. Ventral cerebellar gray matter was used as a reference region for SUVR calculation and to determine the subject‐specific threshold needed for the extent and load calculation.

Result

Over 99% of subjects (449/453) had amyloid measurements greater than 20CL, a threshold used for positivity [Burnham, et al., 2020], consistent with visual read; mean±s.d. was 99.0±31.1 CL. For the 59 patients with baseline tau PET data 95% (56/59) were considered to have elevated tau pathology in the brain (SUVR ≥1.27 in the entorhinal cortex [Betthauser, et al., 2020]). The tau metrics for Braak regions I‐VI are summarized in Table 1.

Conclusion

This analysis confirmed the presence of amyloid pathology in the patients randomized into the trial and suggested a high proportion of patients have tau pathology in the brain. Future analyses will examine how tilavonemab effects tau pathology.
Impact of COVID‐19 on family care partners of persons with dementia in long‐term care settings in Canada: Not a ‘one‐size‐fits‐all’ story
Authors: McAiney Carrie A , Boger Jennifer , Conway Emma , Koch Melissa , Beleno Ron , Boscart Veronique , Dupuis Kate , Dupuis Sherry L , Keller Heather , Kuepfer Jane , Lee Linda , Lopez Kimberly , McKinnon Margaret , Taucar Linda Sheiban
Published: February 2022

Background

COVID‐19 has been devastating for older adults, particularly residents in long‐term care/retirement (LTC) homes. In an effort to curb the transmission of COVID‐19, public health measures have been put in place in many LTC homes, including mask wearing, physical distancing, and visitor restrictions. As the pandemic passes the one‐year mark, we are starting to understand the profound impacts of COVID‐19 and the corresponding public health measures on persons living with dementia (PLWD) and their family care partners (CPs). This research is part of a larger study exploring the impact of COVID‐19 on the wellbeing and social connections of PLWD and CPs. In this presentation, findings from qualitative interviews conducted with CPs of PLWD in LTC homes are shared.

Methods

The overall study used an intrinsic case study design, involving survey and interview data. Following completion of a survey, participants were invited to participate in an in‐depth qualitative interview. Interviews were conducted by phone or online, transcribed verbatim, and analyzed using thematic analysis.

Results

Eighteen CPs were interviewed. The impact of visitor restrictions varied between LTC homes and changed over the course of the pandemic, which was extremely challenging for CPs. At homes with visitor restrictions, the inability to visit family members with dementia was described as stressful, unfair, and frustrating. CPs stressed the importance of being able to visit their relatives, and ensuring their family members had regular social interaction to support their physical, social and emotional wellbeing. Even when CPs could visit, masks and physical distancing made communication with some PLWD challenging. Visitor policies also influenced perceptions of care. Some CPs felt that the needs of their family members with dementia were being met by the home, while others weren’t sure because CPs weren’t in the homes to assist staff and provide support to their family members with dementia.

Conclusion

While COVID‐19 and the pandemic restrictions have been difficult for all CPs of persons with dementia in LTC, for some it has been agonizing. Understanding these varied experiences can help inform the development of individually‐tailored resources to better support the wellbeing of CPs.
Modeling resting state MEG functional connectivity of the prodromal phase of AD using The Virtual Brain
Authors: Susi Gianluca , Méndez Isabel Suarez , Verdejo Juan , García María Eugenia López , Cuesta Pablo , Maestú Fernando
Published: February 2022

Background

Computational multi‐scale brain modeling has been found to be a useful tool for identifying potential disease mechanisms in Alzheimer's disease (AD) [1]. Importantly, structural and functional disruption patterns of AD continuum arise from a chain of degeneration effects which take place even from the preclinical phase of the disease, which characterization has the potential to enable early intervention to counteract and delay cognitive decline.

Method

Magnetoencephalography (MEG), T1‐ and dw‐ magnetic resonance imaging (MRI) have been gathered from 20 healthy controls (HC) and 20 mild cognitive impaired (MCI), to characterize their resting‐state functional connectivity (rsFC), and structural connectivity (SC) profiles. Regarding MEG signal, source reconstruction was performed with linearly constrained minimum variance beamformer and the obtained neural MEG sources were anatomically parcellated according to the Desikan‐Killiany atlas. Resting state activity of the participants has been characterized considering two FC indices (i.e., PLV and AEC) among relevant areas of the Default Mode Network (DMN). Personalized simulations of the 40 subjects have been carried out using The Virtual Brain software and the matching between real and simulated rsFC is finally evaluated. For the MCIs two different degradation patterns are introduced in the model, one based on the gray matter volumes, and one that takes in account white matter integrity.

Result

The inclusion of both types of degeneration patterns in key areas of the DMN results in an increase of the matching between real and simulated rsFC for MCI patients; the inclusion of both simultaneously brought the best results.

