bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural covariance in the affective pain network in Alzheimer’s disease
Authors: Iversen Wm. Larkin , Monroe Todd B. , Failla Michelle D.
Published: February 2022

Background

Pain consists of both sensory and affective networks. Literature exploring the effect of Alzheimer’s disease (AD) on pain is limited. Some evidence suggests that the affective networks are impacted earlier while the sensory networks are preserved until late in the course of disease (Cole 2006). To examine the preservation of networks underlying pain perception in AD, we examined the structural covariance of regions in the pain network. Using structural MRI (sMRI) data, we investigated structural covariance by modeling a network from the correlation of volume between regions. In structural covariance, path length represents the minimum number of steps that must be taken to travel between two nodes and may serve as a proxy for structural brain integrity. Characteristic path length averages together the path lengths for all nodes in a given a priori network to create a global network metric (Paldino 2017). We hypothesized that there would be alterations in altered characteristic and nodal path length in individuals with AD.

Method

As part of a larger study, cortical volume measurements were obtained for 78 participants (39 AD, 39 HC) via Ma‐CRUISE mutli‐atlas segmentation (Huo 2016). The affective pain network consisted of bilateral: anterior and posterior insula, amygdala, anterior cingulate cortex (ACC), and dorsolateral pre‐frontal cortex (dlPFC, specifically the superior frontal and medial frontal gyri, Woo 2017). The analysis was conducted in BRAPH using a undirected weighted graph with negative correlations set to zero. (Mijalkov 2017). Only characteristic and nodal path length were included in this analysis as these metrics are more robust for discriminating differences in AD (Mårtensson 2018).

Result

No significant differences were found for characteristic path length between groups (p = > 0.05). Additionally, no significant differences were found in path length for any of the nodes analyzed following correction with the Benjamini‐Hochberg procedure (Q = 0.05).

Conclusion

Preservation of characteristic and nodal path length metrics in the affective pain network provides preliminary evidence that this network may be preserved in mild to moderate AD. This clinically meaningful finding provides further evidence indicate that affective pain may be preserved longer than originally thought during the course of AD.
α‐Synuclein in oligodendroglia and neuron‐derived blood exosomes distinguishes between synucleinopathies
Authors: Dutta Suman , Hornung Simon , Kruayatidee Adira , Maina Katherine M , del Rosario Irish , Paul Kimberly , Palma Jose Alberto , Perlman Susan L. , Poon Wayne W. , Gylys Karen H , Kaufmann Horacio , Fogel Brent L. , Bronstein Jeff M. , Ritz Beate , Bitan Gal
Published: February 2022

Background

Synucleinopathies are neurodegenerative diseases characterized by aggregation and deposition of α‐synuclein in different brain cells. Diagnosis of these neurological disorders is very challenging due to overlapping complex clinical symptoms. Developing reliable biomarkers that can distinguish among the synucleinopathies is an urgent public health need. Recently, α‐synuclein was shown to transfer via exosomes between different brain cells suggesting that measuring α‐synuclein in specific brain cell‐derived exosomes could serve as a potential biomarker for synucleinopathies.

Method

In this study, we used antibody‐coated magnetic dynabeads to immunochemically enrich specific exosomes released by neurons or oligodendrocytes from serum of healthy individuals and patients with Parkinson’s disease (PD) and Multiple System Atrophy (MSA) and measured biomarker concentration in them by a sensitive electro‐chemiluminescence ELISA. CNS exosomes were isolated from serum/plasma from a discovery cohort and a validation cohort containing 50 patients with MSA, 50 patients with PD and 50 healthy controls in each cohorts.

Result

Significantly higher concentrations of α‐synuclein were observed in both neuronal and oligodendroglial exosomes from patients than in controls. The absolute values of α‐synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the MSA and PD groups, yet the ratio between the two cell types derived exosomal α‐synuclein allowed separating the two disease groups with 90.0% sensitivity and specificity.

Conclusion

α‐Synuclein in CNS‐derived blood exosomes provides a sensitive biomarker for distinguishing these two synucleinopathies using a blood test and suggest that the method can be expanded further for other neurodegenerative diseases.
Psychological influences of architecture on the demented in the care homes of Kerala, India
Authors: Krishnan Kavya P
Published: February 2022

Background

Our built environments have a direct relationship with our mental and physical health. The effects of this relationship are only heightened with age, especially when the process of ageing entails psychological, and physical decline of the human body. This is where the art of space making can elevate the quality of life of the fading. This paper discusses how an architect can create an environment that triggers positive neurological changes in its users in the context of Kerala, India through a set of design guidelines for care environments. Dementia, a public health priority, is largely prevalent in the state as it comprises of the fastest ageing population in the country. There are no designed living environments nor existing guidelines/protocols by which a care facility must abide in order to offer specialized care in this field.

Method

Understanding the current context and background of dementia in the country and in Kerala. This defines the area of research and specifies the objectives to be achieved to formulate the design guidelines. It’s vitally important when designing a facility to understand the residents’ conditions, state of mind and the way they use or interact with the building. This is done through literature reviews which understands and studies dementia, the psychological impacts of home and existing design principles. To understand the theories in practice, five case studies are observed from around the world and compared along with survey responses from neurologists and caretakers.

