bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic aspects in the association between orthostatic hypotension and cognition: a prospective cohort study
Authors: Starmans Naomi LP , Wolters Frank J. , Leeuwis Anna E , Bron Esther E , de Bresser Jeroen , La Rocca Hans‐Peter Brunner‐ , Staals Julie , Muller Majon , Biessels Geert Jan , Kappelle Jaap ,   Heart‐Brain Connection Consortium
Published: December 2023

Background

Orthostatic hypotension (OH) is related to an increased risk of dementia. To explore whether cerebral hypoperfusion could play a role in this relation, we assessed different OH patterns in relation to cognitive functioning and vascular brain injury in hemodynamically compromised participants of the Heart‐Brain Connection Study.

Method

Participants with carotid occlusive disease (COD) or heart failure (HF), and reference participants underwent OH measurements, neuropsychological assessment and a brain MRI at baseline and after 2 years of follow‐up. OH was defined as a drop in blood pressure upon standing of ≥ 20 mmHg systolic or ≥ 10 mmHg diastolic. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity volume and lacunar infarcts with linear and logistic regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms to model different levels of hemodynamic impact.

Result

We included 348 participants (mean age 67.3±8.7 years, 121 females) of whom 192 completed 2‐year follow‐up. OH was present in 118 (33.9%) participants. Overall, prevalence of OH was not associated with cognitive function at baseline, with similar results after stratification by participant group. Still, those with OH did perform worse on cognitive assessment in case of large blood pressure drops (≥25 mmHg systolic or ≥15 mmHg diastolic; β ‐0.07, 95%CI: ‐0.13 – ‐0.02), in case of absent chronotropic incompetence (increase in heart rate ≥8 beats/min; β ‐0.06, 95%CI: ‐0.10 – ‐0.01) or when OH was accompanied by clinical symptoms (β ‐0.10, 95%CI: ‐0.18 – ‐0.01). OH patterns were not associated with change in cognition during follow‐up in the total sample. Brain imaging markers at baseline or follow‐up did not differ between participants with or without OH.

Conclusion

While more severe OH was associated with reduced cognitive function cross‐sectionally, we observed no association with cognitive decline or vascular brain injury on MRI in hemodynamically compromised individuals. These observations do not support the hypothesis that hypoperfusion is the main driver of the association between OH and dementia risk.
Clinical Characteristics and Follow‐up Assessment in Patients Diagnosed with Alzheimer’s Dementia Through Regional Dementia Centers and Conventional Hospital System
Authors: Jeong Eun Hwan , Park Kyung Won , Park Doug Ho
Published: December 2023

Background

The rapidly increasing socioeconomic burden due to dementia is a significant global public health issue. To address this issue in Korea, regional dementia centers (RDCs) have been established nationwide. This study investigated the clinical features and courses in patients diagnosed with Alzheimer’s dementia(AD) through RDCs or conventional hospital system in the community.

Method

This retrospective cohort study was performed in a single general hospital and included patients newly diagnosed with AD from January 2019 to March 2022. Analysis was conducted to compare two groups of patients: the hospital group, who came directly to the hospital, and the RDC group, who were referred to the hospital from the RDCs in Pohang city. Their clinical courses were followed for a year after AD diagnosis.

Result

A total of 1209 study participants were assigned to the hospital (n = 579) or RDC group (n = 630). The RDC group was 80.1 ± 6.6 years old, significantly older than the hospital group (P <0.001). In the linear regression model, the RDC group independently associated the CDR‐SB increment (β = 19.007 and P <0.001). In the multivariable binary logistic regression model, the RDC group showed a significantly lower risk for hospitalization within one year after the diagnosis of AD (odds ratio, 0.54; 95% confidence interval, 0.30–0.98; P = 0.014).

Conclusion

AD patients in the RDCs were older, diagnosed with more advanced conditions, and were rated as having more rapid cognitive decline than patients diagnosed in the conventional hospital system. RDCs may contribute to the initiation of treatment by discovering AD patients hidden in the community due to limited access to healthcare.
Domain‐specific subtle cognitive decline associations with cerebrospinal fluid and plasma β‐amyloid and p‐tau Alzheimer’s disease biomarkers in cognitively unimpaired individuals
Authors: López‐Martos David , Sánchez‐Benavides Gonzalo , Suarez‐Calvet Marc , Escalante Armand González , Milà‐Alomà Marta , Gispert Juan Domingo , Minguillón Carolina , Kollmorgen Gwendlyn , Carboni Margherita , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Grau‐Rivera Oriol
Published: December 2023

Background

Presence of Alzheimer’s disease (AD) core pathology, β‐amyloid (Aβ) and p‐tau, has been proven to impact cognitive function even in cognitively unimpaired (CU) individuals. Although the Aβ and p‐tau (AT) effect has been mainly associated with memory function, recent evidence (Tideman, P., 2022. Neurology) suggested that Aβ levels were associated independently of p‐tau with the cross‐sectional performance in executive functioning. The aim of the present study was to explore specific associations of cerebrospinal fluid (CSF) and plasma Aβ and p‐tau baseline levels with the longitudinal change in several cognitive domains in a sample of CU individuals at increased risk of AD.