Conclusion

This study shows how the inclusion of quantifiable signatures of structural degeneration regarding gray matter volumes and white matter integrity in multi‐scale brain models reflects to a better matching between real and simulated MEG‐rsFC, when modeling MCI patients. This complements the already existing studies in the field and provides new insights towards a precise characterization of patient's MEG resting state networks during the early phases of AD. 1 ‐ L. Stefanovski et al., “Linking Molecular Pathways and Large‐Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer’s Disease,” Front Comput Neurosci, vol. 13, p. 54, 2019.
Vascular and inflammatory plasma biomarkers correlate with human post‐mortem cerebral vascular pathology
Authors: Winder Zachary , Lee Tiffany , Abner Erin L. , Nelson Peter T. , Neltner Janna , Jicha Gregory A. , Wilcock Donna M.
Published: February 2022

Background

Vascular Cognitive Impairment and Dementia (VCID) is a common cause of dementia in Western populations. Small‐vessel disease (SVD), a VCID subtype, can present as arteriolosclerosis and microinfarcts. Currently, identifying this pathology clinically is limited to MRI, which is expensive, limited in terms of small vessel resolution and not widely available. Therefore, a more accessible screening tool is needed to clinically evaluate SVD. Here, we evaluate the relationships between vascular and inflammatory plasma biomarkers with global levels of SVD pathology in human brain.

Method

Plasma and brain tissue samples were obtained from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) Brain Bank. Cases were selected from participants who had an available plasma sample from within two years of death. These plasma samples were analyzed using a digital immunoassay (Quanterix Simoa) to determine biomarker levels of placental growth factor (PlGF), matrix metalloproteinase 9 (MMP9), and tumor necrosis factor α (TNFα). Biomarker levels were categorized by quartiles. Pathological evaluation was performed by UK‐ADRC neuropathologists, blind to clinical data. The association of plasma markers with neuropathology was estimated via multinomial and binary logistic regressions adjusted for age and sex. Global arteriosclerosis was examined using a scale of none/mild/moderate/severe, with none being the reference. Presence or absence of microinfarcts was also examined.

Result

Included cases (n=93) were age 82.0±9.2 years at death; 46.7% were female. Higher plasma placental growth factor (PlGF) levels were associated with less severe arteriolosclerosis: odds ratio (OR)=0.8 (95% CI 0.5‐1.3), 0.8 (0.5‐1.5), and 0.6 (0.2‐1.7); higher plasma MMP9 levels were associated with more severe arteriolosclerosis (OR=1.0 (0.5‐2.1), 0.7 (0.3‐1.5), 0.7 (0.2‐2.4), comparing odds of mild, moderate, and severe to none, respectively), though these results were not statistically significant. Lower plasma PlGF and MMP9, and higher TNFa, were associated with higher odds of microinfarction: OR=0.59 (0.33‐1.02), 0.74 (0.38‐1.42), and 2.28 (0.84‐6.20), respectively.

Conclusion

Our results, while based on a small sample, suggest plasma PlGF and MMP9 levels have an inverse relationship with global SVD pathology, while plasma TNFa is positively correlated with increased global SVD pathology. These results provide support for potential use of plasma biomarkers as a clinical screening tool for SVD pathology.
Mealtime nonverbal communications among nursing home staff and residents with dementia: A secondary analysis of videotaped observations
Authors: Liu Wen , Williams Kristine N , Batchelor Melissa , Perkhounkova Yelena , Hein Maria
Published: February 2022

Background

Mealtime difficulties are common among nursing home (NH) residents with dementia. Quality communications between staff and residents are critical to engage residents in eating. This study characterized dyadic nonverbal communications between nursing home staff and residents and evaluated relationships of nonverbal communications with individual characteristics.

Methods

This secondary analysis of 110 videotaped mealtime observations involved 25 residents and 29 staff (42 unique dyads) in 9 NHs. Nonverbal communication behaviors were coded using the refined Cue Utilization and Engagement in Dementia mealtime video‐coding scheme. Codes for staff nonverbal behaviors include 8 negative and 26 positive behaviors (modification for resident ability n=12, care approaches n=7, and dining environment n=7). Codes for resident nonverbal behaviors include 5 positive/neutral behaviors and 22 negative behaviors (chewing/swallowing difficulties n=4, functional impairment n=6, and resistive behaviors n=12).

