bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of estimated white matter hyperintensity age with cognition in hypertensive elderly
Authors: Kim Jun Sung , Bae Jong Bin , Han Ji Won , Oh Dae Jong , Suh Seung Wan , Kim Jae Hyoung , Kim Ki Woong
Published: December 2023

Background

Hypertension is associated with white matter hyperintensity (WMH) and cognitive impairment. Further, WMH is associated with cognitive impairment including executive, attention and visuospatial functions. The aim of this study was to investigate the effects of controlled hypertension (cHT) and previously developed concept, ‘WMH age’ on cognitive function and the mediating role of WMH in the effect of cHT on cognitive impairment.

Method

We enrolled 855 Koreans without dementia aged 60 years or older, 326 of whom completed 2‐year follow‐up assessment. We measured their blood pressure thrice in a sitting position using an automated blood pressure monitoring device. We estimated ‘WMH age’ of every participant using previously developed WMH probability map of healthy older Koreans. We analyzed the mediating effect of WMH age in the association of cHT and cognitive function using the PROCESS Macro model.

Result

Old WMH age was associated with a faster decline in the Mini‐Mental Status Examination (MMSE; p = .003), Consortium to Establish a Registry for Alzheimer’s Disease total score (CERAD‐TS; p = .003), and Frontal Assessment Battery (FAB; p = .007). Old WMH age showed an approximately‐six times higher risk of incident mild cognitive impairment (OR = 6.47, 95% CI = 1.37 – 9.50, p = .024) compared to young or normal WMH age over the 2‐year follow‐up period in the cHT group. WMH age mediated the effects of cHT on the MMSE, CERAD‐TS, and FAB scores at baseline and two‐year follow‐up period.

Conclusion

WMH mediates the adverse effect of hypertension on cognitive function. Elders with cHT who have older WMH age may be at a higher risk of cognitive decline.
The effect of baseline and longitudinal cognitive reserve on memory ageing in middle and older age adults over a 12‐year period
Authors: Anstey Kaarin J. , Eramudugolla Ranmalee , Zheng Lidan , Brady Brooke , Kootar Scherazad , Wilson Nikki‐Anne , Mortby Moyra E , Chidiac Ben , Cherbuin Nicolas , Leung Yvonne , Andel Ross , Huque Hamidul
Published: December 2023

Background

‘Cognitive reserve’ (CR) refers to a model of active protection against cognitive decline conferred by the adaptability of one’s cognitive processes. Research on life‐course accumulation of reserve and impact of factors like gender is limited. We examined long‐term effects of CR on episodic memory in two population‐based cohorts.

Methods

Participants consists of two cohorts from the PATH Through Life project with 12 years (4 waves) of follow‐up, with had an average of 14.6 and 13.9 years of education. The mid‐life cohort (MA) was aged 40‐44 at baseline (mean age 42.6, 52.7% self‐reported female;47.3% male, 0% other gender, N = 2513) and the older cohort (OA) was aged 60‐64 at baseline (mean age 62.5, 48.1% female, 49.9% male, 0% other gender, N = 2403). A baseline composite CR measure included education, occupational complexity, and cognitive and social engagement measured by the RIASEC scales. Episodic memory (Immediate and delayed recall) was assessed with a 16‐word list. Multilevel models adjusting for baseline age, self‐reported gender, race, APOE and non‐English speaking background; evaluated the effect of both baseline and longitudinal change in CR on the longitudinal change in episodic memory.

Results

On average, women performed better than men on the episodic memory tasks. Compared with participants in the top tertile of CR, those middle and lowest tertiles had larger decline in episodic memory in both MA and OA. Interactions with APOE were not significant, but among those with medium (model derived beta weights 95% CI: 0.35 (0.01‐0.69)) and high (0.48(0.07‐0.90)) CR, women showed less decline than men. Each component of CR (education, occupational complexity, and RIASEC) was protective against decline in immediate and delayed recall. Increase in RIASEC score over time was protective (MA (0.05, (0.04‐0.07); OA 0.13, (0.11‐0.16)) with a larger effect seen in OA.

Conclusion

The current study demonstrated protective effects against cognitive decline for all types of CR measured in both middle and older‐age groups. Increases in CR over time were also protective. The benefits of CR were highest for older women who comprise the age and gender group at most risk of Alzheimer’s disease, indicating the need for CR interventions.
Early life factors and individual differences in the brain through the human lifespan – association of intercept or change?
Authors: Walhovd Kristine B
Published: December 2023

Background

Human fetal development has been associated with brain health at later stages. In this presentation, I review results of analyses by the center for Lifespan Changes in Brain and cognition (LCBC), on whether and how consistently factors present in utero, including genetics (APOE4; polygenic risk for Alzheimer´s Disease; AD), prenatal drug exposure and, especially, growth in utero, as indexed by birth weight (BW), relates to lifespan brain characteristics and changes.

Method

We investigated associations between BW and cortical surface area, thickness and volume as derived from MRIs, across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4‐82 years of age, w/ 386 monozygotic (MZ) twins, followed for up to 8.3 years w/12,088 brain MRIs).