Method

We analyzed the associations of baseline CSF Aβ42/40, and p‐tau181 as well as plasma Aβ42/40, and p‐tau231 levels, with domain‐specific cognitive changes 3 years after baseline in 337 CU participants from the ALFA+ study. We defined AT groups (A‐T‐, A+T‐, and A+T+) using CSF levels, and the A‐T‐ group’s baseline performance served as reference to compute z‐scores for Visual Processing, Semantic Fluency, Executive Functioning, Episodic Memory, and Attentional Processing. Delta scores were computed by subtracting baseline from follow‐up scores and then compared among AT groups by means of ANCOVAs. Multiple linear regressions were performed on the whole sample using CSF Aβ42/40, p‐tau181 and plasma Aβ42/40, p‐tau231 as predictors of change in cognitive function.

Result

A+T+ individuals showed a significant decline in Executive Function (p = 0.005, Cohen’s d = 0.716), and Attentional Processing (p = 0.032, Cohen’s d = 0.563), but not in Episodic Memory (p = 0.334) when compared with A‐T‐ individuals. In the whole sample, CSF Aβ42/40 was associated independently of p‐tau181 with a decline in Semantic Fluency (β = 6.284, p = 0.013), Attentional Processing (β = 3.828, p = 0.020), and Episodic Memory (β = 3.513, p = 0.004). Plasma p‐tau231 levels were associated with a decline in Semantic Fluency (β = ‐0.413, p = 0.045). CSF p‐tau181 and plasma Aβ42/40 were not associated with cognitive changes.

Conclusion

Executive Function and Attentional Processing were more sensitive than Episodic Memory in capturing the early subtle cognitive changes in CU individuals with underlying AD pathology. Attentional Processing was the only cognitive domain associated both with the status of AD biomarkers and with the effect of CSF Aβ levels independently of p‐tau.
Home‐based solutions for dementia management: Results from a survey of dementia caregiver
Authors: Rodriguez Francisca S , Ross Sabrina D , Ziegert Nadja
Published: December 2023

Background

Living with dementia affects almost every aspect of life. Medical care concepts, however, focus mainly on biological aspects of the disease so that many caregivers have to find solutions themselves for dealing with the other aspects of daily life. Aim of the present study was to identify such solutions.

Method

We conducted a survey with seven groups of stakeholders in dementia care, (1) caring spouses, (2) caring family members, (3) professional caregivers, (4) volunteering/nonprofessional caregivers, (5) therapists, (6) counselors for people with dementia, and (7) people with dementia themselves. A total of 131 participants reported their experiences and perceptions in structured interviews.

Result

We will report on home‐based solutions for dementia management our participants have reports. Specifically, we report on the type of solutions, by whom they are conducted, how often they are applied, how they are financed, and what positive effects are experienced. Further, we report on what our participants perceived as most effective for increasing well‐being, reducing cognitive decline, and dealing with behavioral problems or with depression.

Conclusion

Our results indicate a number of useful home‐based solutions for people with dementia. Given the many challenges that come with dementia, care concepts incorporating such solutions are urgently necessary to improve well‐being of those living with dementia.
APOE3 Christchurch heterozygosity delays clinical onset in autosomal dominant Alzheimer’s disease
Authors: Quiroz Yakeel T. , Aguillon David , Zuluaga‐Castaño Yesica , Baena Ana Y. , Vasquez Daniel , Garcia Gloria , Madrigal Lucia , Hincapie Liliana , Sanchez Justin S , Sepulveda‐Falla Diego , Vila‐Castelar Clara , Gomez Liliana Ramirez , Aduen Paula , Acosta‐Uribe Juliana , Kosik Kenneth S. , Johnson Keith A. , Sperling Reisa A. , Reiman Eric M. , Lopera Francisco , Arboleda‐Velasquez Joseph F
Published: December 2023

Background

We previously reported a case of a homozygous woman with the APOE3 Christchurch (R136S, APOE3Ch) variant who demonstrated extreme resistance to autosomal dominant Alzheimer’s disease (ADAD) caused by the PSEN1 E280A variant. In this study, we examined the potential protective effects of APOE3Ch against ADAD by characterizing the clinical profile of individuals who were heterozygous for the APOE3Ch variant from the Colombian kindred with the PSEN1 E280A variant.

Methods

A total of 421 carriers of the PSEN1 E280A variant were included. Of the 421 carriers, 12 were heterozygous for APOE3Ch (including the previously reported homozygous for APOE3Ch). Clinical and neuropsychological assessments were performed in Spanish at the University of Antioquia in Colombia. Four of the APOE3Ch carriers also donated their brains for postmortem studies. A PSEN1 E280A who is heterozygous for the APOE3Ch variant also underwent structural MRI and amyloid and tau PET imaging.

Results

Our findings showed that PSEN1 E280A carriers who are heterozygous carriers of the APOE3Ch variant had a significantly delayed onset for mild cognitive impairment (MCI, median age of 51 vs. 45 years; p = 0.0048) and dementia (52.5 vs. 48 years; p = 0.016), compared to PSEN1 E280A carriers without the APOE3Ch variant. Specifically, APOE3Ch carriers had seven‐time higher odds of developing MCI and three‐time higher odds of developing dementia at a later age than 75% of all the PSEN1 E280A carriers (odds ratio [OR] = 7.6; 95% confidence interval [CI] 1.9, 29.2, p<0.05); dementia OR = 3.07; 95% CI 1.01, 9.33). Initial characterization of brain imaging of a PSEN1 E280A carrier who is heterozygous for the APOE3Ch variant showed levels of medial temporal lobe tau pathology and hippocampal atrophy that were lower than expected for a typical carrier of their age, and similar to our observations in the previously reported APOE3Ch homozygote case.