Results

Staff modifications for resident ability (41.9%) were more prevalent than modifications of care approaches (35.1%) and dining environment (13.6%). Staff negative behaviors (9.3%) (33.5%) were more frequent compared to functional impairment (9.9%). Residents demonstrated positive/neutral behaviors (20.9%). Resident chewing/swallowing difficulties were correlated with resident eating function (p=.002). Resident functional impairment was correlated with staff education (p=.026) and resident age (p=.013), gender (p=.013), and dementia stage (p=.003). Resistive behaviors were correlated with resident comorbidity (p=.003), dementia stage (p=.049), and eating function (p=.001). Resident positive behaviors were correlated with staff race (p=.005) and resident age (p=.002), dementia stage (p=.049), and eating function (p=.002). Modifications for resident functional/cognitive ability were correlated with resident eating function (p<.001), while modifications of care approaches were correlated with staff race (p<.001) and years in current NH (p<.001), as well as with resident gender (p=.003) and eating function (p<.049). Modifications of dining environment were correlated with staff gender (p=.017) and years in current NH (p=.046), as well as with resident dementia stage (p=.008) and eating function (p<.001). Staff negative behaviors were correlated with resident comorbidity (p=.008).

Conclusions

Dyadic mealtime nonverbal communications were dynamic, interactive, and complex. Multiple individual characteristics were related to dyadic nonverbal communications. Findings may inform development of individualized, person‐centered mealtime care interventions.
Plasma TDP‐43 in neurodegenerative diseases assayed with immunomagnetic reduction
Authors: Yang Shieh‐Yueh , Liu H.C. , Chiu Ming‐Jang , Lin Chin‐Hsien , Chen Hsin‐Hsien
Published: February 2022

Background

TDP‐43 is a promising biomarker for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, studies on TDP‐43 in human biofluid are rare. In this work, the authors utilized an ultrasensitive technology, called immunomagnetic reduction (IMR), to develop the reagent for assaying TDP‐43.

Method

The preclinical performance characteristics of the TDP‐43 reagent, such as the standard curve, detection limits, assay linearity, dilution recovery range, assay reproducibility, spike recovery, reagent stability, and interference tests, were explored according to the CLSI guidelines. Plasma samples from normal controls (NC, n = 27) and from patients with frontotemporal dementia (FTD, n = 9), Alzheimer’s disease (AD, n = 34) and Parkinson’s disease (PD, n = 10) were collected for TDP‐43 assays using the IMR TDP‐43 reagent.

Result

The low‐detection limit of assaying TDP‐43 was 0.68 fg/ml, and the upper‐detection limit was 100 pg/ml. There was no significant interference effect when assaying TDP‐43 mixed with hemoglobin, bilirubin, intralipid, albumin, etc. The FTD patients had significantly higher levels of plasma TDP‐43 (0.419±0.193 fg/ml) compared to the NC subjects (0.163±0.097 fg/ml), AD patients (0.165±0.082 fg/ml) and PD patients (0.069±0.068 fg/ml). Through analysis of the ROC curve, the cut‐off value of plasma TDP‐43 for discriminating FTD from the other patient groups was 0.237 fg/ml, which resulted a clinical sensitivity of 0.889 and a specificity of 0.831.

Conclusion

These results demonstrate the feasibility of assaying plasma TDP‐43 to specifically identify FTD.
A role for astrocytes and microglia in synapse loss in Alzheimer’s disease
Authors: Tzioras Makis , Daniels Michael , Davies Caitlin , Hooley Monique , He Xin , Dando Owen R. , Hardingham Giles , McColl Barry , Spires‐Jones Tara L.
Published: February 2022

Background

Neuropathologically, synapse loss correlates most strongly with the progressive cognitive decline observed in Alzheimer’s disease (AD). Despite strong evidence from genetic studies implicating changes in glia as important for disease risk, we are only beginning to understand the role that microglia and astrocytes play in synapse degeneration in AD.

Method

In this study, we have used high resolution imaging of post‐mortem brain tissue to examine whether glia contain synaptic proteins in AD. Cultures of primary mouse and human microglia were exposed to pHrodo‐tagged synapses from human AD or control post‐mortem brain for phagocytosis assays. Mouse models expressing AD associated genes were used for RNA sequencing and translating ribosomal affinity purification (TRAP) followed by RNA sequencing.

Result

We observe both astrocytes and microglia contain synaptic proteins in human AD more than in control brain. Cultured microglia phagocytose synapses from AD brain more and faster than those from control brain. RNA sequencing in AD model mice revealed strong increases neuroinflammatory signals including transcripts expressed in microglia and astrocytes and decreases in transcripts related to synaptic function. When examining the astrocyte specific changes with TRAP, we observed increases in phagosome and lysosome related pathways.

Conclusion

Together, our results indicate that microglia and astrocytes play a role in synapse degeneration or clearance of dead synapses in Alzheimer’s disease.
Effects of 6 months of multicomponent exercise on DTI parameters of MCI in the AD continuum
Authors: Ribeiro Isadora Cristina , Teixeira Camila Vieira de Ligo , Rezende Thiago Junqueira Ribeiro , Magalhaes Thamires Naela Cardoso , Cendes Fernando , Balthazar Marcio
Published: February 2022

Background

The cognitive changes in Mild Cognitive Impairment (MCI) can be associated to the neurodegeneration of Alzheimer´s pathology, such as white matter atrophy. Increasing evidence demonstrates that physical activity is an important modifiable factor not only for cardiovascular fitness, but also for brain health. Therefore, the aim of this study was to analyze possible effects of 6 months of multicomponent exercise (MEP) on structural connectivity of MCI in the AD continuum.