Results

Associations of BW and structural brain characteristics appear to be identifiable through the lifespan, with largely topographically consistent effects across samples of varying age. In developmental (ABCD), older adult and aging (UKB) and lifespan (LCBC) longitudinal samples, positive associations between BW and cortical surface area and volume were remarkably stable within and across samples of different age and origin, with spatial correlations in the range r = .51‐.79. In contrast, there was modest and no consistent effect of BW on brain changes. Effects of BW discordance in the twin subsample indicated the effects were partly environmental. This stable effect of an early life factor (BW), is similar to effects through the lifespan of genetic risk for AD, and persistent effects of prenatal opioid and ‐polydrug exposure in childhood and young adulthood.

Conclusion

The influence of these early life factors, as here shown for BW, on brain topography, appear in part stable through the lifespan, being reliably seen in development, adulthood, and aging, as an intercept effect. These findings support early life influence on the brain through the lifespan according to a threshold model of brain reserve, rather than a maintenance model. To test experimentally whether early life factors may still influence slopes of brain and cognitive change, a navigation training neuroimaging study of twins with known extent of discordance in BW has been conducted, preliminary data from which is also presented.
Chicken vs. Egg? A Lifespan Perspective on Education and IQ in Cognitive Reserve Research
Authors: Kremen William S. , Elman Jeremy A. , Boyle Rory , Panizzon Matthew S. , Franz Carol E
Published: December 2023

Background

Inferences about cognitive reserve and related constructs may be subject to reverse causation, but too often the possibility of reverse causation is not addressed in research on reserve and resilience. A lifespan perspective can shed light on the relationships among education, IQ, and related constructs and what can be concluded about causality with respect to late‐life cognitive and dementia outcomes.

Method

We use general cognitive ability (GCA) to refer to IQ or IQ‐like measures. We provide examples from the literature plus some new findings examining the effect of cognitive reserve on late‐life outcomes and how modifiable factors may impact reserve and resilience effects. Some of the data presented are from genetically‐informative studies that help to clarify issues related to causality.

Result

There is a bidirectional relationship between education and GCA, but the directional influences change across the lifespan. The relationship is not unidirectional in childhood and adolescence, but during that period more education does increase GCA. The effect reaches an asymptote, and in late adolescence and early adulthood, the causal direction shifts toward GCA driving educational attainment. When both education and GCA are in the same model, both longitudinal phenotypic and Mendelian randomization studies show that GCA is a stronger driver of late‐life cognitive and dementia outcomes than education. Appropriately designed studies often support the idea that occupational complexity and engagement in enriching activities are not directly causal, but are downstream effects of GCA. Finally, earlier lifestyle factors can moderate associations between cognitive reserve and late‐life outcomes. For example, favorable early midlife social/health behaviors can offset advanced brain aging in individuals with lower cognitive reserve (i.e., lower young adult GCA).

Conclusion

The results have implications regarding interventions to improve cognitive reserve and resilience, and what the balance should be when it comes to resources for early‐ versus late‐life interventions. The primary direction of causal effects raises questions about how and, importantly, when during the lifespan, increased education, cognitive enrichment/training programs (which may be thought of as a type of education), or other lifestyle factors are likely to increase reserve or resilience, thereby improving cognitive function and reducing dementia risk.
Posterior cortical atrophy in clinical practice
Authors: Maure‐Blesa Lucía , Agüero Pablo , Sainz María José , Téllez Raquel , Lorda‐Sánchez Isabel , Ávila‐Fernández Almudena , Gallego‐Merlo Jesús , Pérez‐Pérez Julián , Gómez‐Tortosa Estrella
Published: December 2023

Background

A consensus classification framework for posterior cortical atrophy (PCA) was proposed in 2017 to define the core clinico‐pathological syndrome. Main features include a variety of visuospatial deficits associated with posterior cortex dysfunction, together with predominant posterior cortical atrophy. Additional neurological symptoms may be present in what is termed PCA‐plus. Several proteinopathies could be the underlying neuropathology, though in vivo biomarkers only allow for identification of Alzheimer’s disease (AD).

Method

We described the clinical phenotype and biomarkers in a series of patients diagnosed at our memory clinic of PCA (n = 13). Retrospective review of age at onset, family history, cognitive symptoms, neurological deficits, patterns of brain atrophy in MRI, AD biomarkers in CSF, and available genetic analyses.

Result

There were eight women and five men; five had a family history of dementia (Goldman score 3.5) while eight were apparently sporadic cases. Age at onset of symptoms ranged from 30 to 75 years (median 66) and first neurological consultation was 1 to 2 years later, though both psychiatrists and ophthalmologists had already evaluated 46% of the cases. Diagnosis of PCA was established between 5 months and 5 years (mean 2 years) of first assessment. Brain atrophy was parieto‐occipital in 11 cases and temporo‐parietal in two (bilateral in seven, left predominant in four and right in two). Three cases had a PCA‐plus syndrome, one with parkinsonism an another two with CBD features. Five cases (including one with CBD) had AD CSF biomarkers studied, all with an A+T+N+ pattern. APOE was available in eight cases, five carried ε3/ε3 and three ε3/ε4 alleles. The patient with younger onset carried a PSEN1 pathogenic mutation (p.Pro436Gln). Three cases had C9orf72 expansion and plasma progranulin levels analyzed with negative results. Most cases were dependent for activities of daily living after five years of evolution.