Conclusions

These clinical, cognitive, and neuroimaging data provide evidence that APOE3Ch heterozygosity delays the onset of cognitive decline and may have a protective, dose‐dependent effect against tau pathology and neurodegeneration. These results provide support for the potential of the APOE3Ch variant as a target for the development of new treatments for AD.
Cost‐effectiveness of amyloid‐targeting therapies: modelling based on 5724 biomarker positive AD patients in the Swedish Registry of Cognitive Disorders
Authors: Jönsson Linus , Skillback Tobias , Kern Silke , Winblad Bengt , Blennow Kaj , Eriksdotter Maria , Zetterberg Henrik , Wimo Anders
Published: December 2023

Background

Lecanemab is an amyloid‐targeting therapy recently approved by the U.S. FDA for treatment of early Alzheimer’s disease. A phase III trial (Clarity AD) demonstrated a reduction of disease progression, however uncertainty remains around the long‐term health outcomes and implications for cost‐effectiveness. Previous economic evaluations have been limited by lack of long‐term follow‐up data on health outcomes and resource utilization in AD patients with biomarker‐confirmed amyloid pathology.

Method

5724 patients with longitudinal follow‐up data were included from the Swedish Registry of Cognitive Disorders (SveDem), linked to other data sources. Amyloid positivity was determined from the CSF beta amyloid 1‐42/p‐Tau ratio, with optimal cut‐off levels determined from Abeta 40/42 ratios. Patients were followed up to 12.9 years from diagnosis (mean 4.9 years). A disease model model was constructed with states defined by cognitive status (MCI/dementia, MMSE score) and care setting (community/institution). The semi‐Markov design allows transition probabilities to vary with time spend in individual states. Hazard rates for disease progression, institutionalization and mortality were estimated using semiparametric survival models based on SveDem linked to the municipal care and death registries. Costs by disease state were estimated from resource utilization data from the national patient and prescription drug registries on formal medical and community care. Health utility values by disease state were derived from previous observational studies in Sweden.

Result

A therapy reducing disease progression to more severe cognitive states by 31% over a treatment period of 18 months (as in Clarity AD) was associated with savings in formal care costs of 41,000 SEK and 0.140 quality‐adjusted life‐years (QALYs) gained. At 1 million SEK per QALY, treatment would be cost‐effective at an annual cost of 121,000 SEK, including costs for diagnosis and monitoring. Almost half of estimated QALY gains were due to reduced mortality; setting survival equal in treated and untreated patients resulted in fewer QALYs gained but higher cost savings.

Conclusion

This is the first study to report on the cost‐effectiveness of amyloid‐targeting therapy based on integrated disease progression and cost data from a large, representative cohort of amyloid‐positive early AD patients. Such data is of critical importance to enable cost‐effective introduction of lecanemab.
Choroid plexus volume, cognitive spectrum, and biomarkers of brain aging in older adults: The MIND‐China MRI Study
Authors: Song Lin , Li Yuanjing , Han Xiaodong , Wang Jiafeng , Li Chunyan , Cong Lin , Hou Tingting , Wang Yongxiang , Du Yifeng , Qiu Chengxuan
Published: December 2023

Background

The choroid plexus (CP) is a major source of cerebrospinal fluid (CSF) production that has been involved in clearance of CSF proteins and regulation of brain function, and possibly, in the pathogenesis of Alzheimer’s dementia. However, population‐based studies have not yet investigated the associations of CP volume with cognitive function and biomarkers of pathological brain aging in older adults.

Method

This population‐based cross‐sectional study included 1220 older adults (age ≥60 years) derived from the Multimodal INterventions to delay Dementia and disability in rural China, who underwent structural brain magnetic resonance imaging scans. CP was automatically segmented and quantified on 3T structural T1‐weighted images. Cognitive function was assessed using a neuropsychological test battery. Dementia, Alzheimer’s disease (AD), and mild cognitive impairment (MCI) were diagnosed following the international criteria. In the subsample (n = 905), we measured plasma amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL) using the Simoa platform. Data were analyzed with logistic and the general linear regression models.

Result

In the total sample (n = 1220), 275 persons were diagnosed with MCI (22.54%), 30 with all‐cause dementia (2.46%), and 26 with AD (2.13%). Controlling for demographics, total intracranial volumes (ICV), cardiovascular risk factors and related disorders, and APOE genotype, larger CP volume was significantly associated with increased likelihoods of dementia (adjusted odds ratio = 2.12; 95% CI = 1.33‐3.36), AD (2.28; 1.37‐3.80), and MCI (1.27; 1.07‐1.50). In addition, larger CP volume was significantly associated with lower z‐scores of verbal fluency, executive function, and global cognition (p<0.05). Furthermore, larger CP volume was associated with smaller volumes of total gray matter and hippocampus, and greater volumes of lateral ventricles, global white matter hyperintensity (WMH), and periventricular WMH (p<0.05). In the plasma subsample, larger CP volume was significantly associated with higher plasma Aβ42 concentration (p<0.05), and marginally with higher plasma Aβ40 concentration (p = 0.07).

Conclusion

Large CP volume is associated with poor performance across the cognitive continuum as well as with biomarkers of cerebral atrophic, neurodegenerative, and microvascular lesions in older adults.
Results from the Systematic Multi‐domain Alzheimer’s Risk Reduction Trial (SMARRT): A Personalized Approach
Authors: Yaffe Kristine , Vittinghoff Eric , Dublin Sascha , Peltz Carrie , Fleckenstein Lynn E , Rosenberg Dori E , Barnes Deborah E , Balderson Benjamin H , Larson Eric B
Published: December 2023

Background

Modifiable risk factors are hypothesized to account for 30‐40% of dementia; yet, few trials have demonstrated that risk reduction interventions, especially multi‐domain, improve risk factors or cognition. We conducted the Systematic Multi‐domain Alzheimer’s Risk Reduction Trial (SMARRT), a 2‐year personalized, pragmatic risk reduction intervention.