Result

The analysis of the data manifests the efficacious relationship between designed spaces and standard of living ergo guiding the development of design strategies for dementia care facilities in Kerala. The guidelines are categorized under the following after data collection and research:‐ Spatial Quality: Layout and distribution, Communal Spaces and Communal Activities, Personal Space: (Lighting, Material and Colour), Landscape, Way finding, Security.

Conclusion

The guidelines are designed to help architects, or any caretaker, make better, more informed design decisions. Establishing the design guidelines will help improve the quality of life and the living environment of the ageing with dementia.
It takes two: APOE4 and air pollution synergistically affect hippocampal volume in women
Authors: Ukraintseva Svetlana , Popov Vladimir , Arbeev Konstantin , Duan Matt , Yashin Anatoliy
Published: February 2022

Background

The APOE e4 allele (APOE4) is the strongest genetic risk factor for Alzheimer's Disease (AD), and exposure to air pollution is emerging as a major environmental AD risk factor. These factors, individually, do not explain most of AD cases though. It is possible that more than one “hit” is required for AD to develop, so different risk factors acting together might synergistically promote AD‐related pathology.

Method

In this study, we explored how different combinations of APOE4 carrier status and exposure to traffic‐generated air pollution may influence right hippocampal volume (RHV) in 10,623 females and 9,682 males aged 60‐75, using the UK Biobank Resource. The higher exposure to traffic pollution was approximated by closeness (50 meters or less) of subject’s primary residence to a major road. The APOE4 status was defined as carrying C allele of rs429358. The RHV was evaluated by the magnetic resonance imaging (MRI). We performed the analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) test.

Result

The RHV was significantly lower in female APOE4 carriers who live 50 meters or less from a major road (N=199) compared to non‐carriers living farther from the road (N=7195) (P‐Value=0.01). Separately, APOE4 or closeness to the road did not significantly influence RHV in females. No significant effects were found in males.

Conclusion

Two hits (APOE4 and high exposure to car exhaust fumes) may be needed to cause brain changes associated with AD pathology, such as reduced RHV. A major component of car exhaust fumes is nitrogen oxides that have been linked to disruption of blood‐brain barrier and increased brain permeability to toxins. The APOE4 was previously associated with reduced myelin damage repair. A potential mechanism might, therefore, involve a synergistic effect of increased brain permeability to damaging factors and decreased brain ability to repair relevant damage. Results of this study also suggest that negative effects of the strongest genetic risk factor for AD (APOE4) on the brain may be attenuated by avoiding damaging exposures, such as to air pollution from car exhaust fumes.
Individual level prediction of cognitive impairment status from neuronal networks using machine learning in the Alzheimer’s Disease Connectome Project
Authors: Kulkarni Arman P. , Adluru Nagesh , Nair Veena A. , Li Shi‐Jiang , Meyerand Elizabeth M. , Alexander Andrew L. , Bendlin Barbara B. , Prabhakaran Vivek
Published: February 2022

Background

Alzheimer’s disease dementia (AD) and mild cognitive impairment (MCI) are characterized by degeneration of myelinated axonal fiber bundles which subserve network connectivity, and degeneration of which ultimately leads to the dementia syndrome. Most of the prior disease related findings derived from diffusion weighted magnetic resonance imaging (dMRI) are based on group comparisons, although individual‐level measures of abnormality would have greater clinical utility as well as serve clinical trial enrichment and provide novel outcome measures. In this study, fiber bundle capacity (FBC) was employed to derive a proxy for “communication bandwidth” between brain regions based on dMRI. The purpose of this study was to perform a preliminary investigation of individual level predictive value of FBC based neuronal networks in the Alzheimer’s disease connectome project using machine learning.

Method

Multi‐shell dMRI data (Table‐1) were processed using a state‐of‐the‐art ‘connectography’ pipeline using FSL, ANTS and MRtrix3. The IIT‐Desikan atlas with 84 nodes was used to derive 3486 neuronal connections (FBC‐edges). FBC‐edges, after feature preprocessing, were input into a stratified three‐fold nested leave‐one‐out cross‐validation framework with a random forest classifier for binary classification (cognitively unimpaired (CU) vs. MCI/AD). Recursive feature elimination was employed in the outer loop to aid with the interpretation of predictive features. Receiver‐operating‐characteristic curves were derived per outer fold, and the area under the curves (AUC) were reported.

Result

The average AUC was 0.73 as shown in Fig‐1, with additional cross‐validation accuracies and test‐set accuracies shown in Table‐2. The top (20) features per outer fold are reported in Fig‐2.

Conclusion

FBC based neuronal networks offer significant predictive value in differentiating the MCI/AD brain from that of the CU brain at an individual level, indicating alterations in information pathways across the brain. Depending on the fold, there were alterations in FBC connections 1) involving the right parietal lobe, and in particular, the precuneus to the left parietal lobe, 2) parietal‐parietal, parietal‐temporal, and parietal‐frontal interactions, and 3) left parietal interactions and intratemporal interactions. Connections of the precuneus with other nodes were predominant across all folds. Future work will determine the extent to which these metrics are predictive of amyloid burden among individuals with asymptomatic preclinical AD.
Unfolding the medial temporal lobe to characterize neurodegeneration due to Alzheimer's disease pathology
Authors: Ravikumar Sadhana , Wisse Laura , Lim Sydney A. , Ittyerah Ranjit , Xie Long , Bedard Madigan L. , Das Sandhitsu R. , Irwin David J. , Lee Eddie B. , Tisdall Dylan M. , Prabhakaran Karthik , Detre John A. , Trojanowski John Q. , Robinson John , Schuck Theresa , Grossman Murray , Mizsei Gabor , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , del Mar Arroyo Jimenez Maria , Munoz Monica , Romero Francisco Javier Molina , del Pilar Marcos Rabal Maria , Sanchez Sandra Cebada , Gonzalez Jose Carlos Delgado , de la Rosa Prieto Carlos , Parada Marta Corcoles , Wolk David A. , Insausti Ricardo , Yushkevich Paul A.
Published: February 2022

Background

Measurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we directly link changes in MTL structure to underlying NFT pathology by combining ex vivo MRI with ratings of NFT severity derived from serial histology using a dataset of 18 human MTL specimens. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.