Conclusion

This series further contributes to the characterization of the clinical heterogeneity of PCA. Anxiety and depression are common in early stages of the disease. Biomarkers are usually consistent with AD.
MONOCYTE‐DERIVED CELLS INVADE AMYLOID PLAQUES IN HUMAN ALZHEIMER’S DISEASE HIPPOCAMPUS
Authors: Mejias‐Ortega Marina , Muñoz‐Castro Clara , Sanchez‐Mejias Elisabeth , Jimenez Sebastian , Trujillo‐Estrada Laura , Vizuete Marisa , Vitorica Javier , Gutierrez Antonia
Published: December 2023

Background

Microglia, the brain‐resident myeloid cells, play a major role in the immune responses of the nervous system and in the pathogenesis of Alzheimer’s disease (AD). However, the presence of peripheral myeloid cells in the AD brains, and their contribution to disease progression, remain to be demonstrated.

Method

Cellular (immunostainings and image analysis) and molecular (qPCR and western blots) approaches have been carried out in post‐mortem hippocampal samples from patients with AD (Braak V‐VI) and age‐matched controls without neurological symptoms (Braak II).

Results

Our study provides evidence that circulating monocytes infiltrate the AD brains. Our findings showed that a high proportion of demented individuals was associated with up‐regulation of genes rarely expressed by microglial cells and abundant in monocytes‐derived cells (MDC), among which stands the scavenger receptor Cd163. These Cd163‐positive MDC invaded the brain parenchyma, acquired a microglial‐like morphology, and were located in close proximity to blood vessels. These cells infiltrated the nearby amyloid plaques contributing to plaque‐associated myeloid cell heterogeneity. Besides, control individuals with high amyloid pathology, showed no signs of MDC brain infiltration or plaque invasion. The MDC infiltration was associated with the progression and severity of AD pathology.

Conclusion

These results reveal the co‐existence of distinct myeloid populations associated with amyloid plaques during disease progression, as well their region‐specific contribution to neuroimmune protection. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only to microglia, but also to peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.

Supported by ISCiii grants(PI21‐0915 (to AG),PI21‐00914 (to JV) co‐financed by FEDER funds from European Union, by Junta de Andalucia grants P18‐RT‐2233 (to AG) and US‐1262734 (to JV) co‐financed by Programa Operativo FEDER 2014‐2020, and by grant PPIT.UMA.B1‐2019‐07 (to ESM).
The proteomic profile of Von Economo neurons supports their selective vulnerability in bvFTD
Authors: Gami‐Patel Priya , Li Ka Wan , Hondius David , Paliukhovic Iryna , Rozemuller Annemieke J.M. , Pijnenburg Yolande A.L. , Hoozemans Jeroen , Smit August B. , Dijkstra Anke A.
Published: December 2023

Background

Von Economo neurons (VENs) are long‐range projection neurons embedded in Layer 5 of the anterior cingulate gyrus (ACC) and frontoinsular cortex. VENs are selectively vulnerable in a number of diseases, most notably in those associated with behavioural, social, and cognitive changes, including the behavioural variant frontotemporal dementia (bvFTD). In particular, VENs of bvFTD donors with TDP43 or FUS pathology appear to be more vulnerable compared to donors with tau pathology. Unravelling the characteristics of VENs and the cause of their vulnerability in specific subtypes of FTD, will provide invaluable insight into disease mechanisms and potential avenues for drug therapeutics.

Method

Single‐cell laser capture microdissection (LCM) in combination with proteomics was used to analyse the proteome of VENs compared to neighbouring Layer 5 pyramidal neurons of the ACC (ACC‐PYR) and the superior frontal gyrus (SFG‐PYR), a region adjacent to the ACC. Immunohistochemistry (IHC) was performed on 10µm thick fresh frozen sections of the ACC and SFG from four neurologically healthy control donors with the neurofilament marker, SMI32. 1000 VENs and three times 1000 ACC‐PYR, and SFG‐PYR were then delineated and captured using LCM. After protein separation, all samples were analysed by label‐free mass spectrometry (LC‐MS/MS) in a data independent manner.

Result

An average 2660 proteins were detected per sample, which accumulated in a total detection of 4718 different proteins over all samples. 69 proteins had a significant change in abundance between VENs and SFG‐PYR, and 36 proteins when VENs were paired against ACC‐PYR. A number of proteins were validated with IHC. GO‐pathway analysis revealed RNA processing and splicing, neurofilament bundle assembly and cytoskeleton organization to be among top deregulated pathways, with many proteins localised to the ribonucleoprotein complex.

Conclusion

We show a number proteins involved in RNA processing to be differentially expressed in VENs compared to neighbouring pyramidal neurons. Since TDP43 and FUS proteins are also involved in RNA processing we hypothesise that the selective vulnerability of VENs in specific FTD subtypes is through altered RNA metabolism.
Adherence to healthy lifestyles during a multidomain lifestyle intervention and extended follow‐up among at‐risk population ‐ the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Ngandu Tiia , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Soininen Hilkka , Kivipelto Miia
Published: December 2023

Background

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2‐year multidomain lifestyle intervention to prevent cognitive decline. We have earlier reported that lifestyles improved during the original intervention period, both as participation in the intervention during the 2‐year period and adherence to goals of the intervention. Our aim was to study how these lifestyle changes are maintained during the long‐term period following the active intervention.