Methods

We recruited 172 adults at elevated risk for dementia (age 70‐89 and ≥ 2 targeted risk factors) from primary care clinics of Kaiser Permanente Washington. Participants were randomly assigned to the SMARRT intervention (personalized risk reduction goals with health/nurse coaching) or to Health Education (HE) control. The primary outcome was change in a composite modified Neuropsychological Test Battery (mNTB); pre‐planned secondary outcomes were change in risk factors and quality of life. Outcomes were assessed at baseline, 6, 12, 18, and 24 months (initially in person, then due to COVID‐19, by phone). We used linear mixed models to compare, by intention‐to‐treat, changes from baseline averaged over the four follow‐up assessments.

Results

Participants had a mean age of 75.7 years (sd 4.8), 63% were women and 81% non‐Hispanic White. After 2 years, compared to the 90 in the HE control, the 82 adults assigned to SMARRT demonstrated larger improvements in the composite cognitive score (average treatment effect 0.15 SD; 95% CI 0.04‐0.26, p = 0.008; an 80% improvement compared to HE change), better composite risk factor score (average treatment effect 0.11 SD; 95% CI 0.02‐0.21, p = 0.02) and improved quality of life (average treatment effect 1.11 points; 95% CI 0.08‐2.14, p = 0.03). There were no between‐group differences in serious adverse events or SAEs (HE = 23, SMARRT = 24, p = 0.59), but the intervention group had greater treatment related AEs such as musculoskeletal pain (14 vs. 0, p<0.001). Both groups expressed high level of satisfaction with the trial with greater satisfaction in intervention arm.

Conclusion

A 2‐year personalized, multidomain intervention led to modest improvements on cognition, most targeted risk factors, and quality of life. Modifiable risk reduction strategies should be considered for older adults at risk for dementia.
The AGED Triad: Opportunities for delaying dementia
Authors: Pieruccini‐Faria Frederico , Finger Elizabeth , Hachinski Vladimir , Montero‐Odasso Manuel
Published: December 2023

Background

Apathy, gait impairment, and executive dysfunction (AGED) commonly occur jointly in the elderly, sometimes masked by the generic description of “late life depression.” The recognition of the triad is clinically useful because it often results from hypertension, which is treatable and preventable. Vascular risk factors, especially hypertension, can insidiously cause brain damage which may increase the risk of dementia in older adults. Hence the AGED triad can be a behavioral marker of cerebrovascular damaging which may lead to cognitive disability. It is unclear, however, whether individuals diagnosed with the AGED triad phenotype are at higher risk of earlier conversion to dementia compared with non‐AGED triad phenotype. We also tested the hypothesis that AGED triad would have better predictive capability than each of the three components separately.

Method

After baseline assessments 275 community‐dwelling older individuals (72.15±6.68 years of age; 58% women) from the Gait and Brain Study underwent face‐to‐face interviews every 6 months for up to 7 years (22.93±20.33 months; 6∼105). Gait performance was assessed electronically; apathy was assessed through the Geriatric Depression Scale‐3A; dysexecutive function was assessed trough the Trail Making test‐part B; dementia was diagnosed through the clinical dementia rating scale. Adjusted Cox‐regression models were used to determine early dementia risk in each exposure group.

Result

A greater percentage of AGED triad individuals at baseline had more than 2 vascular risk factors (p<.01) including hypertension, diabetes, hypercholesterolemia, obesity and smoking history. Incidence of dementia in the AGED triad was 16.8% vs. 6% in the non‐AGED triad. AGED triad significantly increased the risk of earlier conversion to dementia compared with non‐AGED triad by 323% independently of the number of vascular risk factors at baseline. AGED triad predicted earlier conversion to dementia more than the three components separately (HR = 6.60 95%CI 1.48 to 29.46; p = .01; see figure 1).

Conclusion

AGED triad phenotype predicts earlier conversion to dementia compared with non‐AGED triad; and earlier than slow gait, apathy and dysexecutive function separately. AGED triad may be a behavioral marker of severe insidious brain damage over of an individual’s life course likely caused by unmanaged modifiable vascular risk factors.
Exercise‐induced alterations to glial activation in the 5xFAD mouse model of Alzheimer’s Disease
Authors: Birnbaum Allison , Rorrer Shelby , Wilson Anna , Cortes Constanza J
Published: December 2023

Background

Glial activation and subsequent inflammation are well‐described characteristics of Alzheimer’s disease (AD) and have been demonstrated to contribute to disease progression. Exercise contributes to structural and functional changes in the brain, including in models of AD by improving neuronal plasticity and reducing glial activation. The exact glial pathways altered by exercise have not been well‐described, making it difficult to develop therapeutic interventions that can provide similar benefits as physical activity.

Method

We selected to use the 5xFAD model based on the early amyloid plaque development (1.5‐2 months) and neuroinflammation onset (5‐6 months) time points. Two‐month‐old hemizygous 5xFAD and B6SJLF1 control female mice were given free access to running wheels for 16 weeks. All running activity was tracked over 12‐hour cycles. Locked wheels were used for both genotypes as sedentary controls. Hippocampal RNA from all 4 groups was isolated and analyzed using the Nanostring mouse AD and mouse neuroinflammation nCounter panels. We will also examine changes to amyloid plaque burden and morphological differences in astrocytes and microglia in the hippocampus via histological approaches.

