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Background: Aging is consistently associated with cortical gray matter (GM) reductions. Bilingualism has been described as a potential reserve contributor for successful brain aging and has been associated with a variety of structural changes in cortical morphology. In this study we aim to: 1) Explore differences between bilinguals and monolinguals on the whole brain cortical thickness, area and volume, 2) explore if correlations between age and cortical measures are different between bilinguals and monolinguals, and 3) to evaluate age‐bilingualism interaction effects on the cortical characteristics. Method: Cross‐sectional study with healthy volunteers from the Gipuzkoa Alzheimer Project (GAP) cohort. Cognitively unimpaired (CDR Global Score = 0) with available 3T MRI were included and classified as bilinguals or monolinguals based on daily use of both Spanish and Basque languages or only Spanish. Subjects with diffuse white matter lesions (Fazekas scale = 3) were excluded. Cortical reconstruction was performed with Freesurfer package v5.1. as described in Montal et al., 2017. Analyses were conducted in the whole brain using linear modeling of the maps and Monte Carlo simulation corrected for multiple comparisons as implemented in FreeSurfer's QDEC interface. Result: Sample included 88 bilinguals and 83 monolinguals (see Table 1 for demographic and clinical characteristics). Whole brain cortical thickness, area or volume were not significantly different between groups. Age‐cortical thickness and volume correlation maps showed broader areas of negative associations in the monolingual than in the bilingual group, and inverse associations in the relationship with area characterized by negative correlations in monolinguals and positive and negative correlations in bilinguals (Figure 1). More specifically, significant age‐bilingualism interactions were found for thickness in the right superiorfrontal gyrus (p = 0.012), and for the surface area, in the inferiorparietal (p = 0.0001), supramarginal (p = 0.043) and lingual (p = 0.042) regions of the left hemisphere. Conclusion: Cortical thickness and area variations occurring in relation to aging in cognitively healthy individuals could be modulated by bilingualism. [ABSTRACT FROM AUTHOR]

Background: Physical function profiles of older adults (≥ 60years) cognitively unimpaired but at high risk of dementia (CAIDE dementia risk score ≥6) have not been well described. The CAIDE index evaluates both modifiable, cardiovascular (CVRF), and non‐modifiable risk factors such as age, sex and educational level. The association of these factors with physical function has not been thoroughly studied. Method: We present preliminary cross‐sectional data from the first 2 (out of 4) recruitment waves of the CITA Go‐On study, a FINGER‐like multimodal intervention prevention trial. Inclusion criteria were based on age (≥60 and ≤85) and CAIDE score (≥6). Participants were categorized according to their cognitive status. Physical function assessment included gait speed, handgrip strength and maximum leg strength measured as 1 repetition maximum (1RM). We explored physical function by CAIDE scale, regarding hypertension (i.e. systolic >140mmHg or diastolic >90mmHg), hypercholesterolemia (i.e >250 mg/dL) and body mass index (BMI) as modifiable risk factors, and accounting for age, sex and educational level as non‐modifiable ones. Analysis was performed with SPSS v.29. Result: Sample of 380 subjects aged 68.4 ± 5.6 years (mean, SD), 50% women, Mini‐Mental State Examination (MMSE) mean of 28.4 ±1.7 and CAIDE index mean was 7.4 ± 1.3. Of these, 91.6% were cognitively preserved, 5.5% had subjective complaints and 2.9% mild cognitive impairment. Dyslipidemia was present in 23.4%, hypertension in 46.9% and 63.1% showed BMI of overweight or obese. Univariate regression analysis showed that CAIDE index was significantly associated to maximum leg strength (1RM) (η2= 0.05, p = 0.008), after adjusting for non‐modifiable risk factors (age η2= 0.054, p = 0.001; sex η2= 0.453, p = 0.001; and educational level η2= 0.003, p = 0.333) and BMI (η2= 0.156, p = 0.001). Handgrip strength and gait speed were not explained by modifiable factors in our sample (p = 0.12 and p = 0.53). Conclusion: Physical function as measured by maximum leg strength is associated with CAIDE dementia risk index, and most significantly with sex and BMI component, with age displaying a moderate effect. Together with vascular risk factor control, interventions on physical function are important for prevention. [ABSTRACT FROM AUTHOR]

Background: The FINGER study demonstrated the efficacy of a non‐pharmacological multidomain intervention to prevent cognitive decline in at‐risk older adults. After a successful pilot feasibility study, in Q3 2021 we launched the CITA GO‐ON study, inspired by FINGER methodology to demonstrate the efficacy of a risk factor and lifestyles multimodal intervention to prevent cognitive decline in southern Europe. Here we describe the baseline characteristics of participants recruited in the study. Method: The CITA GO‐ON study (ClinicalTrials.gov, NCT04840030) is a two‐year randomized, controlled trial. The primary aim is to reduce the risk of decline in cognitive functioning in the Neuropsychology Test Battery after two years by a multi‐modal intervention on risk factors and protective life‐styles as compared to standard health care. Inclusion criteria are: 60‐85 years old; CAIDE dementia risk score ≥ 6; cognitive frailty; no dementia. The multidomain intervention includes optimized control of cardiovascular risk factors; correction of polypharmacy; cognitive training; physical exercise program; socioemotional intervention; and promotion of adherence to the Mediterranean diet. Results: To date, 1964 individuals completed pre‐screening using self‐administered online survey in REDCap (Research Electronic Capture) and 874 (44.5%) fulfilled criteria for an in‐person screening visit. Screening was successful in 477 of participants. Mean (SD) age is 66.24 (4.99), 13.26 (4.43) years of education, MMSE 28.27 (1.78), CAIDE score 7.48 (1.36), and 235 (49%) are men. Based on CAIDE components, at baseline, 287 (60%) showed high systolic blood pressure, 165 (35%) low physical activity, 122 (26%) high BMI, and 101 (21%) with high cholesterol. Regarding cognitive frailty, 144 (31%) presented low performance on brief cognitive testing (Memory Alteration Test ≤ 40 and/or Fototest ≤ 35), 186 (39%) presented memory complaints (Cognitive Change Index ≥ 20), and 147 (30%) showed both criteria. Currently, 191 have been randomly assigned to the control and 192 to the Intervention groups. So far, adherence to intervention activities is high, ranging from 73% to 97%, depending on the modality. Conclusion: CITA GO‐ON Study recruitment strategy includes participants with high risk of dementia based on modifiable factors and in situation of cognitive fragility, with might increase the probability of obtaining positive efficacy results. [ABSTRACT FROM AUTHOR]

