bluuebunny/crossref_metadata_2025 huggingface dataset:
The circulating sclerostin as a biomarker for brain white matter damage in hemodialysis patients
Authors: Lin Yi‐Ting , Lin Hsiu‐Fen , Wu Ping‐Hsun
Published: December 2023

Background

Patients with kidney disease, especially those receiving hemodialysis, presented a higher risk of cognitive impairment and brain white matter damage than those without kidney disease. Previous research suggests an association between lower bone marrow densities and cognitive impairments. However, the study investigating the relationship between bone turnover biomarkers and brain white matter damage in hemodialysis patients is sparse.

Methods

The enrolled hemodialysis participants were examed on the Fazekas scale of brain magnetic resonance imaging (MRI) white matter lesions and measured 8 bone turnover proteins using the Luminex bead‐based multiplex assay. The Fazekas scale of periventricular lesions was from grade 0 to grade 3. Multivariable ordinal regression and logistic regression models were examined to determine the independent relationship between bone turnover proteins and the Fazekas scale of periventricular lesions.

Results

In 59 hemodialysis patients, older patients had more periventricular lesions on the Fazekas scale, which was connected with a worse Mini‐Mental State Examination score (MMSE). The serum level of sclerostin, one of eight bone turnover proteins, displayed a dose‐response relationship (P value for trend = 0.004), meaning that a greater sclerostin level was connected with a lower grade on the Fazekas scale. Both the ordinal regression model (odds ratio [OR] 0.886; 95% confidence interval [CI] 0.828‐0.947, P value 0.001) and the logistic regression model (odds ratio [OR] 0.828; 95% 0.712‐0.963, P value = 0.014) determined a negative association between sclerostin and the Fazekas scale of periventricular lesions after complete adjustment for potential confounders.

Conclusions

The brain white matter damage was inversely correlated with the level of circulating sclerostin. Our finding suggested a possible connection between bone turnover proteins and brain damage.
Multiple sensory impairments in relation to cognitive function: two nationwide cross‐sectional studies
Authors: Wang Binghan , Chen Hui , Shen Jie , Zhong Wansi , Zheng Yan , Lou Min , Tong Lusha , Yuan Changzheng
Published: December 2023

Background

Sensory impairments (SIs, including visual, hearing, olfactory, and taste impairments) have been individually associated with age‐related cognitive function. Little is known regarding their combined associations with cognitive function.

Method

We included 2,931 participants (mean age of 69.1 years) from the National Health and Nutrition Examination Survey (NHANES, 2011‐2014) and 10,785 participants (mean age of 70.2 years) from the National Health Interview Survey (NHIS, 2021). Status of visual, hearing, olfactory, and taste functions were self‐reported in structured questionnaires. In NHANES, cognitive function was objectively measured by a battery of tests, including memory, verbal fluency, and processing speed. NHIS participants answered a single question about their subjective cognitive complaints (SCC). We used regression models to assess the relation of total number of and the specific sensory impairments to z‐scores of cognitive domains (linear regression) in NHANES and with SCC (logistic regression) in NHIS.

Result

A larger number of SI was related to poorer domain‐specific cognitive function (all P‐trend <0.05), including memory (beta each additional SI = ‐0.12, 95% confidence interval: ‐0.17 to ‐0.08), verbal fluency (‐0.05, ‐0.10 to ‐0.01), and processing speed (‐0.13, ‐0.16 to ‐0.09). In NHIS, each additional SI was related to 96% higher odds of SCC. We also observed independent associations of multiple sensory impairments (except olfactory impairment) with specific domains of cognitive function. In addition, each specific SI showed significant relations to higher odds of SCC (the odds ratios ranged from 1.30 to 1.78).

Conclusion

A larger number of SI was related to worse cognitive function and higher odds of subjective cognitive complaints.
Dietary antioxidants, cognitive impairment and dementia: a systematic review and dose‐response meta‐analysis
Authors: Zheng Ying , Chen Xiao , Yi Qian , Lu Mengxi , Huang Liyan , Tao Yang , Dong Sitong , Chen Hui , Rong Shuang , Song Peige , Yuan Changzheng
Published: December 2023

Background

Dietary antioxidants have been postulated to prevent age‐related cognitive decline. However, the optimal antioxidant level for cognitive benefits remains unknown.

Method

MEDLINE, Embase, and PubMed were searched from inception to 5th September 2021 for cohort studies reporting the associations between the levels of dietary antioxidant, including flavonoids, vitamin E, carotenoids, and vitamin C and cognitive impairment, and dementia. The quality of all studies was assessed by the NHLBI Study Quality Assessment Tool. Random‐effects model was used to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs). Dose‐response meta‐analysis using the Greenland and Orsini method with random‐effects models were performed.