Result

5xFAD runners had significantly higher weights compared to their sedentary littermate controls, suggesting endurance exercise provides metabolic maintenance in this model. In agreement with this, no such weight gain was observed in the B6SJLF1 age‐ and sex‐matched control runners. Surprisingly, we found control mice ran faster and more often per interval than their 5XFAD counterparts. Using Nanostring nCounter, we observed little to no difference between B6SJLF1 running and sedentary groups, however runner 5XFAD mice were closer to control values compared to their sedentary 5XFAD counterparts for many pathways including lipid metabolism and neural connectivity. We are currently investigating the genes in these pathways and other inflammatory genes not included in the two nCounter panels, as well as histological analysis of amyloid plaque burden.

Conclusion

We have observed significant physical changes between running and sedentary 5xFAD mice, supporting the hypothesis that physical activity provides beneficial effects against AD. Data acquired from this study will also aid in our understanding of exercise alterations to signaling pathways, and highlight potential therapeutic targets to reduces neurodegenerative disease‐associated neuroinflammation.
The DECIDE‐initiative: A multi‐dimensional project aiming to reduce sedative drugs of patients with dementia in long term care
Authors: Diehl‐Schmid Janine , Kohl Sarah , Trojan Monika
Published: December 2023

Prescription prevalence of sedative drugs – mostly used for the treatment of neuropsychiatric symptoms ‐ in patients with dementia in Germany is approximately 40%. Since sedative drugs cause a variety of adverse effects and might reduce quality of life significantly, the aim must be to use sedative drugs only as much as necessary and as little as possible.

The DECIDE initiative was founded at the Department of Psychiatry at the Technical University of Munich and funded by the Bavarian State Ministry of Health. DECIDE uses a multidimensional approach to raise awareness among all stakeholders in the health care system for a more conscious and responsible use of sedative medication in people with dementia and thus to sustainably reduce the frequency of prescriptions.

The DECIDE initiative includes a webpage (www.decide.bayern) with thorough and comprehensive information for informal and formal caregivers, legal guardians, nursing staff and doctors; a telephone hotline for patients and caregivers; network building; awareness campaigns; and continuing education.

A particular important component of the DECIDE‐initiative is the DECIDE LTC‐visits. So far, 30 randomly chosen LTC facilities in Bavaria have been visited by a medical specialist for gerontopsychiatry. In each facility the gerontopsychiatrist offered a training event for the nursing home staff in order to explain behavioral symptoms, non‐pharmacological interventions, and the effects and side effects of sedative drugs, as well as the potential for deprescribing. In each attending LTC facility the prescription prevalence of sedative drugs was assessed. Medical and nursing records were checked in order to find out, if deprescribing – according to a deprescribing algorithm that was recently developed within the DECIDE project (Roßmeier et al., 2022, Nervenarzt) ‐ could be recommended. The prescribing prevalence as assessed in 1492 residents with dementia was 51%. In 70 out of 202 residents describing could be recommended and was discussed with the treating physician.

One year follow‐up visits will show if the DECIDE initiative is able to sensitize physicians and nursing homes to the problem of sedating psychopharmacotherapy and the potential for deprescribing, reflected then in a lower prescription prevalence.
Update on [18F]ACI‐12589: a novel and promising PET tracer for a‐synuclein
Authors: Capotosti Francesca , Smith Ruben , Vokali Efthymia , Molette Jerome , Ohlsson Tomas , Schain Martin , Ravache Myriam , Dimitrakopoulos Ioannis K , Delgado Christophe , Kocher Jacqueline , Pittet Laure , Vallet Coralie , Luthi‐Carter Ruth , Hliva Valerie , Pfeifer Andrea , Kosco‐Vilbois Marie , Streffer Johannes , Hansson Oskar
Published: December 2023

Background

Parkinson’s disease (PD) and other synucleinopathies, such as Multiple System Atrophy (MSA), involve a progressive accumulation of a‐synuclein (a‐syn) inclusions which correlate well with clinical manifestations. A PET agent capable of imaging specifically and selectively a‐syn inclusions could significantly improve differential diagnosis and clinical trials for drug candidates targeting a‐syn. Here, we report the preclinical and initial clinical characterization of [18F]ACI‐12589 in patients with different synucleinopathies.

Method

Leveraging AC Immune’s proprietary small molecule Morphomer® library, compounds were optimized for affinity and specificity for pathological a‐syn as well as for selectivity versus frequent co‐pathologies, using autoradiography and radiobinding techniques. Based on these results [18F]ACI‐12589, was selected for initial clinical evaluation. PET scans were acquired for approximately 50 participants including idiopathic and genetic PD, MSA, Dementia with Lewy bodies (DLB) in addition to controls and cases from other neurodegenerative disorders (NDDs). Initial participants underwent 0‐90 min dynamic scans with arterial blood sampling allowing full kinetic modeling, while following scans were acquired as 60‐90 min static scans.

Result

When tested on tissue sections, ACI‐12589 demonstrated a specific signal matching the distribution of pathological a‐syn. This target engagement was observed across a range of cases with different synucleinopathy diagnoses, but also in tissues from other NDDs, when a‐syn inclusions were present as co‐pathology. ACI‐12589 is selective in vitro versus frequent co‐pathologies such as amyloid‐b and Tau and has a clean off‐target profile, including for MAO‐A and B. Initial clinical data indicate that [18F]ACI‐12589 displayed substantial retention in MSA cases in expected disease‐affected brain areas based on clinical manifestations. When quantified, the signal in the cerebellar peduncles was clearly discriminating the MSA group from controls, synucleinopathy cases and other NDDs. In addition, this signal could not be blocked in vivo by the MAO‐B inhibitor Selegiline. Although to a lower level than in MSA cases, some signal retention was observed in different NDDs.