Method

Total of 1259 older adults aged 60‐77 participated in the FINGER trial and were randomized into multidomain intervention (n = 631) or control groups (n = 628). A multidomain lifestyle index (MHLI) was calculated based on self‐reported questionnaire using 12 items to obtain a total score representing all four domains of the intervention: diet, physical activity, cognitive activity, and cardiovascular risk factors (range 0 to 24). The questionnaire was repeated annually during the active intervention period and three times thereafter, total of 6 assessments over 11 years. Mixed‐effects regression analyses were executed.

Result

Among the 1259 participants 1117 (88%) completed the original study period and preliminary data were available for 484 at the 11‐year visit (38% of the original cohort; 58% of those invited). Mean MHLI was 13.5 at baseline and lower MHLI score predicted drop‐out during the post‐intervention follow‐up. In the intervention group the MHLI improved during the active period and maintained higher up to 7 years (within‐group change and difference compared with the control group p <0.05 for each year) but no longer at the 11‐year follow‐up. There were no changes in the control group. Age, education, sex, and baseline cognition were all associated with MHLI but did not modify the intervention effect.

Conclusion

A multidomain lifestyle intervention among at‐risk older adults can have an impact on multidomain healthy lifestyle up to 5 years after the active intervention. Interestingly, average lifestyle did not decrease in the control group either, which would have been expected due to aging. Ongoing detailed analyses will show if this is explained by selective dropout or if participation in the control group may have had some benefits from the participation as well.
Impairment of the locus coeruleus‐transentorhinal cortex pathway in persons at risk of Alzheimer’s disease.
Authors: Quattrini Giulia , Saglia Silvia , Marizzoni Moira , Mega Anna , D'Aprile Ilari , Cattaneo Annamaria , Gasparotti Roberto , Bortoletto Marta , Pievani Michela
Published: December 2023

Background

Recent studies reported microstructural alterations in the locus coeruleus ‐ transentorhinal cortex (LC‐TEC) pathway in patients with Alzheimer’s disease (AD) but data in subjects at risk of AD (i.e., cognitively intact APOEε4 carriers) are missing. In this study, we apply in‐vivo diffusion weighted images (DWI) to study the effect of APOEε4 on the LC‐TEC pathway in cognitively unimpaired subjects.

Method

Forty‐five participants (14 APOEε4 carriers: age = 68±7 years, 45% females, MMSE score = 29±0.9; 31 non‐carriers: age = 68±6 years, 57% females, MMSE score = 30±0.6) underwent multimodal 3T MRI and multidomain neuropsychological exams. DWI were corrected for distortions with topup and eddy tools (part of FMRIB’s Software Library – FSL). Microstructural measures as fractional anisotropy (FA), mean (MD), axial (AxD), and radial (RD) diffusivities maps were estimated using the FMRIB’s Diffusion Toolbox (part of FSL) after the exclusion of cerebrospinal fluid voxels. Microstructural integrity of LC‐TEC was assessed using a thresholded probabilistic atlas non‐linearly warped on native maps with FNIRT (part of FSL). A Bonferroni multivariate generalized linear model, corrected for age and sex, was conducted to compare the diffusivity indexes between APOEε4 carriers and non‐carriers. Association with memory functioning (immediate and delayed recall) was also tested using Spearman’s rank correlations test.

Result

APOEε4 carriers and non‐carriers were comparable for cognitive performance (p>.246). Compared to non‐carriers, APOEε4 carriers showed lower FA (p = 0.048) and higher RD (p = 0.036) in the left LC‐TEC. In APOEε4 carriers, left RD negatively correlated with both immediate (rho = ‐0.808, p<0.001) and delayed (rho = ‐0.673, p = 0.025) memory recall.

Conclusion

Microstructural alterations of the LC‐TEC pathway are detectable in subjects at‐risk for AD and correlate with lower memory performance. These preliminary results support the view that LC‐TEC impairment may play a role in AD pathophysiology since its early stages.
Cognitive impairment acceleration after late‐life depression in a model of Alzheimer´s disease
Authors: Vegas‐Gomez Laura , Lopez‐Castillo Ines , Fernandez‐Valenzuela Juan Jose , Gutierrez Antonia , Moreno‐Gonzalez Ines
Published: December 2023

Background

Clinical studies suggest that depressive symptoms could be considered an important risk factor for the future development of cognitive impairment and even Alzheimer’s disease (AD). In fact, there is a strong association between depression in later life and AD. The age of onset of AD has been shown to be accelerated in patients with mild cognitive impairment (MCI) with a history of depression, and women appear to be particularly more vulnerable to this condition. In addition, individuals with MCI who present with depressive symptoms have an elevated burden of amyloid‐beta (Aβ), the main toxic protein associated with Alzheimer’s pathology, and a higher risk of developing AD compared to non‐depressed MCI patients. However, it is unknown whether depression can be considered a risk factor for the development of AD. Although it has been described that some transgenic models of AD can develop signs similar to depression in advanced stages, the induction of Alzheimer’s pathology due to a depressive process has not been studied under experimental conditions to emulate late‐life depression as a risk factor for AD.

Method

In this study, we induced chronic unpredictable mild stress (CUMS) in P301S tau transgenic mice to determine whether depression is a cause, rather than a consequence, of the development of AD.

Result

The results of our study indicate that the induction of CUMS in transgenic animals of the disease give rise to changes in depressive state of the animals.