Result

A total of 14 cohort studies were included in the meta‐analysis. Comparing highest to lowest dietary intake levels, flavonoids was associated with lower odds of cognitive impairment and dementia (RRQ4 vs. Q1 = 0.84, 95% CI = 0.72–0.98), while no significant association was observed for vitamin E, carotenoids and vitamin C (RRQ4 vs. Q1 = 0.86, 95% CI = 0.58–1.27, RRQ4 vs. Q1 = 0.84, 95% CI = 0.64–1.10, RRQ4 vs. Q1 = 0.87, 95% CI = 0.68–1.11, respectively). In dose‐response analysis, a J‐shaped relation was observed for dietary vitamin C intake with protective associations detected for less than 85 mg/day intake (P<0.05 for non‐linearity). Meanwhile a significant linear protective relation was observed for dietary carotenoids (range, 0‐20mg/day, RR = 0.98, [0.95‐1.00] for each 1mg/day increment) (P<0.05 for linearity).

Conclusion

The meta‐analysis results suggest potential beneficial roles of long‐term intake of dietary flavonoids, carotenoids and vitamin C in the primary prevention of cognitive impairment and dementia.
Associations Between Lifetime Musical Activity and Resting‐State Functional Connectivity in Higher‐Order Brain Networks
Authors: Liebscher Maxie , Dell'Orco Andrea , Böttcher Adriana , Peters Oliver , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Wagner Michael , Heneka Michael T. , Wolfsgruber Steffen , Roeske Sandra , Wirth Miranka
Published: December 2023

Background

Engagement in complex leisure activities, such as playing a musical instrument, may help preserve cognitive and brain health in older age (e.g. Böttcher et al., 2022). In this study, we investigated the associations between leisure‐time musical activity and resting‐state functional connectivity (RSFC) in three higher‐order networks, the Default Mode. Fronto‐Parietal and Salience Networks, in older adults.

Method

In total, 130 cognitively unimpaired older (aged 60 years and older) participants of the DZNE ‐ DELCODE (Jessen et al., 2018) were assessed. Two groups matched for their reserve proxies were identified (with musical activity during life: n = 65 and controls: n = 65) based on self‐reported musical instrument playing during life, as measured by the Lifetime of Experiences Questionnaire. The two groups were compared in global and local (seed‐to‐voxel) RSFC patterns using pre‐specified seeds of the three brain networks. A mediation analysis explored the interrelations between lifetime musical activity, RSFC, and cognitive composites (Wolfsgruber et al., 2020).

Result

Older participants with musical activity showed higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal regions, namely the bilateral temporal poles as well as the right inferior and middle temporal gyrus, compared to controls (see Figure 1). There were no group differences in global RSFC of the three networks and no mediation effects of musical activity‐related RSFC on global and domain‐specific cognition.

Conclusion

We show that self‐reported lifetime musical activity relates to higher RSFC between frontal and temporal core regions of the Default Mode Network in older adults. The finding implies that playing a musical instrument during life may help preserve neural functioning in a key network that is vulnerable to aging and AD.

References:

Böttcher et al. Frontiers in Psychology 2022.

Jessen et al. Alzheimer’s Research & Therapy 2018.

Wolfsgruber et al. Neurology 2020.
Neuronal hyperexcitability in AD
Authors: Ranasinghe Kamalini G
Published: December 2023

Background

Because neuronal and network deficits are the imperative immediate consequences of pathological changes of disease mechanisms, neurophysiological manifestations associated with Aβ and tau are uniquely positioned to demonstrate the abnormal homeostatic and maladaptive circuit alterations and the dynamic integrated effects of underlying genetics and neuropathological changes in Alzheimer’s disease (AD). Importantly, network dysfunction manifesting as abnormal hyper‐ as well as hypo‐active oscillatory brain rhythms is detectable even during the prodromal phase of disease. Here we leveraged the higher spatial and precise temporal resolution of Magnetoencephalography (MEG) to define frequency‐specific and region‐dependent patterns of oscillatory deficits in AD patients, and to demonstrate the earliest neurophysiological abnormalities associated with AD neuropathology and their mechanistic relationships to network hyperexcitability.

Method

We studied the resting brain oscillations in individuals with AD‐spectrum (n = 88) and age‐matched controls (n = 70) using MEG. In addition, subsets of participants were evaluated with positron emission tomography (PET) with Aβ and tau specific tracers and fluid biomarker including plasma P‐tau181 and Neuro‐Filament‐Light (NFL). We used statistical mixed models to investigate the associations between neural oscillations and pathology. We used a linear Neural‐Mass‐Model (NMM) in combination with empirical MEG spectra to derive the excitatory‐to‐inhibitory activity within neuronal subpopulations in AD patients. Based on standard neurophysiological monitoring we determined clinical evidence of hyperexcitability as AD with and without epileptiform activity (AD‐EPI+; AD‐EPI‐).

Result

While increase and decrease of oscillatory activity are distinctly associated Aβ and tau, respectively, the characteristic frequency‐specific manifestation in AD was increased spectral signature within delta‐theta (2‐7Hz) and reduced spectral signature within alpha (8‐12Hz). Earliest spectral changes were detected in Aβ+ cognitively unimpaired and the increased spectral signature associated with Aβ was replicated in identical associations with plasma p‐tau181. The presence of APO‐E4 allele strengthened these associations. NMM demonstrated greater excitatory‐inhibitory‐activity in AD‐EPI+ vs. AD‐EPI‐ while these were specifically correlated with the reduced alpha spectrum which was more profound in AD‐EPI+ as well as uniquely associated with increased tau depositions.