Conclusion

[18F]ACI‐12589 displays the preclinical and clinical characteristics deemed necessary to become a reliable and accurate PET radiotracer for the detection of a‐syn pathology in MSA. Additional evaluations of this tracer will focus on the longitudinal and early disease stage assessments.
Synaptic proteins in pre‐symptomatic Alzheimer’s disease: biomarkers for early detection of Cognitive Decline
Authors: Ao Jiarui , Labonté Anne , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   the PREVENT‐AD Research Group
Published: December 2023

Background

Synaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre‐symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease.

Method

The PREVENT‐AD cohort includes symptom‐free (upon enrolment) elderly participants who are at risk of developing AD from their family history. We used enzyme‐linked immunosorbent assay kits to assess CSF samples from 129 such participants for the “classical” AD biomarkers total tau, phosphorylated (181) tau and Aβ42. We also used neuroimaging data (MRI, PET) and neuropsychological assessments (MMSE, RBANS) as potential indicators disease progression. We then used in the CSF samples to measure the soluble synaptic biomarkers ADAM 22 (post‐synaptic), ADAM23 (pre‐synaptic). Immunoprecipitated SYT1 (pre‐synaptic) from CSF were analyyzed using high‐resolution selected ion monitoring analyses on a quadrupole–orbitrap mass spectrometer Q Exactive. Statistical analysis of the association of these markers with evidence of disease in analyses were done included sex and APOE e4 status as covariates.

Result

Among participants who remained cognitively unimpaired, we observed significant correlations between baseline CSF ADAM 22 levels and t‐tau (R2 = 0.22, p < 0.0001), p‐tau (R2 = 0.22, p < 0.0001), and Aβ42 (R2 = 0.06, p = 0.01488). We also found similarly suggestive correlations also between CSF ADAM 23, CSF SYT1 and the same disease markers. Covariate analyses suggested little or no variation in the associations between these synaptic proteins with t‐tau and p‐tau by sex, APOE e4 status, negative PET amyloid positivity (standardized uptake value ratio ≤ 1.37) and negative CSF total tau positivity (≤ 335pg/ul). PET amyloid positivity was significantly associated with ADAM22 and p‐tau interactions whereas SYT1 was significantly associated with t‐tau and p‐tau in CSF tau‐positive participants. In linear regression analyses, baseline CSF ADAM22 levels correlated with the language cognitive performance trajectory slopes estimated over the course of 5 to 8 years on the RBANS (R2 = 0.04, p = 0.03912). We found no significant interaction between other baseline CSF synaptic protein levels and other subscales of the RBANS.

Conclusion

CSF synaptic protein levels show promising correlation with landmark AD proteins and emerging cognitive deficits.
Effects of Acceptance and Commitment Therapy (ACT) group intervention for the treatment of anxiety in family carers of people with dementia: an exploratory randomised controlled trial
Authors: Ferreira Michele Gomes , Kishita Naoko , de Faria Renata Caetano Vieira , Plautino Maria Eduarda Almeida , Yonamine Gustavo Campos , Torres Suellen Caroline Ribeiro , Caramelli Paulo
Published: December 2023

Background

The prevalence of anxiety symptoms is estimated to be equal to or higher than the prevalence of depressive symptoms in family carers of people with dementia. However, anxiety is currently somehow neglected in the carer literature. Previous studies demonstrated that Acceptance and Commitment Therapy (ACT) is effective for treating anxiety symptoms in family carers of people with dementia, but these studies were mainly conducted in developed countries. The current study explored the effectiveness of an ACT group intervention on the anxiety symptoms in Brazilian family carers of people with dementia.

Method

A single‐centre, unblinded, double‐arm exploratory randomised trial was conducted. Fifty‐seven family carers of people with dementia presenting with mild to severe anxiety symptoms were randomised to the intervention group (n = 29) or waiting list group (n = 28). The intervention group received eight weekly sessions of Group ACT, delivered through videoconference. Participants completed the measure of anxiety and depressive symptoms, caregiver burden, psychological flexibility and quality of life at Week 0, Week 9 and Week 20. Multiple linear regression analyses were performed to evaluate whether there was a significant difference in scores between the intervention and control groups, at week 9 and week 20, while controlling for the baseline scores using both intention‐to‐treat and completers data analyses.

Result

Participants were mostly women, from low‐ to middle‐income socioeconomic levels, with a mean age of 52 years and median education of 15 years. Participants in the intervention group had lower scores of anxiety and depression symptoms compared to participants in the control condition at weeks 9 and 20 in both the intention‐to‐treat and completer analyses. Only participants who attended six or more sessions (i.e. completer sample) demonstrated reduced caregiver burden at both follow‐up points. The completer sample also showed improvement in quality of life at week 9. The results did not show any effect of the intervention on psychological flexibility.