Conclusion

The findings generated in this project could provide evidence of depression as a risk factor for AD, its mechanisms of action, use as early biomarkers, as well as the discovery of new therapies for AD.

The objectives proposed in this research have specific funding from the Brain and Behavior Research Foundation (27565 2018 NARSAD), the B1‐2019_06 of the Own Plan of the University of Malaga, and the UMA20‐FEDERJA‐ 104FEDER Operational Program Andalusia 2014‐2020, as well as the Ramón y Cajal Program (RYC‐2017‐21879), all awarded to Dr. Inés Moreno.
Developing a tool for assessment of infographics aimed at people living with Vascular Dementia
Authors: Harkness Kirsty , Dean Laura , Thompson Celia , Nesbitt Graham , Craig Claire , Bell Simon M
Published: December 2023

Introduction

People living with vascular dementia (VaD) have an altered neuropsychological profile, including visuospatial deficits, decreased attention, altered colour perception and executive function problems. Because of this, they perceive and interpret information differently, thus we cannot assume that they read and absorb information in the same format as cognitively healthy individuals. This paper reviews current infographics available for patients with VaD and the appropriateness of information delivery within these documents.

Methods

A literature review identified the ideal features of infographic design that allow people living with VaD to engage with the infographic. Many of these ideal infographic features are not found within existing VaD resources. We developed a rating scale for the construction of future infographics, and infographic examples to ensure optimal accessibility and understanding for people living with VaD. A questionnaire was distributed to dementia clinicians across the UK to validate the scoring system and assess their views on current infographics available. A focus group of people living with dementia and their carers reviewed prototype infographics and fed back to the research team about how best to use infographics in dementia care.

Results

The literature review suggested the most important factor that determines ability of an infographic to transfer information to people living with VaD was text formatting. Of 164 clinicians the questionnaire was distributed too, we had 36 respondents (22% response rate) across 9 health care occupations. 35 (97%) believed that infographic material is useful in the memory clinic setting but only 21(58%) use these resources. Care providers felt that the most important feature of infographic design is the use of graphics (56.3%), followed by language (37.5%). The general consensus was that information should be kept simple, concise and complemented by pictures, and patients should be involved in infographic development to incorporate their opinions. Patient groups identified that having infographic information that evolved in complexity as the disease progressed would be best for patients.

Conclusion

We have developed a framework for infographic design specifically aimed at those living with VaD. This framework can be used to develop infographics best suited to the altered neuropsychological profile in VaD.
The impact of COVID‐19 lockdown on mortality rate in memory clinic patients
Authors: Bakker Els D. , Zwan Marissa D. , Gillissen Freek , Bouwman Femke H. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , van Maurik Ingrid S. , van der Veere Pieter J.
Published: December 2023

Background

People with (pre‐)dementia were particularly at risk for mortality during the COVID‐19 pandemic due to severe outcome of a COVID‐19 infection and the negative consequences of restrictive measures. Here we study whether patients during the COVID‐19 pandemic had a higher mortality rate compared to historical controls.

Method

In this case‐control study, we included patients from the Amsterdam Dementia Cohort: 1) Pandemic patients (n = 1022) with a baseline visit between January 2017 and December 2018 and 2) Historical controls (n = 930) with a baseline visit between January 2015 and December 2016. Both groups were followed for three years (pandemic patient until 2021 and historical controls until 2019). Absolute standardized mean differences were analyzed in order to determine whether groups were well‐balanced in terms of demographics and cognition at baseline. Cox proportional hazards analyses were performed to compare mortality rate during COVID‐19 pandemic with historical controls. Age, sex, diagnosis, MMSE score, education level, and comorbidity were added as covariates to the model.

Result

Both groups were well‐balanced, as mean age of the pandemic patients was 63±9 years, n = 423 (41%) were female and mean MMSE score was 24.5±5.0. Mean age of the historical controls was 63±8 years, n = 404 (43%) were female and MMSE score was 24.2±5.2. The absolute standardized mean differences were under 0.1 for all selected covariates. Among the pandemic patients, n = 180 (18%) patients died during the previously described follow‐up time. In the historical control group, n = 131 (14%) patients died. Cox proportional hazards models showed that pandemic patients had higher risk for mortality than historical controls (HR [95%‐CI] = 1.27 [1.02‐1.59]). Results remained significant after adjusting for covariates age, sex, diagnosis, MMSE score, education level, and comorbidity (HR [95%‐CI] = 1.37 [1.09‐1.72]).

Conclusion

Memory clinic patients had increased risk on mortality during times of COVID‐19 lockdown compared to historical controls. This indicates that COVID‐19 lockdown regulations have accelerated disease. Even though the cause of mortality is unknown, it is likely that the excess mortality is not only due to COVID‐19 infections, but also caused by the restrictive measure of the COVID‐19 lockdown restrictions (e.g. social isolation and loss of structure).
Effects of enlarged perivascular space in Parkinson’s disease and related cognitive decline
Authors: Kanekar Sangam , Du Guangwei , Chen Hairong , Maffie Jonathan , Lewis Mechelle , Kong Lan , Huang Xuemei
Published: December 2023

Background

The glymphatic system plays a key role in brain toxics clearance. Many studies demonstrated that disrupted glymphatic system is responsible for insufficient clearance of Aβ and tau protein in Alzheimer’s disease. Its contribution in Parkinson’s disease (PD) and related cognitive function decline has not been fully studied. Enlarged perivascular space (PVS) may be a sign of glymphatic function decline, hence leading to PD pathology and PD‐related cognitive function decline. Our objective was to study the PVS in PD and related cognitive function decline.