Method

19 MCI subjects were diagnosed using the core criteria of the NIA/AA for MCI and altered CSF amyloid. All of them underwent MRI on a 3.0T Philips Achieva scanner. They were divided into MEP group (3x/week for 6 months) and control group (CG, were stimulated to continue with their normal routine). Aerobic fitness was assessed by graded maximal exercise testing on a motor‐driven treadmill. For WM analysis, we used the Tract‐based‐spatial‐statistics (TBSS) method (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS) to compare the diffusion parameters maps (fractional anisotropy FA, medial diffusivity MD, radial diffusivity RD, axial diffusivity AxD) between times (p‐value<0.05).

Result

Repeated measures Anova indicated significant differences between groups and within groups (p=0.008 and p=0,011, respectively), while MEP showed higher values of VO2max (from 24.0 (4.3) to 27.3 (4.4) ml/kg/min‐1), CG reduced (21.0 (3.8) to 19.7 (2.3) ml/kg/min‐1) after 6 months. TBSS demonstrated an increase in FA and AxD values for MEP while FA and AxD values decreased in CG, in the following areas: corpus callosum, forceps major, corticospinal tract, inferior fronto‐occipital fasciculus, inferior and superior longitudinal fasciculus and cingulum. In the same areas mentioned above, MD and RD values decreased for MEP group and increased for CG after the intervention period.

Conclusion

We found a positive influence of multicomponent exercise under supervision on aerobic fitness and in the DTI parameters of the participants. Six months of MEP seems to increase the white matter integrity of MCI due to AD.
Social contact, social participation, and their changes among elderly people in the United States during the COVID‐19 pandemic
Authors: Zhang Yun , Luo Amber , Hou Luke , Clouston Sean AP
Published: February 2022

Background

The study aims to assess changes of social contact and social participation during the COVID‐19 pandemic among the US elderly, and what roles the prior physical and cognitive performances of the elderly played.

Method

Data were from the National Health and Aging Trends Study (NHATS) COVID‐19 questionnaire in 2020 (n=3,188, response rate=80.5%).1 Data was linked to the 2019 round to include the demographics, physical and cognitive performances of the participants. Participants that reported COVID‐19 diagnosis and symptoms (n=288) and represented by proxies (n=414) were excluded. Frequencies of social contact with family and friends (phone calls/emails/texts/person visits) and with health care providers, and social participation (working, volunteering, attending religious services, and attending organized activities) prior to and during the COVID‐19 were compared using paired t test for summed scores, Wilcoxon signed rank for paired categorical variables, and McNamara test for paired binary variables. Weighted linear and logistic regressions adjusted for multiple covariates were used to investigate the effects of prior physical and cognitive performances on social contact and social participation, prior to, during, and changes in the COVID‐19.

Result

A total of 2,486 participants were included (mean age: 78.24 years; female: 56.20%; non‐Hispanic White: 88.43%). The COVID‐19 resulted in significant increased social contact with family and friends but decreased social participation, among the elderly. Furthermore, elder people with better prior physical performance reported significant increased social contact with family and friends and social participation, both prior to and during the COVID‐19, while they reported significant decreased social participation during the COVID‐19. Specially, better prior physical performance was associated with significant increased video calls and volunteering work during the COVID‐19. However, prior cognitive ability was not found a significant risk factor.

Conclusion

The COVID‐19 pandemic affected the pattern of social contact and social participation of the US elderly. Prior physical performance, rather than prior cognitive ability, significantly affected the social way old people respond to a pandemic crisis.
Cognitive decline and healthy aging: An online activities and psychoeducational program for older adults in the context of COVID‐19 pandemic: Preliminary results
Authors: Feldberg Carolina , Tartaglini María Florencia , Hermida Paula Daniela , Somale Maria Veronica , Orellano Anabell , Ortiz Juan , Teran Claudio , Kasten Sergio , De Cara Josefina , Degtiar Marina , Langer Camilo , Benetti Laureana , Redoni Emiliano , Garcia Claudia
Published: February 2022

Background

The preventive and compulsory social isolation regulations due to COVID‐19 affected the entire population, but this became more emphasized in the group of older adults. Many older adults who attended workshops, retirement centers and clubs had to interrupt their activities. This has impacted negatively on their activity level, socialization, and emotional state. The aim of the present study is to analyze preliminary results of the implementation of an online activities and psychoeducational program to prevent cognitive decline and promote healthy aging habits in older adults who live in Argentina in the context of Covid‐19 Pandemic.