Conclusion

Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ, in patients with AD.
Noninvasive neuromodulation in Alzheimer’s disease: current status and future perspectives
Authors: Santarnecchi Emiliano
Published: December 2023

Background

Alzheimer’s disease is a multifactorial disorder with multiple pathological substrates converging into clinical symptoms and cognitive deficits. Recent evidence suggests alterations of brain function beyond known pathways related to protein clearance, involving altered oscillatory activity in specific brain functional networks and alterations of synaptic plasticity within specific brain structures.

Method

In this context, the possibility to interact with cortical dynamics offered by noninvasive non‐pharmacological approaches pertaining to electrophysiology might open the way to a better understanding of the disease, and potentially lead to novel therapeutic interventions.

Results

In particular, noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia over the last decade, considered their promising value as diagnostic biomarkers of altered neural activity, as well as for their therapeutic potential of modulating network dysfunction and boosting residual cognitive functions.

Conclusion

As part of the symposium, I will (i) review and discuss experimental NiBS applications in Alzheimer’s Disease (AD) and related dementias, including Transcranial Magnetic Stimulation (TMS) and transcranial Alternating Current Stimulation (tACS) interventions; (ii) provide an overview of multimodal TMS‐EEG perturbation‐based biomarkers for early diagnosis and monitoring, and (iii) discuss the potential of informing these applications via computational models mapping circuit‐level pathology in AD.
Associations between accelerometer‐based physical activity and brain white matter microstructure: Findings from the population‐based Rhineland Study
Authors: Fox Fabienne A.U. , Koch Alexandra , Breteler Monique M.B. , Aziz N. Ahmad
Published: December 2023

Background

White matter (WM) integrity declines with age and is affected by neurodegenerative diseases. Physical activity promotes neuronal health in animals, and is associated with WM microstructure metrics in humans. However, previous diffusion tensor imaging (DTI) studies were limited by small sample sizes and subjective questionnaire‐based physical activity assessments. Moreover, recently introduced neurite orientation dispersion and density imaging (NODDI) may offer complementary insights. Therefore, we examined the association between accelerometer‐based physical activity and DTI and NODDI measures of WM microstructure in a large population‐based cohort.

Method

We analyzed data of 2,455 participants (57.9% women, mean age: 54.7 years) with valid physical activity and MRI measurements from the Rhineland Study, a prospective cohort study in Bonn, Germany. We recorded physical activity using accelerometers and derived metabolic equivalent (MET)‐hours, step counts and time spent performing sedentary, light‐intensity and moderate‐to‐vigorous (MVPA) activities. DTI (fractional anisotropy (FA), mean diffusivity) and NODDI (orientation dispersion index, neurite density index) measures were obtained from 3T MR images using the microstructure diffusion toolbox. The association of physical activity with WM microstructure was assessed using multivariate polynomial regression, while adjusting for age, sex, education, body mass index and smoking status.

Result

Physical activity was associated with several global and tract‐specific DTI and NODDI measures. Effects were strongest at low physical activity quantities and weakened at higher levels. While higher MET‐hours, step counts and light and moderate‐to‐vigorous intensity activities were related to greater global FA, sedentary time was associated with reduced FA. We observed the strongest tract‐specific effects for moderate‐to‐vigorous intensity activities on the corpus callosum and corona radiata (standardized effects: MVPA on FA corpus callosum, ßlin = 0.0009 [95% CI: 0.0001; 0.0018] and ßqu = ‐0.0006 [95% CI: ‐0.0011; ‐0.0001]; MVPA on FA corona radiata, ßlin = 0.0011 [95% CI: 0.0001; 0.0021] and ßqu = ‐0.0009 [95% CI: ‐0.0014; ‐0.0003]). We obtained similar results for NODDI measures.

Conclusion

Our findings suggest that WM microstructure and particularly tracts connecting motor regions profit from physical activity. Sedentary individuals may benefit more from additional physical activity than already active individuals. NODDI metrics provide valuable complementary insights into the effects of physical activity on WM microstructure.
Alzheimer’s Disease: Novel Findings, Challenges and Implications for Healthcare Systems
Authors: Uwishema Olivier
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive, degenerative brain damage that impairs thinking and problem‐solving skills and causes memory loss as well as behavioural and emotional abnormalities. Amyloid plaques and tau tangles, aberrant protein clusters that cause cognitive deterioration, are the disease’s hallmark. The illness is a serious obstacle for the patient, their family, and caretakers, as well as for the healthcare system. This study aims to summarize the recent discoveries linking microorganisms and Alzheimer’s disease, the difficulties in confirming the theory, and suggestions on how scientists can improve alternative methods to study the underlying causes of AD.

Method

Academic publications were retrieved from the databases MEDLINE, Ebscohost, PubMed, Ovid, Embase, ScienceDirect, and Google Scholar using a unique search strategy. Emphasis was given to recent studies that provide insight into the current state, methods for diagnosis, and treatment options. Keywords in special combinations were used to retrieve information from various databases.

Result

Evidence suggests that viruses can cause an increase in β‐amyloid peptide synthesis and tau phosphorylation, leading to the formation of senile plaques and neurofibrillary tangles. The absence of experimental evidence connecting microbes to the cognitive deficits and neuropathological alterations of AD, as well as the ambiguous composition and origin of the amyloids observed in senile plaques, are a few of the difficulties that researchers must overcome.