Method

Ex vivo specimens from 18 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. Following MRI scanning, the specimens underwent histological processing with staining for cytoarchitecture and in 15 specimens, immunohistochemistry (IHC) with the anti‐tau AT8 antibody. Using a topological unfolding method (DeKraker et al. 2018), we created 2D representations of the extra‐hippocampal cortex which implicitly align cortical folding patterns across specimens (Fig. 1). An average MTL subregion segmentation was generated in unfolded space using manual segmentations completed in 11 specimens on the basis of cytoarchitecture. Additionally, heat maps quantifying NFT burden in each of the specimens with anti‐tau IHC sections were generated using a deep learning algorithm (Yushkevich et al. 2021). Using the heatmaps and the average subregion segmentation, we investigated the relationship between NFT severity and cortical thickness.

Result

Correlation analysis between NFT measures and thickness (correcting for age) reveals strong associations in the entorhinal cortex and the border of Brodmann Area 35, consistent with the early Braak regions, and parts of Brodmann Area 36 (Fig. 2).

Conclusion

We present an unfolding framework applied to the MTL cortex, which allows us to visualize, for the first time, the distribution of MTL subregions and NFT pathology in an unfolded space. This framework provides a promising tool for detailed investigation of structural changes due to NFT pathology while explicitly accounting for the complex topology of the MTL, thereby enhancing our understanding of early AD.
Characterization of vascular dementia with TMS: A systematic review and meta‐analysis
Authors: Salcido‐Montenegro Alejandro , Quintanilla‐Sanchez Carolina , Nañez‐Terreros Homero
Published: February 2022

Background

Vascular dementia (VaD) is the second most common cause of dementia. However, the variety of lesions in different vessels make VaD heterogeneous. VaD has been studied using transcranial magnetic stimulation (TMS) in patients with multi‐infarct dementia, subcortical ischemic vascular dementia (SIVD), and with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is, however, some controversy about the reported impairment in cortical excitability and cortical circuits in VaD(1–5). Therefore, we reviewed systematically TMS characterization in patients with VaD.

Method

We conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to VaD and TMS and was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies, comparing any type of VaD to healthy controls (HC) using TMS. Case reports and series were excluded. Risk of bias was assessed using QUADAS. Meta‐analyses comparing various TMS parameters between VaD and HC were conducted. Demographic data (age, sex, comorbidities, years of education, onset age, diagnosis information), subtype of vascular dementia, reference standard, and TMS parameters were extracted.

Result

After duplicates were removed our search yielded 216 results. After applying the eligibility criteria, 26 articles were fully screened and finally 8 articles were reviewed and included in the meta‐analysis(4–11). A total of 145 patients with VaD were analyzed, and most of them had SIVD (69.65%) and CADASIL (11.72%); 140 HC were also analyzed. When compared VaD patients to HC, the mean differences of resting motor threshold (RMT) and short‐latency afferent inhibition (SAI) values were statistically significant (Fig 1‐2).

Conclusion

This is the first systematic review to describe the differences of TMS parameters between patients with VaD and HC. RMT and SAI values were significantly altered in patients with VaD suggesting that both cortical excitability and cholinergic transmission are affected. These parameters could be further used to understand the impact of vascular events in neurotransmission. Furthermore, because of the difficulty of detecting vascular lesions in structural imaging studies, TMS characterization may allow a clearer diagnosis of VaD.
Association between basal forebrain tau and memory in older adults without dementia
Authors: MacAlpine Maiya F. , Bañuelos Cristina , Resnick Susan M. , Bilgel Murat , Shafer Andrea T
Published: February 2022

Background

Tau pathology is a hallmark of Alzheimer’s disease and can be assessed in vivo using 18F‐Flortaucipir positron emission tomography (PET). Recent literature suggests a role of the basal forebrain (BF) early in tau accumulation pathways, but knowledge on BF tau and cognition is limited. We assessed the utility of BF flortaucipir PET signal and its relationship with cognition in a sample of individuals without dementia.

Method

114 older adults in the Baltimore Longitudinal Study of Aging underwent flortaucipir PET imaging. Standardized uptake value ratio (SUVR) was computed in regions of interest (ROI’‐s) (BF, entorhinal cortex (EC), hippocampus (HC)) and in a control region with no tau pathology (4th ventricle, including choroid plexus). 110 participants had concurrent and prospective cognitive testing (memory). The relationship between BF SUVR and cognition was assessed with correlation and linear mixed effects models.