Method

Design: Descriptive study. Subjects: 396 self‐validated older adults, male and female. Instruments: socio‐demographic and social participation questionnaire. Procedure: The intervention consists of a series of workshops (yoga, meditation, gym, singing lessons, memory, preparation for retirement and reflection about grief) and monthly specialist ´s talks on different topics about healthy aging. All the activities where done through zoom platform. All participants where offer one to one capacitation and written material about how to use this platform. Older adults could choose in how many activities they would take part in.

Result

Data of 396 older adults who have taken part in the on‐line version of the program on 2020 indicate that median age was 70.66 years old (ds= 8,7) of which 86 % were women. 73 % took part in specialists talks and 68 % on workshops and talks.

Conclusion

These results provide empirical evidence regarding the need to implement online intervention programs for older adults. Participating in an online educational program could increase participant’s cognitive healthy habits literacy, empowerment and engagement in brain health promotion activities, which in turn could reduce their dementia risk and feeling of loneliness in pandemic context.
Disentangling brain heterogeneity via semi‐supervised deep‐learning and MRI: Application to dimensional representations of Alzheimer’s disease
Authors: Yang Zhijian , Nasrallah Ilya M. , Shou Haochang , Wen Junhao , Doshi Jimit , Habes Mohamad , Erus Guray , Abdulkadir Ahmed , Resnick Susan M. , Wolk David A. , Davatzikos Christos
Published: February 2022

Background

Heterogeneity of neurodegenerative diseases, including Alzheimer’s disease (AD), has hampered precision diagnosis and prognosis. Machine learning methods are able to dissect neuroanatomical heterogeneity and enable identification of disease subtypes via their imaging signatures.

Method

We apply a novel semi‐supervised deep‐learning clustering method to derive dimensions of neurodegeneration, and investigate longitudinal paths in this dimensional system. Analyses used structural MRIs (from the Alzheimer’s Disease Neuroimaging Initiative and the Baltimore Longitudinal Study of Aging; total 2,832 participants; 8,146 scans) including controls and patients with Mild Cognitive Impairment (MCI) and AD.

Result

Smile‐GAN identified 4 neurodegenerative patterns/axes (Figure 1): P1, normal anatomy; P2, mild/diffuse atrophy; P3, focal medial temporal atrophy; P4, advanced neurodegeneration. Further application to longitudinal data revealed two distinct progression pathways: P1→P2→P4 and P1→P3→P4. Clinically, P2 participants showed worse performance in executive function than P3 participants (median ADNI‐EF= ‐0.29 vs. ‐0.1, with p=0.038) but had better memory (ADNI‐MEM= ‐0.13 vs. ‐0.39, with p=0.003) (Figure 2). Progression to P4 occurred more rapidly from P3 than P2, with median survival time to progression of 4.5 years and 3.2 years for P2 and P3 MCI/Dementia participants, respectively. Baseline expression of these patterns predicted the pathway and rate of future neurodegeneration, with high accuracy for determining whether P1 participants would progress and whether they would progress to P2 or P3 (Cox‐proportional‐hazard model average concordance index (CI) on the validation set of 0.8±0.02). Pattern expression offered better performance (CI=0.72±0.02) in predicting clinical conversion from MCI to Dementia compared to amyloid/tau (CI=0.69±0.02), with all three together showing modest improvement over pattern performance (CI=0.76±0.02). A composite risk score comprised of pattern probabilities, Abeta, pTau, presence of APOE E4, and ADAS‐cog score was able to predict survival time with an average concordance index, 0.78±0.02 on randomly split validation sets. (Figure 3).

Conclusion

Four reproducible volumetric patterns, and 2 major longitudinal pathways were revealed using deep learning, which can be determined on an individual patient basis and has implications for rate of future decline. These pattern‐based biomarkers can enrich the N‐dimension of the A/T/N framework which may inform on clinical trial enrollment and monitoring outcomes in a more personalized manner.
Relationship between brain tissue loss and levels of blood biomarkers in patients with Alzheimer’s disease
Authors: Jahng Geon‐Ho , Lee Jiyoon , Rhee Hak Young , Ryu Chang‐Woo , Choe Wonchae
Published: February 2022

Background

The heme oxygenase‐1 (HO‐1) is known as up‐regulator in AD. The peptidylprolyl isomerase A (PPIA) (also known as cyclophilin A, CyPA) provides protection of neurons against copper‐mediated oxidative stress. The inositol‐requiring enzyme 1 (IRE1) is a major stress transducer in endoplasmic reticulum (ER) stress and abnormal protein aggregation. There is no study to evaluate the relationship between gray matter volume (GMV) loss and the three blood‐based biomarkers. Therefore, in this study, we evaluated the relationship between imaging biomarker by GMV changes and blood biomarkers by plasma levels of HO‐1, PPIA, and IRE1 in the groups of cognitively normal (CN), amnestic mild cognitive impairment (MCI), and AD participants.