Conclusion

Further research is pivotal in shaping the future of Alzheimer’s disease to fully comprehend the disease mechanism and treatment challenges. The development of tools to understand the complexity of the disease pathogenesis and its multifaceted aetiology is crucial. Additionally, in people who are predisposed to certain infections, early diagnosis of such infections may help delay the start of AD.
Hospital‐diagnosed infections, autoimmune disease, and subsequent incidence of Alzheimer’s disease, vascular dementia, and other major dementias
Authors: Janbek Janet , Waldemar Gunhild
Published: December 2023

Background

It has been debated whether specific infections may be causally linked to dementia development. The hypothesis has been principally directed towards Alzheimer’s disease (AD) pathology, prompted by findings that Aβ peptide, whose deposition is a hallmark of AD, has antimicrobial properties. Previous epidemiological population‐based studies have reported that observed links between infection and dementia were more prominent for vascular dementia (VaD), whereas there was either a small or no increased AD risk. Similar findings have been reported for autoimmune disease, although links were overall close to null. Investigating the two exposures together gives insights into the involvement of the immune system in dementia risk. However, data on dementia subtypes in the previous studies predominantly relied on electronic health data with generally low or unknown validity. Therefore, it remains unknown whether links with infection are attributed to AD, VaD, or other dementias. It is also unknown whether the general lack of link with autoimmune disease could be modified by dementia subtypes. Further, evidence is lacking regarding young‐onset dementias, with at least one study suggesting higher dementia risk in cases diagnosed at <60 years. The aim of this study was to investigate the association between infections, autoimmune diseases, and subsequent incidence of major dementia disorders.

Methods

We conducted a nationwide nested case‐control study of dementia cases in the Danish Quality Database for Dementia (DanDem). This is a nationwide register of all dementia diagnoses given by memory clinics and are thus advantageous over previously used data on subtype diagnoses in our and other general health registries. Conditional logistic regression estimated incidence rate ratios for cases of AD, VaD, and other dementias, compared with controls, following exposure to infection and autoimmune disease (in the prior 35+ years).

Results

We identified all incident dementia cases between 2016 and 2018 and matched them to up to three controls on age and sex. Majority of cases were diagnosed with AD, followed by mixed dementia and VaD.

Conclusion

The results of this study will further knowledge on the role of the immune system for dementia risk and contribute with new data regarding the risk of different dementias.
Markerless motion capture technology to quantify functional performance in dementias: a systematic review
Authors: Jeyasingh‐Jacob Julian , Shah Harshvi , Crook‐Rumsey Mark , Joseph Theresita , Daniels Sarah , Sharp David J , Haar Shlomi
Published: December 2023

Background

Quantifying functional performance objectively and unobtrusively could offer vital insights for clinical decision making on the level of support required by people living with dementia and other neurodegenerative conditions. Markerless motion capture (MMC) is more suitable for deployment in clinical and real‐world settings because single sensor MMC systems are less expensive and less complex compared to marker‐based systems. The aim of this study was to complete a systematic review of published literature on the use of MMC with full‐body tracking in people with dementias.

Method

We systematically searched for relevant articles using the search terms motion capture, motion analysis and movement analysis combined with dementia, mild cognitive impairment (MCI) and Parkinson’s disease (PD) which yielded a total of 1103 results. Inclusion criteria were MMC and full‐body tracking. Studies evaluating marker‐based motion capture, body‐worn sensors or Inertial Measurement Units, virtual reality, kinetics and interventions like DBS or exercises were excluded. 134 studies were included for full article screening out of which 17 eligible studies that met the selection criteria were included in the review.

Result

MMC devices used in the reviewed studies included Microsoft Kinect (n = 15) and unspecified 2D motion camera (n = 2). Patient groups included in the studies were PD (n = 12), dementia (n = 4) and MCI (n = 1). Functional performance components evaluated were gait (n = 16), sit to stand (n = 2), turning (n = 1) and stepping in place (n = 1). About half the studies used advanced machine learning methods whereas the other half used descriptive statistical methods. The lack of standardisation in the measures used prevented us from comparing and synthesizing study results.

Conclusion

Although MMC has the potential to be used for quantifying functional performance in people with dementia, MCI and PD, there appears to be significant variation in the methods used in its evaluation. Although features of mobility were measured, none of the reviewed studies analysed activities of daily living tasks, a key component of functional performance. Standardising the process for extracting features and assessing accuracy would enable more effective validation of real‐world impact. Further research is required in people with neurodegenerative conditions for MMC to be routinely used in clinical and real‐world applications.
Co – Design of a Dance Exercise Intervention for People Living with Dementia and their Care Partners
Authors: Kelly Niamh , Skelly Fiona , Dowd Kieran , O'Neill Desmond , McCaffery Noel , McDermott Clare
Published: December 2023

Background

Living with dementia can negatively impact quality of life (QOL) by affecting social, physical, and mental capabilities (Thumuluri et al. 2022). Care partners are at an increased risk of decline to their physical and mental health due to their role (Teahan et al. 2021). Dance provides benefits associated with an exercise intervention, including protective measures against cognitive decline, benefits in strength, brain function and connectivity with added balance and memory enhancements found in dance interventions (Tao et al. 2021, Wu et al. 2021). The study’s aim is to explore exercise preferences of PLWD, care partners and recommendations from the literature.