Result

4th ventricle SUVR was positively associated with SUVR of the EC (Pearson’s r=.33, p<.001) and HC (r=.55, p<.001), but not the BF (r=.16, p=.10). In unadjusted analyses, higher BF SUVR was associated with amyloid positivity (difference in means=.12, p=.01) and lower memory (r=‐.21, p=.03) at baseline. There was no association between baseline BF SUVR and concurrent or prospective change in cognition once adjusted for age, sex, and education.

Conclusion

The lack of a relationship between BF and 4th ventricle SUVR may indicate lower susceptibility of BF to non‐specific binding signal spillover compared to the EC and HC. BF SUVR was associated with amyloid positivity and memory in the expected directions, but the association with memory was not statistically significant after controlling for factors relevant to cognition. Further analysis is necessary to assess whether the lack of an association with cognition is due to limited statistical power.
Towards fingerprinting and identifiability within the Alzheimer’s continuum using resting‐state functional connectivity
Authors: Stampacchia Sara , Asadi Saina , Ribaldi Federica , Tomczyk Szymon , Altomare Daniele , Pievani Michela , Frisoni Giovanni , Amico Enrico , Garibotto Valentina
Published: February 2022

Background

Resting‐state functional connectivity (FC) has been extensively investigated in AD and yet its susceptibility to noise prevents its use as biomarker. Moreover, previous studies focused on group averages, overlooking heterogeneity among individuals and often lacked characterisation of amyloid and tau pathology. Recently, it has been showed that FC‐patterns are reliable across test‐retest in the healthy, and that they can be used to identify a given individual from a population (Finn et al., 2015), hence constituting a “fingerprint”. Yet, it is unclear whether FC‐fingerprints could be used for mapping disease from human brain data. To this aim, here we investigate the associations between brain connectivity fingerprints and measures of AD pathology.

Method

We analysed memory‐clinic individuals having rs‐fMRI (N=85) and explored associations with ATN biomarkers and clinical measures – acquired within a maximum gap of 20 months – using structural MRI, amyloid‐PET, tau‐PET and neuropsychology. For each participant, a functional connectome (FC) was computed as matrix of pairwise Pearson correlations between 278 grey‐matter regions. FC‐fingerprint was computed as (i) test‐retest reliability across the first 100 and second 100 volumes within the same scan (I‐self) and (ii) similarity scores of each patient’s FC profile against controls (N=16 cognitively unimpaired amyloid negative; I‐clinical). FC and FC‐fingerprint measures were extracted within‐and‐between 7+1 cortical and subcortical resting state networks.

Result

FC‐patterns resembled those previously found in the literature, i.e., reduction in FC for cognitively impaired (CI, N=61) vs. unimpaired (CU, N=24) in the Default Mode network (DMN) yet comparisons did not survive FDR 𝛼=.05. All cases showed higher similarity with themselves (I‐self) as opposed to others, with no differences across groups, confirming the reliability of fingerprinting in AD. I‐clinical (i.e., similarity to controls) was significantly higher in CU+ (N=8; CU amyloid or tau positive) vs. CI (N=61) in Salience, DorsalAttention‐Frontoparietal and Salience‐Frontoparietal networks (FDR 𝛼=.05), showing deviation from normality. Finally, while FC measures were not significantly associated with AD biomarkers, we found associations between I‐clinical and I‐self with ATN measures (Amyloid & TauSUVRs and hippocampal volume; FDR 𝛼=.05).

Conclusion

These results suggest that FC‐fingerprinting could constitute a new promising biomarkers of brain dysfunction in AD.
Baseline neuroimaging characteristics in the randomized pivotal study of renew NCP‐5 for the treatment of mild cognitive impairment (MCI) due to Alzheimer's disease or mild dementia of the Alzheimer's type
Authors: Salat David H. , Almaktoum Randa , Helfgott Jonathan S. , Helmer Karl G. , Jacoby John , Jang Ikbeom , Juttukonda Meher R. , Loveley Allison , Moreno Tom , Peled Noam , Stufflebeam Steven , Greve Douglas N.
Published: February 2022

Background

Renew NCP‐5 is an FDA‐cleared, external counterpulsation (ECP) device used clinically to improve coronary and peripheral vascular hemodynamics by sequential compression and decompression of vascular beds in synchrony with the cardiac cycle. NCP‐5 treatment may have a beneficial effect on disorders of blood flow including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We describe here the baseline neuroimaging characteristics of the participants from a randomized pivotal study of Renew NCP‐5 for the treatment of MCI due to AD or mild dementia of the Alzheimer's type.

Method

Neuroimaging was conducted across ten sites in the United States for safety screening, baseline imaging assessment including disease severity, and for acquisition of exploratory neuroimaging markers of treatment modification. Imaging protocols were based on the cross‐platform protocols developed for the Alzheimer's Disease Neuroimaging Initiative (ADNI3). Participant characterization and exploratory outcome neuroimaging measures included T1‐weighted hippocampal volume and arterial spin labeling‐based measures of cerebral blood flow (CBF).

Result

Baseline structural data were acquired in 97 participants in the NCP‐5 group, and 89 participants in the active sham group. ASL data were available on a subset of scanners and acquired in 60 participants in the NCP‐5 group and 48 participants in the active sham group. Baseline neuroimaging assessment revealed expected variation with age and disease severity in the total cohort. A difference in baseline hippocampal volume and CBF was detected between the randomized groups with the NCP‐5 group having reduced measures (reduced hippocampal volume and reduced CBF) compared to the active sham group. These effects were apparent when splitting the treatment groups by disease severity and cardiovascular risk.