Method

We obtained MRI and plasma levels of the three blood biomarkers from 45 CN, 34 amnestic MCI, and 39 AD. To assess the relationship between GMV or WMV loss and the three blood biomarkers, the voxel‐based multiple regression analysis was performed for using all participant data. In addition, region‐of‐interest (ROI)‐based analysis was performed to determine correlations between ROI‐based brain tissue volumes and plasma biomarkers. To investigate the relationship between GMV or WMV at each ROI and the plasma levels of HO‐1, PPIA, and IRE1, we performed the Pearson correlation analyses.

Result

The CypA value was significantly positively correlated with MMSE scores. The HO‐1 value was significantly negatively correlated with age, but was positively correlated with the K‐MMSE score. The IRE1 value was significantly positively correlated with age, but was negatively correlated with K‐MMSE scores. GMV was positively correlated with CypA and HO‐1, but negatively correlated with IRE1.

Conclusion

Our study demonstrates that subjects with AD have lower circulating levels of HO‐1 than subjects with MCI and the plasma HO‐1 levels were positively associated with the global GMV. This also shows that subjects with AD have lower circulating levels of CyPA than cognitively normal control and the plasma CyPA levels were positively associated with the GMV whereas subjects with AD have higher circulating levels of IRE1 than subjects with MCI and normal control.
Diagnostic accuracy of the telephone interview for cognitive status (TICS) for the detection of dementia in primary care in the Netherlands
Authors: Abdulrahman Hanna
Published: February 2022

Background

Dementia is underdiagnosed in primary care, partly due to limited time and lack of simple diagnostic tools. In the Netherlands, the Mini‐Mental State Examination (MMSE) is the most frequently used diagnostic tool for cognitive screening in clinical practice. The MMSE has several limitations in primary care. The telephone interview for cognitive status (TICS), might be a simple and accurate alternative for cognitive screening, particularly when in‐person testing is not feasible.

Methods

810 community‐dwelling older people, aged 86.4 years (±2.4SD), with no dementia at baseline, recruited from the prevention of Dementia by Intensive Vascular care (preDIVA) observational extended (POE) trial, and were administered the TICS. Electronic health records of all participants with a TICS ≤30, and a random sample of participants with a TICS‐score >30, were screened for the presence of a dementia diagnosis. Multiple imputation was performed to manage missing data and to correct for verification bias.

Results

19.1% (155/810) of participants had a TICS‐score ≤30, vs 82.1% (655/810) of participants with a TICS‐score >30. Electronic health records reported 8.4% (13/154) of participants with TICS ≤30 had been diagnosed with dementia, versus none of the participants with a TICS‐score >30. The optimal TICS cut‐off score of the imputed data was at ≤30, with a sensitivity of 86.9%, specificity of 94.9%, positive predictive value of 77.4%, negative predictive value 97.2%, and an area under the curve of 90.9% (95%CI=81.2‐90.9).

Conclusion

The TICS seems to be a valid and reliable screening instrument for excluding dementia in primary care, particularly when face‐to‐face screening is not feasible. The ability of TICS to reach large numbers of people at low cost, could contribute to more efficient medical management in primary care.
Altered local gyrification index and corresponding functional connectivity in Alzheimer disease
Authors: Zhao Hui , Shao Peng Fei
Published: February 2022

Background

Cortical gyrification is a promising surface anatomical marker to study Alzheimer disease, however, few studies combined the gyrification and functional connectivity together to explore the Potential mechanism in Alzheimer disease.

Method

The study consisted of three groups, healthy control(n=37), Mild cognitive impairment(n=39), and Alzheimer disease(n=30). Comparison between groups of gyrification was performed using ANOVA within CAT12 and SPM 12, age and cortical thickness were returned as covariates. After the LGI analyses, the surface areas with changed LGI were taken as seed regions for functional connectivity (FC) analyses. Comparison between groups of FCs was performed using ANOVA within dpabi 4.3 and RESTplus; age was returned as a covariate. False discovery rate (FDR)‐corrected and P < 0.05 was considered statistically significant.

Result

Compared with NC and MCI group, we found significantly decreased LGI(local gyrification index) in left insula and right insula, and the changed LGI in bilateral insula was negatively correlated with disease onset age and positively correlated with global cognitive scores. The following functional connectivity analyses identified decreased functional connectivity between right insula and middle temporal gyrus. The decreased functional connectivities were correlated with disease duration, and global cognitive scores.