Method

A base of evidence was identified, by a literature review, focusing on how physical activity, exercise and dance interventions impact PLWD and care partners. A patient advisory group (PAG) was established to provide feedback on study methods. Interview guides were created for PLWD and care partners using the Behaviour Change Wheel Framework (Michie et al. 2011) (BCW). The PAG gave their insight on the suitability of the questions. Questions were based around physical activity knowledge and preferences of the participants. A range of recruitment methods were used, relevant organisations were contacted, site visits were made, recruitment information was shared on social media. Focus groups and interviews are currently being conducted with PLWD and care partners, data collection will be completed by March. The results will be analysed by thematic analysis using NVivo software.

Result

The literature review found physical activity and exercise provide physical and psychological benefits for PLWD and care partners. Dance is impactful as it combines physical, social and cognitive activities. Preliminary findings from the focus groups identified themes including, physical activity, exercise, dance, and social support. Participants were aware of the benefits of physical activity and exercise. Many participants described dance as enjoyable, but intimidating to join a class. The social aspect of the class is one of the most important components for these populations.

Conclusion

The lived experience of PLWD and care partners highlights dance as a potential intervention approach to improve QOL, increase social support, and to enhance the acceptance and impact of the intervention.
Detecting sleep‐related breathing disorders using overnight pulse oximetry in patients with dementia and mild cognitive impairment
Authors: Li Haoxuan , Gabb Victoria , Morrison Hamish , Blackman Jonathan , Biswas Bijetri , Kendrick Adrian , Coulthard Elizabeth
Published: December 2023

Background

Sleep disturbance is commonly reported in Alzheimer’s disease (AD), Lewy body dementia (LBD) and mild cognitive impairment (MCI). Early identification of sleep changes is crucial as poor sleep could contribute to cognitive decline and worsen disease progression. Sleep‐related breathing disorders (SBD), including obstructive sleep apnoea, have been associated with dementia and its treatment using continuous positive airway pressure (CPAP) may improve cognitive trajectory (Osorio et al., 2015). The Remote Evaluation of Sleep To enhance understanding of Early Dementia (RESTED) study is an ongoing cohort study conducted at the University of Bristol, aiming to characterise sleep changes in early dementia using remote tools. Here, we outline preliminary data from a small group of RESTED participants undergoing overnight pulse oximetry to screen for SBD.

Method

Older adults with AD or MCI due to AD (AD‐MCI), LBD or MCI due to DLB/PD (LBD) and age‐matched healthy controls (HC) were recruited from memory clinics and volunteer databases at North Bristol NHS Trust. Participants completed baseline questionnaires including Epworth Sleepiness Scale (ESS) and STOP‐BANG, in addition to undergoing pulse oximetry testing on two consecutive nights at home. Parameters including oxygen desaturation index 3% (ODI3%) and pulse rise index were analysed. Those with suspected SBD were referred to tertiary sleep services. Mann‐Whitney test was conducted to investigate differences in ODI3% between ESS or STOP‐BANG classification cut‐offs.

Results

Overnight pulse oximetry was well‐tolerated across groups, with all participants completing at least one full night’s recording. Preliminary results demonstrated an abnormal ODI3% in eight of 13 participants (AD‐MCI n = 3/6, LBD n = 3/3, HC n = 2/4). Of the remaining 5, 2 (HC) were referred for further testing due to abnormal pulse rise index and 3 (AD‐MCI) did not demonstrate suspicion of SBD. No significant difference in ODI3% was found between ESS≤10 and >10 (p = 0.28) or STOP‐BANG<3 and ≥3 (p = 0.15).

Conclusion

Overnight pulse oximetry serves as an easy to use, objective method in screening for SBD, which could provide an additional avenue for targeting dementia risk. Routine screening may be implicated for older adults with cognitive impairment who may otherwise not be considered high risk for SBD, particularly in the absence of subjective daytime sleepiness.
Examining the microglial TSPO phenotype in Alzheimer’s disease
Authors: Garland Emma F , Kulagowska Laura , Scott Thomas , Antony Henrike , Bottlaender Michel , Nicoll James AR , Boche Delphine
Published: December 2023

Background

Neuroinflammation is a key pathological feature of Alzheimer’s disease (AD), with microglia being the main inflammatory cell type in the CNS. In order to examine these cells in vivo, PET ligands targeting the microglial translocator protein (TSPO) have been developed. However, it remains unclear the specific target of these ligands, whether this is all microglia or a subset of cells. We aim to elucidate this by identifying the microglial phenotype most associated with TSPO in humans.

Method

Human post‐mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak stage (0‐II, III‐IV, V‐VI; each n = 10) were immunostained for pan‐Aß, pTau, and microglial markers TSPO, Iba1 and HLA‐DR with protein load quantified. Double immunofluorescent staining was performed with TSPO and microglial markers HLA‐DR and CD68 with positive cells counted.