Conclusion

We present here the baseline characteristics for the participant cohort for the randomized pivotal study of Renew NCP‐5 for the treatment of MCI due to AD or mild dementia of the Alzheimer's type. Imaging measures were in accord with expected directional effects for age and for disease. There was an unexpected difference between the NCP‐5 treatment and active sham group at baseline with the NCP‐5 group having greater neurodegeneration. Longitudinal imaging data are being examined in ongoing work.
Loneliness, social connectedness, and resilience during COVID pandemic among those with and without cognitive impairment
Authors: Padala Kalpana P , Wilson Kerrie B , Jendro Ashlyn M , Crawford Christina G , Gauss C Heath , Das Aparna , Padala Prasad R
Published: February 2022

Background

Loneliness in older adults is multifactorial. Social connectedness and resilience are protective against loneliness and have been adversely affected by the COVID pandemic. The objective was to measure loneliness in older adults with and without cognitive impairment and to compare the interaction of loneliness with resilience and social connectedness in these subgroups.

Methods

A cross‐sectional study was conducted in community dwelling older adults (N=254) (November 2020‐ongoing). Demographic data were collected along with variables related to social determinants of health. Loneliness was assessed with the 3‐item loneliness questionnaire, resilience with the Brief Resilience Coping Scale (BRCS) and social connectedness using the 6‐item Lubben social network scale.

Results

Mean age was 74.6 (±8.0) years, 93.7% male, 50.8% rural, 79.5% Caucasian, and 17.3% African American. Mean education was 14 years (±2.4). The majority of the participants reported loneliness (57.5%). Mean Lubben social network score was 14.7 (±7.1) and mean resilience score was 15.0 (±4.1). Loneliness was higher in those living alone compared to those living with someone (5.6 vs. 4.6, p<0.001, 95% CI: ‐1.6, ‐0.48). There were strong negative correlations between social connectedness and loneliness (p<0.001, r=‐0.43) and resilience and loneliness (p=0.001, r=‐0.19). Compared to those without cognitive impairment (N=151), participants with cognitive impairment (N=101) had a significantly lower mean social network score (p=0.007, 95% CI: 0.69, 4.23). Compared to those without cognitive impairment, participants with cognitive impairment had lower mean resilience score, however the difference was not statistically significant (p=0.080, 95% CI: ‐0.11, 1.97). T‐MoCA and FAQ mean scores for the cognitively impaired older adults were 15.2 (±4.6) and 8.0 (±9.3), respectively. The strong negative correlation between resilience and loneliness scores persisted in the subgroup with cognitive impairment (p=0.028, r=‐0.22).

Conclusions

Loneliness was commonly reported among older adults during the COVID pandemic. Loneliness was negatively correlated with social connectedness and resilience. Compared to cognitively intact counterparts, those with cognitive impairment reported significantly lower social connectedness. This finding indicates that those with cognitive impairment may need more attention during natural disasters that foster physical separation.
Determination of diagnostic cutoffs for tau‐PET: A preliminary study based on tau and beta‐amyloid PET measurements
Authors: Pereira Helena Rico , Ferreira Hugo Alexandre
Published: February 2022

Background

Alzheimer’s Disease (AD) is characterized by abnormal concentration of beta‐amyloid (AB) and tau proteins which can be assessed using positron emission tomography (PET). Currently, no relative standardized uptake value (rSUV) cutoff defines an AD diagnostic tau‐PET, and the literature is mainly focused on defining a cutoff per Braak stage which correlates with disease progression.

Method

In this study, we used tau‐rSUV values of cortical and subcortical regions to define three diagnostic cutoffs for tau‐PET using age‐ and gender‐matched data (average age = 72.9 ± 7.36 y.o.; gender = 56.1% male) of AD and mild cognitive impairment (MCI) patients, and cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative. The diagnostic groups were: 1) CN (n = 54) vs MCI and AD (nMCI = 46, nAD = 14); 2) AB negative CN (n = 35) vs AB positive MCI and AD (nMCI = 26, nAD = 12); and 3) AB negative (n = 87: 65 CN, 20 MCI, 2 AD) vs AB positive (n=73: 36 CN, 26 MCI, 12 AD).

Tau‐rSUV values were normalized for each region volume using the inferior cerebellum as a reference. Regions that provided significant differences in rSUV values between the diagnostic groups were considered to compute a composite tau‐rSUV value. Then, for each case, a cutoff value was defined using the composite tau‐rSUV value that maximizes the chi‐square statistic value with the highest significance.

Result

For the case CN vs (MCI+AD) the diagnostic cutoff tau‐rSUV value was 1.10 (Qui‐square = 19.9; p‐value < 0.001); for AB negative CN vs AB positive MCI and AD the cutoff tau‐rSUV was 1.16 (Qui‐square = 30.3; p‐value < 0.001); while in AB negative vs AB positive the cutoff tau‐rSUV was 1.21 (Qui‐square = 31.0; p‐value < 0.001).