Method

High‐resolution T1‐weighted and T2‐weighted MRI data were acquired from 60 PD patients and 58 age‐ and sex‐matched controls. The PVS from the centrum semiovale of the white matter (CS), striatum (ST) and midbrain (MB) of the basal ganglia were segmented using the enhanced images from T1‐ and T2‐weighted images. Total intracranial volumes (TIV) were obtained to account for individual head sizes. Montreal Assessment of Cognition (MoCA) was used to quantify cognitive function. MDS‐UPDRS III scores were obtained for motor function deficits. ANCOVA was used to compare PVS metrics between PD patients and controls adjusted for age, sex, and TIV. Multiple regression was used to corelate PVS metrics and MoCA in PD patients with age, sex, MDS‐UPDRS III score and TIV as covariates.

Result

Compared to controls, PD patients had enlarged PVS in MB (p = 0.0028), but not in CS and ST. PVS metrics were strongly associated with age (p < 0.0001 for CS, p < 0.0001 for ST, and p = 0.0092 for MB), but only PVS in MB was associated sex (p = 0.0001). In PD patients, the MoCA was associated with the PVS in CS (p = 0.0132), MB (p = 0.0275) and total PVS (p = 0.0088) but only trending with PVS in ST (p = 0.0737). There is no association between MoCA and PVS metrics in controls.

Conclusion

Our findings suggested that PD patients have enlarged PVS in the midbrain, and their cognitive function is associated with enlarged PVS in both CS and MB. The enlarged PVS might be an etiological factor for PD pathology and related cognitive decline.
Computerized decision support is an effective approach to select memory clinic patients for amyloid‐PET
Authors: Rhodius‐ Meester Hanneke F.M. , van Maurik Ingrid S. , Collij Lyduine E. , van Gils Aniek M. , Koikkalainen Juha , Tolonen Antti , Pijnenburg Yolande A.L. , Barkhof Frederik , van de Giessen Elsmarieke , Lötjönen Jyrki , van der Flier Wiesje M.
Published: December 2023

Background

The use of amyloid‐PET in daily clinical practice is upcoming. Yet, ttranslation of the appropriate use criteria (AUC) to clinical practice is challenging, hampering successful implementation of amyloid‐PET. Tools that guide selecting patients for whom amyloid‐PET has most clinical utility are needed. Therefore, we developed and evaluated a computerized decision support approach to select patients for amyloid‐PET testing.

Method

We included 286 subjects (136 controls, 116 Alzheimer’s disease (AD) dementia, 26 frontotemporal lobe dementia (FTD), and 8 vascular dementia (VaD) from the Amsterdam Dementia Cohort, with available neuropsychology, APOE, MRI and [18F]florbetaben amyloid‐PET. In our computerized decision support approach, we first classified the subjects using only neuropsychology, APOE, and MRI data. Then, for uncertain subjects (probability of correct class (PPC) < 0.75) we tested the classification by adding amyloid positive (AD like) and negative (normal) visual PET read results, and assessed whether either of the values makes the diagnosis reliable (PPC≥0.75). If the threshold of PCC was reached, the actual visual PET read result was used in the final classification. We compared the proportion of PET scans and patients diagnosed with sufficient confidence (PPC ≥0.75) in the computerized approach with three scenarios: 1) without amyloid‐PET (only demographics, neuropsychology, APOE and MRI), 2) amyloid‐PET according to the AUC and 3) amyloid‐PET for all patients. The study was performed using five‐fold cross‐validation.

Result

The computerized approach advised PET in n = 76(27%) patients, leading to a diagnosis with sufficient confidence in n = 190(66%) patients. This approach outperformed the other three scenarios: 1) without amyloid‐PET, diagnosis was obtained in n = 147(51%), 2) applying the AUC resulted in amyloid‐PET in n = 113(40%) and diagnosis in n = 160(56%), and 3) performing amyloid‐PET in all patients resulted in diagnosis in n = 165(58%).

Conclusion

Our computerized data‐driven approach restricted the application of amyloid‐PET to 27% in a memory clinic cohort of controls, AD, FTD, and VaD, without compromising diagnostic accuracy. This approach can support clinicians in making a balanced decision in ordering additional biomarker testing during the dementia workup. Thus, innovative use of resources can be stimulated, which is essential when disease‐modifying drugs increase the demand for biomarker testing.
Longitudinal changes of amyloid (A) and tau (T) image‐based biomarker in Alzheimer’s disease spectrum
Authors: Kim Han‐Kyeol , Cho Hanna , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung
Published: December 2023

Background

To investigate long‐term changes in dichotomous profiles of amyloid (A) and tau (T) image‐based biomarker in Alzheimer’s disease (AD) spectrum.

Method

During the initial visit (V1), a total of 275 participants [96 cognitively unimpaired (CU), 108 mild cognitive impairment (MCI), and 71 AD] who completed 18F‐florbetaben and 18F‐flortaucipir PET studies were followed up to three times. Two years later, 189 participants (74 CU, 77 MCI, and 38 AD) were enrolled in the second visit (V2), and 83 participants (34 CU, 39 MCI, and 10 AD) were enrolled in the third visit (V3) five years later (mean 4.8 years) to complete the same PET studies. The A and T biomarker profile was determined based on the cut‐off standardized uptake value ratio of the most vulnerable region in each pathology.