Result

TL showed an increase in Aβ (P<0.0001), pTau (P<0.0001) and TSPO (P<0.0001) protein load, but not Iba1 or HLA‐DR, with progressing Braak stage. Aβ (P = 0.0008) and Iba1 (P = 0.012) load increased in the Cb, but not pTau, TSPO or HLA‐DR. Of note, TSPO load in TL was associated with pTau. In both areas, no difference was found in number of HLA+ or CD68+ cells, though TL TSPO+ cell number increased significantly (P = 0.0347). There was no difference in the number of HLA‐DR+/TSPO+ or CD68+/TSPO+ cells with progressing Braak stage. However, significantly more CD68+/TSPO+ than HLA‐DR+/TSPO+ cells were detected in both the TL (P<0.0001) and Cb (P = 0.009) regions.

Conclusion

The results suggest that TSPO expression is related to late stage disease (pTau) and microglial phagocytosis (CD68), a function we have previously identified associated with the presence of dementia, cognitive decline and tau pathology. Further additional analysis with other microglial markers is currently ongoing.
Foundational changes to improve dementia care: Implementing person‐centered, dementia‐specific education for nursing assistant programs
Authors: Crance Sara J , Yu Fang , Hamilton Gillan , Ordonez Belinda
Published: December 2023

Nursing assistants are responsible for direct care of individuals living with dementia in long‐term care (LTC) settings. Due to their cognitive impairment, care activities often cause behavioral and psychological symptoms of dementia (BPSD), such as stress, fear, agitation, and anger. Most states, including Arizona, do not require nursing assistant (NA) training programs to provide dementia‐specific content, despite >50% of all LTC residents having dementia. The purpose of this project was to design and integrate dementia‐specific curriculum into NA programs through training the trainer. The curriculum was designed to be easily implemented in NA programs with the goal of changing the way the state educates NAs.

Training was provided to 12 RNs that identified as NA program coordinators or instructors in Arizona. All 12 trainees were female, ranging in age from 30s ‐70s, 83% identified as Caucasian, 8% Latino, and 8% African American. A complete, portable didactic lesson and a lab lesson were provided, consisting of dementia basics, person‐centered care, dementia simulation, teaching techniques, and two complete one‐hour lessons to implement in the classroom after the training. Knowledge and confidence were tested pre/post‐training and barriers to implementation were assessed at one‐month follow‐up.

Knowledge increased from 4±1.15 to 6.75±0.43 (t = ‐7.63, p<.001). Confidence increased from 6.64±1.63 to 9.27±0.79(t = ‐4.34, p = .001) on knowledge confidence, from 6.55±1.63 to 9.18±0.87 (t = ‐4.14, p = .002) on teaching techniques, from 6.36±1.21 to 9.27±0.79 (t = ‐5.67, p<.001) on teaching dementia‐specific content, from 6.09±1.22 to 9.18±0.87 (t = ‐5.65, p<.001) on integrating dementia‐specific skills into lab and clinical, and 6.27±1.19 to 9.36±0.81 (t = ‐6.25, p<.001) on integrating dementia‐specific education into course content. At one month follow‐up, all participants planned to or already had implemented the training into their curriculum.

Trainees increased their knowledge and confidence to successfully implement person‐centered, dementia‐specific education into their NA programs without barriers. In addition, this project gained support to change the NA program curriculum in 2023 to require dementia‐specific education for all NA programs in the state, thus changing practices for front‐line healthcare workers in the state.
White matter microstructural changes in sporadic and genetic FTD using neurite orientation dispersion and density imaging
Authors: Bocchetta Martina , Todd Emily G. , Malone Ian B , Cash David M , Thomas David L , Warren Jason D , Zhang Hui , Rohrer Jonathan D.
Published: December 2023

Background

Frontotemporal dementia (FTD) is characterized by abnormal white matter (WM) integrity measured with conventional diffusion tensor imaging techniques. No study has yet investigated the microstructural WM changes across different clinical FTD forms using the novel neurite orientation dispersion and density imaging (NODDI). Here, we focused the analyses on symptomatic individuals, investigating the difference between the sporadic and genetic origin within the same diagnostic group.

Method

Neurite density index (NDI) and orientation dispersion index (ODI) were extracted from NODDI sequences, processed and then corrected for tissue‐weighted means. Images were acquired on a 3T MRI Siemens Prisma scanner from a cohort of participants seen in clinic at the National Hospital for Neurology and Neurosurgery, University College London, UK. Data were available for 27 individuals with behavioural variant FTD (bvFTD) and 27 with primary progressive aphasias (11 svPPA, 8 nfvPPA, 4 lvPPA, 4 PPA‐NOS). 18 of these individuals (16 bvFTD and 2 PPA‐NOS) carried an FTD‐linked genetic mutation (6 C9orf72, 7 MAPT, 5 GRN). W‐scores for NDI and ODI were computed from a regression model on 62 non‐carrier healthy individuals, adjusting for their age, sex, and total intracranial volumes.