Conclusion

Our diagnostic cutoff tau‐rSUV values are within the interval of values [1.19 to 1.34] previously reported [1]–[3]. The results highlight that the cutoff values are related to AB status: if the latter is unknown, the cutoff may be more restricted; while the third cutoff indicates that AB negative MCI and AD subjects already show the presence of tau protein.
Reduced brain atrophy by gamma sensory stimulation in Alzheimer’s disease patients
Authors: Hajos Mihaly , Megerian Jonathan Thomas , Hempel Evan , Vaughan Brent , Malchano Zach
Published: February 2022

Background

Accelerated brain atrophy, correlating with cognitive decline and loss of function in Alzheimer’s disease (AD) patients compared to age‐matched healthy subjects is well established. Since recent experimental findings demonstrated that sensory‐evoked brain gamma oscillation reduces brain atrophy and neurodegeneration in AD‐related transgenic mice, effects of gamma sensory stimulation were explored on brain volumetric changes in AD patients.

Method

Patients with clinical presentation ranging from prodromal to MCI and mild‐moderate AD (MMSE 14‐26, inclusive; n=74) were randomized 2:1 to receive daily, one‐hour, EEG‐calibrated, 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Brain volumetric changes, including whole brain (excluding CSF/ventricles), lateral ventricle and hippocampal volumes were assessed by MRI, taken at baseline and after 6‐months of treatment. Assessments of occipital and temporal lobe volumes and temporal lobe composite cortical thickness are currently in progress.

Result

Quantitative MR imaging analysis revealed that whole brain volume loss in the sham group (n=19) was 1.5%, comparable to the historic value of 1.12% in this patient population, whereas in active treatment group (n=30) whole brain volume loss was 0.6%, demonstrating a significant, 65% reduction in brain atrophy (p<0.01) by gamma sensory stimulation over a 6‐month period. No significant differences in volumes of lateral ventricles or hippocampi were detected between groups.

Conclusion

Brain atrophy in patients on the AD spectrum was significantly reduced by gamma sensory stimulation indicate potential disease‐modifying effects of this therapy. These findings are in accord with a recent report of reduced brain atrophy in mild AD patients by applying the same therapy (medRxiv 2021.03.01.21252717).
The impact of mild cognitive impairment on the neural dynamics serving verbal working memory
Authors: Proskovec Amy L. , Davenport Elizabeth M. , Bell Natalie , Rossetti Heidi , Cullum Munro , Longoria Anthony , Berry Jarett D. , Maldjian Joseph
Published: February 2022

Background

In healthy adults, neural oscillatory activity within a predominantly left‐lateralized network of brain regions underlies verbal working memory (VWM) performance, but how mild cognitive impairment (MCI) impacts these oscillatory dynamics is not well characterized. The present study utilized the spatiotemporal precision of magnetoencephalographic (MEG) brain imaging to investigate the effects of MCI on the neural oscillations serving specific phases (i.e., encoding, maintenance) of VWM. In congruence with the compensation‐related utilization of neural circuits hypothesis (CRUNCH), we hypothesized that MCI patients would recruit greater neural resources during VWM.

Method

Sixty‐one adults (13 clinically‐diagnosed MCI, 48 controls; 28 females; M age: 63.5) completed a Sternberg‐type VWM task during MEG. Only correct trials were analyzed, and the average number of trials included did not differ between groups. All MEG data underwent standard preprocessing, were transformed into the time‐frequency domain, and significant neural oscillatory responses relative to baseline were imaged using a beamformer. To determine the effect of group (MCI vs. controls), ANCOVAs were performed on the resulting encoding and maintenance whole‐brain maps with age as a covariate.

Result

Throughout encoding and maintenance, decreases in alpha/beta (9‐16 Hz) oscillatory activity were seen in left fronto‐temporal regions, which were significantly larger in MCI patients during the encoding phase (p < .05, corrected). Additionally, significant group differences were detected in right inferior frontal and superior temporal cortices throughout both encoding and maintenance, such that MCI patients exhibited decreased alpha/beta activity within these regions, while these responses were largely absent in controls (p < .05, corrected). Interestingly, the strength of the alpha/beta response within the right inferior frontal cortex significantly predicted behavioral performance on the task, such that individuals who demonstrated stronger decreases in alpha/beta within this region during encoding and maintenance, tended to have faster reaction times (p < .01).

Conclusion

While both groups recruited a similar left‐hemispheric cortical network during VWM encoding and maintenance, individuals with MCI recruited some nodes more strongly and additionally recruited right fronto‐temporal regions. Additionally, stronger recruitment of the right inferior frontal cortex was beneficial for task performance. These results offer supporting evidence for CRUNCH.
B vitamin intakes modify the association between particulate air pollutants and incidence of all‐cause dementia: Findings from the Women's Health Initiative Memory Study
Authors: Chen Cheng , Whitsel Eric A. , Espeland Mark A. , Snetselaar Linda , Hayden Kathleen M. , Lamichhane Archana P. , Serre Marc L. , Vizuete William , Kaufman Joel D. , Wang Xinhui , Chui Helena C. , D'Alton Mary E. , Chen Jiu‐Chiuan , Kahe Ka
Published: February 2022

Introduction

Particulate air pollutants may induce neurotoxicity by increasing homocysteine levels, which can be lowered by high B vitamin intakes. Therefore, we examined whether intakes of three B vitamins (folate, B12, and B6) modified the association between PM2.5 exposure and incidence of all‐cause dementia.

Methods

This study included 7183 women aged 65 to 80 years at baseline. B vitamin intakes from diet and supplements were estimated by food frequency questionnaires at baseline. The 3‐year average PM2.5 exposure was estimated using a spatiotemporal model.