Result

In A‐ participants, 5.4% (6/111) of participants converted to A+ at V2 and 17.9% (7/39) converted to A+ at V3. Likewise, 2.9% (4/138) of participants in T‐ participants converted to T+ at V2, and 17.7% (11/62) converted from T‐ to T+ at V3. Compared to the low conversion rate from T‐ to T+ in A‐T‐ participants [0.9% (1 A‐T+ / 106 A‐T‐) at V2 and 5.1% (2 A+T+ / 39 A‐T‐)] at V3, A+T‐ participants showed higher conversion rates from T‐ to T+ [9.4% (3 A+T+ / 32 A+T‐) at V2 and 39.1% (9 A+T+ / 23 A+T‐) at V3].

Conclusion

The conversion of the at biomarker profile was observed more prominently in the long term than in the short term, and the conversion of the T biomarker in A+ compared to A‐ was over seven times more frequent in five years follow‐up.
Genetic dissection of Hippocampal sclerosis MRI surrogates
Authors: Olivé Clàudia , de Rojas Itziar , Zhang Linda , Sotolongo‐Grau Oscar , Quintela Inés , García‐González Pablo , García‐Sánchez Ainhoa , Puerta Raquel , Valero Sergi , Cano Amanda , Calero Miguel , Rabano Alberto , Pastor Ana Belén , Ser Teodoro , Medina Miguel , Sanchez‐Juan Pascual , Strange Bryan A , Carracedo Angel , Marquié Marta , Tárraga Lluís , Boada Mercè , Ruiz Agustin
Published: December 2023

Background

Hippocampal sclerosis of aging (HS) is one of the most predominant causes of dementia in elder populations and it is often misdiagnosed as Alzheimer’s disease (AD). HS has recently been found to show a hippocampal atrophy pattern that might be key for the differentiation of this pathology from AD in the early stages of dementia.

Method

In this study, we aimed to find SNPs associated with AD diagnosis that might be related to HS. To that end, we calculated a polygenic risk score (PRS) combining SNPs associated with AD by Bellenguez et al. (2022) and assessed their relation with HS‐by‐proxy based on magnetic resonance imaging (MRI) data of hippocampal subfield volumes from 1,130 individuals without dementia syndrome.

Result

Our results show a significant association of AD‐PRS with fimbria and hippocampal body and head volumes. Association with these hippocampal subfields was also observed on the individual effects of the AD‐related variants in the SHARPIN (rs34173062) and TNIP1 (rs871269) genes. Besides, these loci remained consistently associated to HS‐aging after increasing the sample size by including an independent cohort of healthy individuals (N = 729).

Conclusion

The results presented in this study suggest that some SNPs that have recently been identified as AD variants might be closely related to atrophy in hippocampal subfields instead of AD, and hence, could be instrumental to refine AD and HS pathways, their interrelationships, and to elaborate specific treatment for each condition.
Repetitive transcranial magnetic stimulation increases synaptic plasticity of cortical axons in the APP‐PS1 mouse model of amyloidosis
Authors: Fulopova Barbora , Bennett William , Canty Alison Jane
Published: December 2023

Background

Repetitive transcranial magnetic stimulation (rTMS) is non‐invasive brain stimulation with therapeutic potential for use in diseases causing dementia. We previously demonstrated that low intensity (LI) rTMS induced functional improvements in the accuracy and rate of learning in adult mouse skilled reaching paradigms (Tang, Bennett et al, Scientific Reports, 2018) and induced dendritic spine changes in cortical motor neurons after a single application of LI‐rTMS (Tang, Bennett et al, Brain Stimulation, 2021). Here, we investigate the effect of LI‐rTMS on axonal boutons of excitatory axons in the presence of amyloid pathology in the APP‐PS1 mouse.

Method

APP/PS1 mice were crossed with Thy1‐GFPM mice to visualise excitatory axon circuitry in the presence of amyloid plaque pathology. Multiphoton imaging through a cranial window was used to identify cortical axons in the upper layers of the sensorimotor cortex in adult animals (10‐12 months old) and monitor the stability and turnover (gains and losses as a fraction of total number of synapses) of axonal boutons in the presence (APP‐GFPM) or absence (WT‐GFPM) of amyloid pathology. Axons were imaged at 48‐hour intervals for 8 days either side of a single session of LI‐rTMS.

Result

The density of axonal boutons along the axon shaft was stable and comparable in APP‐GFPM and WT‐GFP mice, before and after LI‐rTMS. The turnover of synapses was significantly (p < 0.05) reduced in APP‐GFPM cortical axons compared to WT‐GFPM prior to stimulation. A single session of LI‐rTMS induced a significant (p < 0.01)and sustained increase in synaptic turnover in both genotypes. Interestingly the initial lower turnover of boutons in the APP‐GFPM cortex was increased to the levels observed in WT‐GFPM axons at baseline.