Result

The most abnormal values (<2.5th percentile of controls) were found in bvFTD (NDI: anterior corona radiata and left cingulum), lvPPA (NDI and ODI: left superior corona radiata; ODI: splenium of the corpus callosum) and PPA‐NOS (NDI: left uncinate fasciculus) (Figure). Sporadic bvFTD and PPA‐NOS showed more abnormal and widespread WM abnormalities compared to symptomatic mutation carriers.

Conclusion

Changes in WM structure in this cohort of patients with symptomatic FTD appear to be related primarily to a reduction in axonal density. Despite similar clinical features, sporadic forms tend to show more severe and widespread WM involvement than genetic cases.
Subjective Cognitive Decline and Cognitive Change among diverse Hispanics/Latinos: Results from the Study of Latinos – Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Márquez Freddie , Tarraf Wassim , Kuwayama Sayaka , Stickel Ariana M , Paredes Alejandra Morlett , Guerrero Lourdes , Perreira Krista M , Gonzalez Sara , Salazar Christian R. , Wassertheil‐Smoller Sylvia , Daviglus Martha L , Gallo Linda C , González Hector M
Published: December 2023

Background

The potential utility of subjective cognitive decline (SCD) as an early risk marker of Alzheimer’s disease and related dementias is under consideration, yet few studies have examined SCD among Hispanics/Latinos. In this study, we examined associations between SCD and cognitive change among diverse middle‐aged and older Hispanics/Latinos in the U.S. Furthermore, we examined SCD and cognitive change among cognitively healthy participants.

Method

Participants were recruited from a longitudinal multisite prospective cohort study of diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and its ancillary study, the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA). The mean age was 56.37 ± 8.10 years at Visit 1 (2008‐2011) and Visit 2 (n = 6,225; 2016‐2018) occurred 7‐years later, on average. SCD was measured with the short‐form Everyday Cognition Scale (ECog‐12) at Visit 2. Global SCD and executive function and memory subdomain SCD were generated by averaging the component items. Cognitive performance was measured at both visits and operationalized using standardized scores of learning, memory, verbal fluency, executive function, and global cognition. Cognitive change was assessed using regression‐based change models. We used survey generalized regressions to model the cognitive outcomes as a function of SCD. Cognitively healthy participants did not meet criteria for Mild Cognitive Impairment.

Result

All ECog‐12 exposures were associated with global cognitive decline (ECog‐12 global: B = ‐0.17, SE = 0.02; ECog‐12 executive: B = ‐0.15, SE = 0.02; ECog‐12 memory: B = ‐0.14, SE = 0.02, p’s<0.001). Furthermore, higher global and memory‐related SCD was associated with memory decline among those that were cognitively healthy (ECog‐12 global: B = ‐0.06, SE = 0.02; ECog12 memory: B = ‐0.05, SE = 0.02, p’s<0.01). The associations were slightly attenuated but remained significant after adjustment for demographic and cardiovascular disease risk covariates.

Conclusion

The results from this study support that SCD may be an indicator of concurrent decline in cognition among diverse middle‐aged and older community dwelling Hispanics/Latinos. Furthermore, the utility of memory‐related SCD as a preclinical indicator of cognitive decline may warrant further investigation. This study highlights the importance of evaluating cognitive concerns among middle‐aged and older Hispanics/Latinos during routine healthcare visits.
Amyloid and Tau PET Positivity in Progressive Apraxia of Speech and Agrammatic Aphasia
Authors: Utianski Rene L , Tosakulwong Nirubol , Duffy Joseph R , Clark Heather M , Tetzloff Katerina A , Machulda Mary M. , Botha Hugo , Whitwell Jennifer L , Josephs Keith A
Published: December 2023

Background

The spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.

Methods

65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.

Results

There was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).

Conclusions

Aβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.
Liraglutide as a potential drug repurposing candidate for Alzheimer’s disease and related dementia: Real World Evidence
Authors: Wang Tiansheng , Buse John B , Pate Virginia , Garden Gwenn A , Stürmer Til
Published: December 2023

Background

Previous studies suggested GLP‐1 receptor agonists (GLP1RA) may improve cognitive function and liraglutide’s effect on Alzheimer’s disease is being evaluated by the ELAD (Evaluating Liraglutide in Alzheimer’s Disease) clinical trial.

Method

To examine whether liraglutide decrease Alzheimer’s disease and related dementia (ADRD) risk compared with other antidiabetics, we implemented an active comparator, new user cohort design identifying initiators of liraglutide, DPP‐4 inhibitors (DPP4i), respectively, using a US nationwide 20% random sample of fee‐for‐service Medicare beneficiaries aged 70+ with parts A, B, and D coverage from 2007‐2019. We required patients to have 2nd prescription of the same drug class and be free of ADRD in the 3‐year window (during which requiring 3‐year continuous enrollment of parts A, B) prior to drug initiation. The ADRD outcome was defined as 1) ³1 ADRD claims in 1 year AND 2) ³1 ADRD claims in another year or nursing home stay ³ 6 months in the 3‐year follow‐up period. We estimated propensity scores (PS) to balance confounders across cohorts and estimated adjusted risk difference (RD) and 95% CI using inverse probability treatment and censoring weight.