Results

During a mean follow‐up of 9 years, 342 participants developed all‐cause dementia. We found that residing in locations with PM2.5 exposure above the regulatory standard (12 μg/m3) was associated with a higher risk of dementia only among participants with lower intakes of these B vitamins.

Discussion

This is the first study suggesting that the putative neurotoxicity of PM2.5 exposure may be attenuated by high B vitamin intakes.
Crosswalk between the Mini‐Mental State Examination and the Telephone Interview for Cognitive Status (TICS‐27/30/40)
Authors: Hlávka Jakub P. , Yu Jeffrey C. , Lakdawalla Darius N.
Published: February 2022

Background

We develop a crosswalk between the Mini‐Mental State Examination (MMSE) and Telephone Interview for Cognitive Status (TICS)‐27, TICS‐30, and TICS‐40 for adults 65 years and older.

Methods

We examined the scores of 1809 participants, with and without cognitive impairment, who completed the MMSE and the TICS assessment in the 2016 Health and Retirement Study and the 2016 Harmonized Cognitive Assessment Protocol study. Crosswalks between MMSE and TICS‐27/30/40 were developed via equipercentile equating.

Results

We present crosswalks for MMSE and TICS‐27/30/40 for the 65+ population representative of the US elderly. While monotonic, the pattern of the TICS‐30 to MMSE crosswalk differs from the other two crosswalks (MMSE to TICS‐27/40).

Conclusion

Our analysis offers an empirical crosswalk between two commonly used cognitive measures—the MMSE and TICS. Our findings suggest the need for validated and robust measures that allow for the comparison of scores on different cognitive scales.
Traumatic brain injury and dementia risk in male veteran older twins—Controlling for genetic and early life non‐genetic factors
Authors: Plassman Brenda L. , Chanti‐Ketterl Marianne , Pieper Carl F. , Yaffe Kristine
Published: February 2022

Introduction

This study leveraged the twin study design, which controls for shared genetic and early life exposures, to investigate the association between traumatic brain injury (TBI) and dementia.

Methods

Members of the National Academy of Sciences–National Research Council's Twins Registry of World War II male veterans were assigned a cognitive outcome based on a multi‐step assessment protocol. History of TBI was obtained via interviews.

Results

Among 8302 individuals, risk of non‐Alzheimer's disease (non‐AD) dementia was higher in those with TBI (hazard ratio [HR] = 2.00, 95% confidence interval [CI], 0.97–4.12), than for AD (HR = 1.23, 95% CI, 0.76–2.00). To add more control of genetic and shared environmental factors, we analyzed 100 twin pairs discordant for both TBI and dementia onset, and found TBI‐associated risk for non‐AD dementia increased further (McNemar odds ratio = 2.70; 95% CI, 1.27–6.25).

Discussion

These findings suggest that non‐AD mechanisms may underlie the association between TBI and dementia, potentially providing insight into inconsistent results from prior studies.
Genetic Encoding of Cyanopyridylalanine for In‐Cell Protein Macrocyclization by the Nitrile–Aminothiol Click Reaction
Authors: Abdelkader Elwy H. , Qianzhu Haocheng , George Josemon , Frkic Rebecca L. , Jackson Colin J. , Nitsche Christoph , Otting Gottfried , Huber Thomas
Published: February 2022

Cyanopyridylalanines are non‐canonical amino acids that react with aminothiol compounds under physiological conditions in a biocompatible manner without requiring added catalyst. Here we present newly developed aminoacyl‐tRNA synthetases for genetic encoding of meta‐ and para‐cyanopyridylalanine to enable the site‐specific attachment of a wide range of different functionalities. The outstanding utility of the cyanopyridine moiety is demonstrated by examples of i) post‐translational functionalization of proteins, ii) in‐cell macrocyclization of peptides and proteins, and iii) protein stapling. The biocompatible nature of the protein ligation chemistry enabled by the cyanopyridylalanine amino acid opens a new path to specific in vivo protein modifications in complex biological environments.
Nutzung von elektronenarmen Iminiumintermediaten zur Synthese von wertvollen Aminen
Authors: Hsu Che‐Sheng , Gonçalves Carlos R. , Tona Veronica , Pons Amandine , Kaiser Marcel , Maulide Nuno
Published: February 2022

Die Entwicklung von Reaktionen zur Umwandlung von Alkenen und Alkinen in wertvolle Bausteine ist nach wie vor eines der Hauptziele in der synthetischen Chemie. In dieser Arbeit berichten wir von der Nutzbarmachung von stark elektronenarmen, seltenen und kurzlebigen Iminiumionen zur Synthese von Aminen. Dies ermöglicht die milde Herstellung von Aminen mit z. B. trifluormethylierten Einheiten. Dieses umfassende Konzept wird durch die Aminierung von Chinin zu einem biologisch interessanten neuen Analogon verdeutlicht.
Double Lock Label Based on Thermosensitive Polymer Hydrogels for Information Camouflage and Multilevel Encryption
Authors: Lou Dongyang , Sun Yujing , Li Jian , Zheng Yuanyuan , Zhou Zhipeng , Yang Jing , Pan Chuxuan , Zheng Zhikun , Chen Xudong , Liu Wei
Published: February 2022