Conclusion

Our findings revealed abnormal LGI in bilateral insula and the connectivity between right insula and middle temporal gyrus maybe used as imaging metrics of Alzheimer disease.
How do tau PET and amyloid PET imaging markers correlate to changes in grey matter microstructure as detected by diffusion MRI?
Authors: Kullakanda Durga Prasad , Chen Jenny , Ades‐Aron Benjamin , Osorio Ricardo , Fieremans Els
Published: February 2022

Background

Diffusion MRI (dMRI) allows non‐invasive mapping of microstructural changes in the brain. In this study, we assess the relationship between amyloid and tau deposition and grey matter microstructure as detected with diffusion kurtosis imaging (DKI) [1,2]. We hypothesize that inflammation associated with amyloid deposits might result in more restricted diffusion and neuronal death associated with tau pathology might result in less restricted diffusion.

Method

38 cognitively healthy subjects received 3‐T PET‐MR imaging, each including anatomical MPRAGE, DKI and static PET scans either with 18F‐Florbetaben (n=20, 12 females, age = 67.20±5.75 years) or 18F‐MK‐6240 tracer (n=18, 14 females, age = 66.56±5.23 years) to probe amyloid or tau deposition, respectively. For each subject, regions of interest (ROIs) were automatically segmented on MPRAGE using Freesurfer, combined and narrowed down to 4 regions of interest: primary motor cortex as a control, anterior/posterior cingulate cortex as high amyloid regions, and entorhinal cortex as a high tau region. The standardized uptake values in these ROIs normalized to grey matter cerebellum yielded cortical relative SUV (SUVR). DKI processing provided parametric maps of the mean diffusivity (MD), kurtosis (MK) and fractional anisotropy (FA). Pearson correlation between tau PET SUVR/amyloid PET SUVR and MD, FA, and MK was calculated with significance testing.

Result

Correlation analysis (Tables 1, 2) showed positive correlations between amyloid PET SUVR and MD in posterior cingulate cortex, tau PET SUVR and MD in anterior cingulate cortex and posterior cingulate cortex, and tau PET SUVR and MK in primary motor cortex. Negative correlation was observed between PET SUVR and FA in entorhinal cortex.

Conclusion

Increased amyloid and tau burden on PET correlated with less restricted diffusion as indicated by higher MD and lower FA, suggesting sensitivity of dMRI to cortical atrophy and late‐stage neuronal death, as previously observed in cortex and white matter tracts [2, 3]. The current study of healthy controls is limited by the narrow range of amyloid and tau burden. Future work will extend to subjects with mild cognitive impairment. References: [1] Jensen & Helpern, NMR Biomed., 2010(23):698‐710; [2] Dong et al, Neurobiol. Aging 2020(89):118‐128; [3] Montal et al, Alzheimer’s Dement., 2017(14):340‐351.
Formal and informal care use over the course of dementia among adults with limitations in daily activities
Authors: Choi HwaJung , Langa Kenneth M , Norton Edward C , Cho Tsai‐Chin , Connell Cathleen M
Published: February 2022

Background

The dynamics between formal and informal care among persons with an activity limitation may substantially differ over the course of their cognitive decline.

Method

Based on a nationally representative study of older adults, the sample included 3,685 adults (11,856 year‐persons) who had at least one activity of daily living (ADL) limitation at the time of interview and transitioned to dementia between the years of 1998 – 2016. We estimated probabilities of using formal care and informal care in the years prior to and over the course of dementia, after controlling for sociodemographic factors, survey mode, and proxy interview status.

Result

Among study participants with an ADL limitation, the probability of receiving care from an informal helper increased before the onset of dementia: 36% (95% CI 32‐40) in 4 years prior to the onset (T=‐4); 46% (95% CI 43‐50) at T=‐2; and 48% (95% CI 46‐51) at T=0 (onset); the likelihood of receiving care changed very little over the subsequent years of dementia. In contrast, changes in the probability of receiving formal care are pronounced primarily at the onset of dementia. For example, the probability of overnight nursing home stay was significantly greater at the onset of dementia compared to the years prior to the onset: 12% (95% CI 10‐15) at T=‐2 vs. 31% (95% CI 28‐34) at T=0; this increased over the subsequent years of dementia (e.g., 39% at T=6; 95% CI 34‐43). The probability of receiving nursing home care at the onset of dementia was significantly greater for women vs. men (e.g., Adjusted risk ratio (ARR)=1.21; p=0.010); non‐Hispanic white vs. Hispanic (e.g., ARR=1.62; p=0.004); those with low wealth vs. high wealth (e.g., ARR=1.60; p<0.001); those without a spouse vs. with a spouse prior to the onset (e.g., ARR=1.39; p<0.001); and those with all adult children living far vs. at least one coresident adult child prior to the onset (e.g., ARR=1.51; p=<0.001).