Conclusion

This study provides evidence supporting the use of group ACT, delivered through videoconference, with family carers of people with dementia to help them cope better with anxiety and depressive symptoms.
Decline in white matter volume and EEG delta oscillations in mild cognitive impairment
Authors: Özbek Yağmur
Published: December 2023

Background

Changes in white matter (WM) may be associated with progression and risk of Alzheimer’s disease (AD) (Nasrabady et. al, 2018) along with conversion to Mild Cognitive Impairment (MCI) (Smith et. al, 2008). Total WM volume and its relation with EROs in MCI remain unclear. As a general notion, greater delta EROs occurring in the post‐stimulus time‐period indicate better cognitive responses in contrary to dynamics of resting state EEG. Surgical WM disruptions are associated with alterations more prominently in low frequency brain oscillations (EROs) (Hawasli et al, 2016). The current study aims to investigate WM volumes and EROs in cognitively unimpaired individuals (CU) and MCI.

Method

Sixteen individuals with MCI were compared with demographically matched 16 CU using EROs elicited by a visual classical‐oddball paradigm along with WM volumes obtained 3D T1‐weighted TFE‐sequence. WM volumes analyzed with univariate ANOVA. Repeated measures ANOVAs conducted for delta(0.5‐3.5Hz), theta(4‐7Hz), alpha(8‐13Hz), beta(15‐30Hz), and gamma(30‐48Hz) amplitudes. Binary logistic regression analyses conducted for significant WM volume variables and EROs. Correlations between WM and EROs were analyzed with Person correlation coefficient.

Result

Delta ERO amplitudes were diminished [F(5,145) = 3.373,p = .035] in MCI at frontal (p = .011), central (p = .014) and parietal (p = .006) electrode locations. Furthermore, WM in right middle orbitofrontal [F(1,29) = 4.599,p = .041], left inferior temporal [F(1,29) = 4.198,p = .049] and left parahippocampal gyrus [F(51,29) = 5.182,p = .030] demonstrated less volume in MCI compared to CU. Binary logistic regression indicated that [X2(9) = 26.615,p = .002] combined WM volumes and delta EROs can classify MCI and CU with 87.1% accuracy. There were positive correlations between occipital delta and left (r = .501, p = .003) and right gyrus rectus (r = .374, p = .003) WM volumes.

Conclusion

This study showed WM volumes and delta EROs were reduced in MCI. Decreased amplitudes of delta EROs seem to reflect volume loss of WM in MCI, possibly indicating an underlying demyelination or axonal loss. Delta EROs and WM changes may be helpful tools to monitor MCI focusing on axons and myelination/oligodendrocytes. Furthermore, their combined measurements can classify MCI from healthy individuals sufficiently.
Lobe‐specific changes in white matter volume and myelination following 6‐month 40 Hz gamma sensory stimulation in patients on the Alzheimer’s disease spectrum
Authors: Cimenser Aylin , Da Xiao , Hempel Evan , Malchano Zach , Vaughan Brent , Megerian Jonathan Thomas , Hajos Mihaly
Published: December 2023

Background

Although morphometric changes in Alzheimer’s Disease (AD) occur both in gray and white matter, gray matter changes had been the primary focus of previous work. Recent studies have highlighted the importance of pathological changes in white matter and myelination in AD patients, including early changes to oligodendrocytes and transcription of myelin protein genes in the white matter prior to symptoms of cognitive decline, even in subjects with AD but without other neurological comorbidities (Ferrer et al., 2020). Since neuronal activities, particularly network oscillations have been shown to promote myelination, the present study examined how 40Hz gamma stimulation affected white matter volume and myelination in different cortical lobes in patients with AD.

Method

Data were obtained from the Overture trial (NCT03555281) in which treatment participants received daily, at‐home, 40Hz gamma sensory stimulation for six months, while placebo participants received sham stimulation (treatment‐to‐placebo ratio 2:1). Magnetic resonance imaging (MRI) data were collected at 1.5 Tesla at baseline, month 3, and month 6. MRI T1 images and T1w/T2w ratios were used to estimate volume (N = 38) and myelination (N = 36), respectively. Using Bayesian linear mixed effects modeling, we estimated white matter volume and myelination percent changes with respect to baseline. Treatment group results were reported in relation to the placebo group.

Result

With respect to the placebo group: In the left hemisphere, the treatment group exhibited reduced white matter atrophy in the frontal lobe (‐3.27±1.4, p = 0.0225), in the temporal lobe (‐3.9±1.76, p = 0.0306), in the parietal lobe (‐3.32±1.43, p = 0.0236), in the occipital lobe (‐4.1±1.72, p = 0.0195) and reduced demyelination in the frontal lobe (‐5.13±2.12, p = 0.0186), in the temporal lobe (‐5.33±2.42, p = 0.0321), in the parietal lobe (‐5.7±2.07 (p = 0.0079), in the occipital lobe (‐5.65±2.52, p = 0.0296). In the right hemisphere, the treatment group trended towards reduced white matter volume loss and demyelination in all lobes, however, demyelination was significantly reduced in the parietal lobe (‐4.48±2.09, p = 0.037), and in the occipital lobe (‐5.5±2.22, p = 0.0165).

Conclusion

White matter atrophy and demyelination were statistically significantly reduced in all lobes of the left hemisphere and trended towards reduction in the right hemisphere, demonstrating that 40Hz sensory stimulation can reduce the neurodegeneration associated with AD.
Gestational Diabetes Mellitus Triggers Maternal Premature Brain Aging and Brain Pathologies
Authors: Huang Huatuo , Oo Thura Tun , Apaijai Nattayaporn , Suntornsaratoon Panan , Charoenphandhu Narattaphol , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

It has been well‐documented that diabetes mellitus (DM) causes brain pathologies and premature brain aging. Previous studies showed that women with gestational diabetes mellitus (GDM) are at a high risk to develop depression. It is unclear whether GDM can lead to brain pathologies and premature brain aging, thus contributing to cognitive behavior changes as observed in human and animal studies.