Result

The initiators of liraglutide (n = 1260) and DPP4i (n = 15952) were followed for a median (IQR) duration of 3.0(2.0 to 3.0) and 3.0 (1.7 to 3.0) years, respectively. During follow‐up, incident cases of ADRD was 196 and 3215 in liraglutide and DPP4i, respectively; and incident rate was 63 and 85 per 1000 person‐years, respectively. Adjusted RD (%) was ‐4.4 (95%CI ‐6.6 to ‐2.39) comparing liraglutide to DPP4i. Results were consistent across sensitivity analyses with varying exclusion criteria, baseline period, and outcome definitions.

Conclusion

Our active comparator, new user cohort study of older patients showed liraglutide is associated with a decreased ADRD risk compared with alternatives. This study is limited by the relatively short duration of treatments.
Distinct amyloid‐β deposits inversely correlate with glial activation and tangles in Alzheimer’s disease subtypes
Authors: Boon Baayla D.C. , Kouri Naomi , Labuzan Sydney A. , Peng Zhongwei , Tranovich Jessica F. , Frankenhauser Isabelle , Lincoln Sarah J. , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R , Dickson Dennis W. , Murray Melissa E.
Published: December 2023

Background

The coarse‐grained plaque is a biochemically and morphologically distinct amyloid‐β (Aβ) deposit that was discovered in clinically‐defined atypical Alzheimer’s disease (AD). Unlike other Aβ deposits, this plaque is not observed in cognitively normal people. This study investigates the hypothesis that the coarse‐grained plaque is distinctly associated with AD neuropathologic change and glial activation within the context of AD subtypes.

Method

Sixty AD cases from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort were assessed. We included 20 hippocampal sparing (HpSp) AD, 20 typical AD, and 20 limbic predominant AD. Immunohistochemistry was performed on the middle frontal, inferior temporal, and inferior parietal cortex for AD neuropathology (Aβ [6F/3D], phospho‐tau [AT8], tau [GT38]) and glial activation (CD68 [KP1] and GFAP). Digital pathology was used to quantify burden. Thioflavin‐S tangle counts were performed at time of neuropathologic diagnosis. Distinct deposit types, including classic cored plaques, coarse‐grained plaques, cerebral amyloid angiopathy (CAA)‐Type 1, and CAA‐Type 2, were semi‐quantitatively scored on Aβ (Fig. 1). Correlations between demographic, clinical, and neuropathologic characteristics were assessed using Spearman rho analysis and reported if p<0.05. An independent cohort of ∼100 HpSp AD cases will be assessed to validate initial findings.

Result

In the frontal cortex of HpSp AD, higher scores of classic cored plaques correlated with older age at onset and death, non‐APOE ε4 carriership, and less CAA‐Type 1 and Type 2 (Fig. 2). On the contrary, the severity of coarse‐grained plaques correlated with a younger age at onset and death, APOE ε4 carriership, higher scores for CAA‐Type 1, CAA‐Type 2, and increased burden of Aβ, GFAP, and CD68. Classic cored plaques correlated negatively with phospho‐tau and tau, whereas coarse‐grained plaques correlated positively with phospho‐tau, tau, and tangles. The two deposit types were negatively correlated with each other. Correlations were weaker but showed similar trends in other AD subtypes (Fig. 2) and regions.

Conclusion

Within HpSp AD, classic cored and coarse‐grained plaques show distinct correlations with glial activation, (phospho‐)tau, and tangles. These results suggest opposite directions of association for these deposits on AD neuropathologic change that may impact clinical symptoms. These findings are relevant to therapies targeting overall Aβ pathology.
Longitudinal Changes in Grey Matter Correspond to Changes in Cognition Across the Lifespan: Implications for Theories of Cognition
Authors: Smith Evan T. , Hennessee Joseph P. , Wig Gagan S , Frank Sarah , Gonzalez Hector , Bacci Julia R. , Chan Micaela , Carreno Claudia , Kennedy Kristen M , Rodrigue Karen M , Hertzog Christopher , Park Denise C.
Published: December 2023

Background

Interpretations of brain and cognitive reserve were tested by assessing the parallel, longitudinal relationship between grey matter atrophy and cognitive decline in an adult lifespan sample.

Method

Cognitive battery and structural MRI images were assessed in 463 healthy participants of age 20‐89. Participants were assessed up to 3 times over up to 10 years. Change‐over‐time in cortical grey mater, subcortical grey matter, and general cognitive ability were modeled via latent growth curve modeling, and covariance of these latent change scores were assessed via parallel‐process latent change modeling.

Result

Latent change in general cognition was found to significantly covary with latent change in both cortical grey matter. Cortical grey matter volume, subcortical grey matter volume, and cognition at baseline were found to significantly relate to longitudinal cognitive decline, such that individuals with higher volume and better cognitive performance experienced less decline over the observation period.

Conclusion

Individual differences in cognitive and grey matter decline are demonstrably related. Both cognitive and grey matter resources at baseline reserve to differentiate longitudinal patterns of cognitive decline. Grey matter volume appears to provide a good estimate of what some refer to as “brain reserve” and the latent cognition factor estimated “cognitive reserve.” Overall, these latent measures may be parsimoniously viewed as measures of neoro‐cognitive resource that do not require invoking the construct of “reserve” to explain individual differences in brain structure and cognition.