Developing extra safety encryption technologies to prevent information leakage and combat fakes is in high demand but is challenging. Herein, we propose a “double lock” strategy based on both lower critical solution temperature (LCST) and upper critical solution temperature (UCST) polymer hydrogels for information camouflage and multilevel encryption. Two types of hydrogels were synthesized by the method of random copolymerization. The number of −CO−NH2 groups in the network structure of the hydrogels changed the enthalpic or entropic thermo‐responsive hydrogels, and ultimately precisely controlled their phase transition temperature. The crosslink density of the polymer hydrogels governs the diffusion kinetics, resulting in a difference in the time for their color change. The combination of multiple LCST and UCST hydrogels in one label realized information encryption and dynamic information identification in the dimensions of both time and temperature. This work is highly interesting for the fields of information encryption, anti‐counterfeiting, and smart responsive materials.
Reversible Three‐Color Fluorescence Switching of an Organic Molecule in the Solid State via “Pump–Trigger” Optical Manipulation
Authors: Yang Runqing , Ren Xue , Mei Lijun , Pan Guocui , Li Xiao‐Ze , Wu Zhiyuan , Zhang Song , Ma Wenyue , Yu Weili , Fang Hong‐Hua , Li Chong , Zhu Ming‐Qiang , Hu Zheng , Sun Tianmeng , Xu Bin , Tian Wenjing
Published: February 2022

In photoswitches that undergo fluorescence switching upon ultraviolet irradiation, photoluminescence and photoisomerization often occur simultaneously, leading to unstable fluorescence properties. Here, we successfully demonstrated reversible solid‐state triple fluorescence switching through “Pump–Trigger” multiphoton manipulation. A novel fluorescence photoswitch, BOSA‐SP, achieved green, yellow, and red fluorescence under excitation by pump light and isomerization induced by trigger light. The energy ranges of photoexcitation and photoisomerization did not overlap, enabling appropriate selection of the multiphoton light for “pump” and “trigger” photoswitching, respectively. Additionally, the large free volume of the spiropyran (SP) moiety in the solid state promoted reversible photoisomerization. Switching between “pump” and “trigger” light is useful for three‐color tunable switching cell imaging, which can be exploited in programmable fluorescence switching. Furthermore, we exploited reversible dual‐fluorescence switching in a single molecular system to successfully achieve two‐color super‐resolution imaging.
Real‐Time NMR Recording of Fermentation and Lipid Metabolism Processes in Live Microalgae Cells
Authors: Nami Faezeh , Ferraz Maria Joao , Bakkum Thomas , Aerts Johannes M. F. G. , Pandit Anjali
Published: February 2022

Non‐invasive and real‐time recording of processes in living cells has been limited to detection of small cellular components such as soluble proteins and metabolites. Here we report a multiphase NMR approach using magic‐angle spinning NMR to synchronously follow microbial processes of fermentation, lipid metabolism and structural dynamic changes in live microalgae cells. Chlamydomonas reinhardtii green algae were highly concentrated, introducing dark fermentation and anoxia conditions. Single‐pulse NMR experiments were applied to obtain temperature‐dependent kinetic profiles of the formed fermentation products. Through dynamics‐based spectral editing NMR, simultaneous conversion of galactolipids into TAG and free fatty acids was observed and rapid loss of rigid lipid structures. This suggests that lipolysis under dark and anoxia conditions finally results in the breakdown of cell and organelle membranes, which could be beneficial for recovery of intracellular microbial useful products.
NHC Catalysis for Umpolung Pyridinium Alkylation via Deoxy‐Breslow Intermediates
Authors: Wu Terence , Tatton Matthew R. , Greaney Michael F.
Published: February 2022

Umpolung N‐heterocyclic carbene (NHC) catalysis of non‐aldehyde substrates offers new pathways for C−C bond formation, but has proven challenging to develop in terms of viable substrate classes. Here, we demonstrate that pyridinium ions can undergo NHC addition and subsequent intramolecular C−C bond formation through a deoxy‐Breslow intermediate. The alkylation demonstrates, for the first time, that deoxy‐Breslow intermediates are viable for catalytic umpolung of areniums.
Enantioselective Recognition of Helicenes by a Tailored Chiral Benzo[ghi]perylene Trisimide π‐Scaffold
Authors: Teichmann Ben , Krause Ana‐Maria , Lin Mei‐Jin , Würthner Frank
Published: February 2022

Enantioselective molecular recognition of chiral molecules that lack specific interaction sites for hydrogen bonding or Lewis acid–base interactions remains challenging. Here we introduce the concept of tailored chiral π‐surfaces toward the maximization of shape complementarity. As we demonstrate for helicenes it is indeed possible by pure van‐der‐Waals interactions (π–π interactions and CH–π interactions) to accomplish enantioselective binding. This is shown for a novel benzo[ghi]perylene trisimide (BPTI) receptor whose π‐scaffold is contorted into a chiral plane by functionalization with 1,1′‐bi‐2‐naphthol (BINOL). Complexation experiments of enantiopure (P)‐BPTI with (P)‐ and (M)‐[6]helicene afforded binding constants of 10 700 M−1 and 550 M−1, respectively, thereby demonstrating the pronounced enantiodifferentiation by the homochiral π‐scaffold of the BPTI host. The enantioselective recognition is even observable by the naked eye due to a specific exciplex‐type emission originating from the interacting homochiral π‐scaffolds of electron‐rich [6]helicene and electron‐poor BPTI.