Conclusion

Public policies and interventions aimed at planning and providing for the needs of people with dementia should consider disparities in care use over the course of dementia and the potential role of economic resources and family care availability.
A disbalance of matrix metalloproteinases and their inhibitors in the cerebrospinal fluid from patients with cerebral amyloid angiopathy
Authors: Kuiperij H. Bea , Vervuurt Marc , de Kort Anna M. , Kersten Iris , Marques Tainá M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Verbeek Marcel M.
Published: February 2022

Background

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in extracellular matrix (ECM) modelling and regulation of basement membrane integrity. A chronic disbalance in the expression and activity of these proteinases and their inhibitors in favor of MMPs can lead to excessive degradation of the ECM, dysfunction of the blood‐brain barrier (BBB) and subsequent (micro)bleeds. Cerebral amyloid angiopathy (CAA) is characterized by accumulation of the amyloid‐β (Aβ) protein in cerebral vessel walls and decreased BBB integrity, and is a major cause of intracerebral hemorrhage and cognitive decline. Currently, diagnosis of CAA is based on neuroimaging, but there is a need for alternative methods as these neuroimaging methods are not optimal for detection of CAA during life at an early stage. Previously, Aβ40 levels in the cerebrospinal fluid (CSF) have been suggested as promising biomarker for CAA. We hypothesize that a disbalance in MMP/TIMP expression is associated with CAA and is reflected in the CSF, and may besides Aβ40, be a potential biomarker candidate for detection of CAA at an early stage. In this study, we aimed to quantify levels of MMPs, TIMPs and Aβ proteins in the CSF to gain more insight in the pathophysiology of CAA and to establish their potential biomarker value for CAA.

Method

We used immunoassays to quantify MMP‐14, TIMP‐1 and Aβ40 levels in CSF in a group of controls (n=40) and CAA patients (n=28).

Result

The MMP‐14/TIMP‐1 ratio was decreased in CAA (0.016 ± 0.005) vs. controls (0.022 ± 0.008; p=0.0007), which was a stronger difference than observed for either MMP‐14 (not significant: p=0.53) or TIMP‐1 (p=0.0027) alone, or for Aβ40 (p=0.038). The difference of the MMP‐14/TIMP‐1 ratio was robust and remained after correction for age and total protein levels.

Conclusion

Our results suggest that a disbalance in the expression of MMP‐14 and TIMP‐1 in CSF is associated with CAA, and may be a promising biomarker both to identify CAA, with a higher diagnostic value than CSF Aβ40, as well as to obtain more insight into the pathophysiological processes in CAA.
Comparing drawing under instructions with image copying for mild cognitive impairment (MCI) or dementia screening: A meta‐analysis of 92 diagnostic studies
Authors: Bat Baker Kwok Kwan , Chan Joyce YC , Chan Tak Kit , Huo Zhaohua , Yip Benjamin HK , Wong Martin CS , Tsoi Kelvin KF
Published: February 2022

Background

Drawing is a major component of cognitive screening for dementia. It can be performed without language restriction. Drawing pictures under instructions and copying images are different screening approaches. The objective of this study was to compare the diagnostic performance between drawing under instructions and image copying for MCI and dementia screening.

Method

A literature search was carried out in the OVID databases with keywords related to drawing for cognitive screening. Study quality and risk of bias were assessed by QUADAS‐2. The level of diagnostic accuracy across different drawing tests were pooled by bivariate analysis in a random effects model. Summary estimates of sensitivity and specificity with 95% CI and prediction region were presented in a hierarchical summary receiver operating characteristic (HSROC) curve. The area under the hierarchical summary receiver‐operating characteristic curve (AUC) was constructed to summarize the diagnostic performance.

Result

Ninety‐two studies with sample size of 22,085 were included. The pooled results for drawing under instructions showed a sensitivity of 79% (95% CI: 76 – 83%) and a specificity of 80% (95% CI: 77 – 83%) with AUC of 0.87 (95% CI: 0.83 – 0.89). The pooled results for image copying showed a sensitivity of 71% (95% CI: 62 – 79%) and a specificity of 83% (95% CI: 72 – 90%) with AUC of 0.83 (95% CI: 0.80 – 0.86) (Fig. 1). Subgroup analysis for the diagnostic accuracy for MCI and dementia showed that both drawing under instructions and image copying have better diagnostic performance for patients with dementia. The AUC of drawing under instructions and image copying for patients with dementia were 0.88 (95% CI: 0.85 – 0.91) and 0.85 (95% CI: 0.82 – 0.88) and the AUC for patients with MCI were 0.77 (0.73 – 0.80) and 0.73 (95% CI: 0.69 – 0.77), respectively. Most of the studies used clock‐drawing test as the screening test.

Conclusion

Drawing under instructions showed a similar diagnostic performance when compared with image copying for cognitive screening and the administration of image copying is relatively simpler. Self‐screening for dementia is feasible to be done at home in the near future.