Conclusion

In the presence of amyloid pathology, synaptic density in excitatory cortical axons is unchanged, however the dynamic fraction of synapses is reduced in compared to aged‐matched controls. LI‐rTMS boosts synaptic plasticity in mature cortical axons in both the presence and absence of plaque pathology. Together with our findings of improved functional performance following stimulation, these results suggest not only possible mechanisms of action but also a potential clinical benefit in the management of Alzheimer’s disease.
Benzodiazepine use in relation to long‐term dementia risk and imaging markers of neurodegeneration: a population‐based cohort study.
Authors: Hofe Ilse E. M. , Stricker Bruno H. , Vernooij Meike W , Ikram M. Kamran , Ikram M. Arfan , Wolters Frank J.
Published: December 2023

Background

Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well‐established acute adverse effects on cognition. However, long‐term effects on dementia risk remain uncertain, and on subclinical imaging markers of neurodegeneration largely undetermined.

Method

We included 5443 cognitively healthy participants (MMSE≥26) from the population‐based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005‐2008) was derived from ATC‐coded pharmacy records, from which we determined drug type (anxiolytics vs. sedative‐hypnotics vs. both) and cumulative dose. We determined the association of benzodiazepine use with dementia risk until 2020 using Cox regression, and with change in neuroimaging markers during 5‐yearly repeated brain MRI using linear mixed models. Models were adjusted for demographics, lifestyle factors and comorbidity, including presence of anxiety, depression and sleeping problems.

Result

During a mean follow‐up of 11.2 years, 726 participants (13.3%) developed dementia. Benzodiazepine use occurred in 1675 (30.8%) participants, of whom 845 (50.4%) had used anxiolytics, 390 (23.3%) had used sedative‐hypnotics, and 440 (26.3%) had used both. Current use of any type of benzodiazepine at baseline, but not former use, was associated with an increased dementia risk during follow‐up (HR[95%CI] for current users: 1.56[1.17‐2.09]; and past users: 1.07[0.87‐1.31]). Excess risk in current users persisted after excluding a 2‐year lag‐time of benzodiazepine use prior to baseline. Dementia risk was dependent on cumulative dose (>median: HR[95%CI] 1.31[1.05‐1.63] vs. < = median: HR[95%CI] 1.01[0.78‐1.31]). Use was not associated with volume of grey matter, white matter, hippocampus, amygdala or thalamus at baseline. During follow up, high cumulative dose was associated with accelerated decrease in hippocampal volume (p = 0.021). Regarding drug type, dementia risk was increased with anxiolytics (overall HR[95%CI]: 1.37[1.10‐1.71]), which was paralleled by accelerated atrophy of grey matter (p = 0.036), albeit no dose‐response relationship was observed. Sedative‐hypnotics were not associated with dementia risk or brain atrophy. Combined use of anxiolytics and sedative‐hypnotics at baseline was associated with increased dementia risk (HR[95%CI]: 1.70[1.05‐2.76]), but this attenuated after excluding use during a 2‐year lag time before baseline (HR[95%CI]: 1.08[0.71‐1.64]), and was not associated with brain atrophy.

Conclusion

Chronic use of benzodiazepines in a population of cognitively healthy older adults is associated with increased dementia risk.
A DIAGNOSIS APPROACH FROM DIFFERENT NATURE BIOMARKERS TO PREDICT THE ALZHEIMER DISEASE RISK
Authors: Cháfer‐Pericás Consuelo , Álvarez Lourdes , Peña‐Bautista Carmen , Ferré‐González Laura , Lara Sergio , Deltell Anabel Forte , Baquero Miguel
Published: December 2023

Background

Alzheimer Disease (AD) diagnosis requires invasive and expensive techniques (cerebrospinal fluid (CSF) biomarkers, neuroimaging), which could not be extended to general population. So, minimally‐invasive, specific and accurate AD diagnosis are needed. Recent studies have identified blood compounds (lipid peroxidation compounds, lipids, proteins…) as potential diagnosis biomarkers. Therefore, research focused on the development of diagnosis models from different nature blood biomarkers is required, allowing to obtain information about the molecular mechanisms in AD. In this sense, the present study consists of the study of different plasma biomarkers (lipids, lipid peroxidation metabolites, microRNAs) impairment, and the development of a potential diagnosis model.

Method

Participants provided informed consent, these are patients who come to the neurology unit with memory complaint. They were neuropsychologically evaluated, and cerebrospinal fluid samples (CSF) were obtained to determine some biomarkers (β‐amyloid‐42, β‐amyloid‐40, p‐Tau, t‐Tau, neurofilament light chain). A total of 85 participants, aged 50 to 79 years, were included in this study. They were classified into early AD patients (mild cognitive impairment (MCI), mild dementia), other dementias (frontotemporal dementia, Lewy body dementia, vascular dementia) and people cognitively healthy. Also, blood samples were taken to determine some potential biomarkers (lipid peroxidation compounds, microRNAs) by means of mass spectrometry and quantitative PCR. Finally, statistical Bayesian analysis were carried out to develop the optimum diagnosis model.

Result

Some lipids, lipid peroxidation compounds and microRNAs showed different blood levels among participants groups. From these results, and considering the variables Bayesian selection (18_0_Lyso_PC, 16_0_SM, 18_0_SM, total neuroprostanes, total isoprostanes), it was developed the optimum model to predict early AD. This model showed satisfactory diagnosis indexes.

Conclusion

Different nature biomarkers are involved in AD development, reflecting the complex disease physiopathology. Therefore, a multi‐nature biomarkers approach could provide a useful tool for early and minimally invasive screening.