Method

Female Sprague‐Dawley rats were fed either a normal diet (ND, 5% kcal from fat) or a high‐fat diet (HFD, 45% kcal from fat) throughout the entire study. At week 4, rats were mated overnight with ND‐fed male rats, and successful pregnancy was denoted as pregnancy day 0 (P0). At P0, HFD‐treated rats were intraperitoneally injected with a single‐dose streptozotocin (STZ, 35 mg/kg) to induce DM or the same amount of vehicle as HFD‐control. The ND‐treated rats received the same amount of vehicle as the ND‐control. Oral glucose tolerance test and plasma insulin levels were assessed at pregnancy day 16 to confirm the GDM model. At postpartum day 21, maternal rats were sacrificed, and brains were rapidly removed to determine brain pathologies and premature brain aging in the prefrontal cortex and hippocampus.

Result

Rats treated with HFD and HFD+STZ developed prediabetes and diabetes conditions, respectively. GDM induced brain inflammation and brain cell senescence, as indicated by increases in nuclear factor kappa‐light‐chain‐enhancer of activated B, senescence‐associated beta‐galactosidase, and p16 expression in the prefrontal cortex and hippocampus (Figure 1). Furthermore, mitochondrial fusion was enhanced, while brain apoptosis was attenuated in the prefrontal cortex and hippocampus of GDM rats (Figure 1).

Conclusion

GDM triggers maternal brain pathologies as well as premature brain aging in both prefrontal cortex and hippocampus. Our findings highlight that the brain may have compensatory mechanisms that can help guard against the negative effects of GDM.
Correlation between depressive symptom severity and functional status in patients with mild cognitive impairment
Authors: Won Wangyoun
Published: December 2023

Background

Although depression is a common co‐morbid disorder in patients with mild cognitive impairment (MCI), not all patients with MCI exhibit depressive symptoms. This study aimed to investigate the effect of depression on cognitive and functional decline in MCI.

Method

281 patients with MCI (MCI) defined by 0.5 score on Clinical Dementia Rating were included in the study. Patients were divided into three groups based on their Geriatric Depression Scale (GDS) scores: MCI without depression (GDS<10, n = 50), MCI with mild depression (GDS10∼19, n = 120), and MCI with severe depression (GDS>20, n = 111). Cognitive function tests (cognitive domains in CERAD‐K including letter fluency, trail making test‐A and B, and verbal learning test) and Blessed Dementia Scale‐Activities of Daily Living (BDS‐ADL) were measured. Group differences were analyzed using an analysis of variance (ANOVA). Correlation between GDS scores and BDS‐ADL were analyzed.

Result

An ANOVA test showed that activities of daily living differed significantly across groups (F(2, 276) = 13.53, p<0.001). Post‐hoc analysis showed MCI with severe depression had a significantly higher mean BDS‐ADL score compared with both MCI without depression and MCI with mild depression (both, p<0.001). Correlation analysis showed significant positive correlation between GDS and BDS‐ADL (r = 0.366, p<0.001). However, mean scores of cognitive function tests were not different among three groups.

Conclusion

The present study suggests that co‐morbid depressive symptoms may have negative impact on functional status in patients with MCI. This may further suggest the importance of evaluation and treatment of depressive symptoms in patients with MCI.
Possible role of gut derived metabolites in communication between systemic inflammation and CNS in delirium development.
Authors: Trzpis Monika
Published: December 2023

Background

Dementia and delirium are strongly correlated. Patients with dementia are more prone to develop delirium, while delirium can lead to accelerated cognitive decline. Biomarkers present in the CSF have been considered to belong to the pathophysiological pathways between systemic inflammation, neuroinflammation, gut microbiota and consequently, contribute to the etiology of both the cognition impairments, ie. delirium and dementia. Despite multiple studies on inflammatory biomarkers in CSF, the link with systemic inflammation has still not been deciphered. Multiple studies have indicated that inflammatory pathways in patients with cognitive decline are mediated by gut microbiota.

Method

In this narrative review we screened PubMed for studies, where neuroinflammatory biomarkers detected in CSF were investigated in relation to delirium. We will explain the link to microbiome by comparing these delirium studies to microbiome studies in dementia. These studies were published in English till January 2023.

Result

We found that in patients with Alzheimer’s disease (AD) and delirium altered levels of at least 70 different neuroinflammatory biomarkers in CSF were found. Also altered microbiome has been identified in AD and its correlation with the CNS inflammation was shown. Interestingly, in case of AD, a recent study demonstrated that a microbial‐derived metabolite, trimethylamine N‐oxide (TMAO), reaches the CNS and that its elevated levels are present in AD patients.

In case of delirium, we found two studies indicating contribution of disbalanced gut microbiota in acute CNS inflammation in human. It has been shown that preoperative status of gut microbiota can allow prediction of postoperative delirium in patients with gastric cancer. Interestingly, there was already one case described where fecal microbiota transplantation ameliorated patient’s infection and delirium. No studies on microbiome‐derived metabolites, which could constitute a possible link with the acute inflammation of CNS in delirium, have been found.

Conclusion

There is irrefutable evidence that altered levels of neuroinflammatory biomarkers in CSF are associated with pathology of both AD and delirium. Implication of the microbiome, and microbial‐derived metabolite TMAO in inflammatory processes and in pathophysiology of AD has already been found. This has encouraged us to investigate the role of TMAO in the acute CNS inflammatory condition, i.e. delirium.