Background: FINGER trial has demonstrated the potential for dementia prevention by targeting different lifestyle domains in older adults. It highlighted the importance of selecting the correct window of opportunity for preventive actions by including participants at high risk of dementia. This approach is being tested worldwide to support future public health interventions, where the selection of the appropriate target population is crucial. Here we share our approach and results in recruiting older adults with increased dementia risk and cognitive frailty from the general population for the CITA Go‐On trial. Method: CITA GO‐ON is a single‐center randomized controlled trial in which non‐demented‐adults between 60‐80y will be allocated to receive standard care or a risk factor control and lifestyle‐based multidomain intervention. It replicates FINGER trial inclusion criteria, but the recruitment strategy is based on the community level in Gipuzkoa (Spain) instead of a previous health registry. Together with press and social media releases, mailing, and small group talks, the main recruitment strategy has been coordinated with local governments. Interested people fulfill an online form that allows identifying those who meet the pre‐established requirements (CAIDE dementia risk score ≥6) prior to attending an individualized face‐to‐face cognitive screening visit (evaluation of exclusion criteria and brief cognitive testing). Result: By December 2022, we have reached and informed about the trial more 24000 people including all citizens older than 60 in three small municipalities in collaboration with the local town halls. Of these, 1919 completed the pre‐screening questionnaire using REDCap, 868 were screened and 450 recruited (mean age: 68,57 (6,58), 50,87% female, and mean CAIDE: 7,49 (1,39)). In person calculated (mean (sd): 6,98 (1,70)) and self‐reported (mean (sd): 7,23 (1,77)) CAIDE score is similar (p = 0,062) in our experience. Table 1 resumes age, sex, CAIDE and MMSE of the interested sample. Recruitment period is still opened. Conclusion: CITA GO‐ON recruitment is a multi‐disciplinary population oriented efficient strategy to identify adults at high risk of dementia understanding and willing to participate in a multi‐modal intervention prevention trial. It allows to select candidates from the whole population, and not only those linked to specialized health care systems or registries. [ABSTRACT FROM AUTHOR]

Objectives: We studied a sample of cognitively unimpaired individuals, with and without subjective cognitive decline (SCD), in order to investigate accelerated long-term forgetting (ALF) and to explore the relationships between objective and subjective cognitive performance and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers.Methods: Fifty-two individuals were included and SCD was quantified through the Subjective Cognitive Decline Questionnaire (SCD-Q), using its validated cutoff to classify participants as Low SCD-Q (n = 21) or High SCD-Q (n = 31). These groups were further subdivided according to the presence or absence of abnormal levels of CSF Aβ42 . Objective cognitive performance was assessed with the Ancient Farming Equipment Test (AFE-T), a new highly-demanding test that calls for acquisition and retention of novel object/name pairs and allows measuring ALF over a 6-month period.Results: The High SCD-Q group showed a significantly higher free forgetting rate at 3 months compared to the Low SCD-Q (F [1,44] = 4.72; p < 0.05). When stratifying by amyloid status, High SCD-Q/Aβ+ showed a significantly lower performance than High SCD-Q/Aβ-on the final free and cued learning scores (F [1,27] = 6.44, p < 0.05 and F [1,27] = 7.51, p < 0.05, respectively), the 1-week free and cued recall (F [1,24] = 4.49; p < 0.05 and F [1,24] = 7.10; p < 0.01, respectively), the 1-week cued forgetting rate (F [1,24] = 5.13; p < 0.05), and the 3-month cued recall (F [1,24] = 4.27; p < 0.05). Linear regression analyses showed that higher SCD-Q scores were associated with higher forgetting rates on the AFE-T (β = -0.212; p < 0.05).Conclusions: It is possible to detect ALF in individuals with high SCD ratings, appearing especially in those with abnormal CSF Aβ42 levels. Both in research and the clinical field, there is an increasing need of using more demanding cognitive measures, such as the AFE-T, for identifying and tracking the earliest cognitive changes in these populations. [ABSTRACT FROM AUTHOR]

Accelerated long‐term forgetting (ALF) refers to a rapid loss of information over days or weeks despite normal acquisition/encoding. Notwithstanding its potential relevance as a presymptomatic marker of cognitive dysfunction, no study has addressed the relationship between ALF and Alzheimer's disease (AD) biomarkers. We examined ALF in APOE ɛ4 carriers versus noncarriers, and its relationships with AD cerebrospinal fluid (CSF) biomarkers. We found ALF over three months in APOE ɛ4 carriers (F(1,19) = 5.60; P < 0.05; Cohen's d = 1.08), and this performance was associated with abnormal levels of the CSF Aβ42/ptau ratio (r = −.614; P < 0.01). Our findings indicate that ALF is detectable in at‐risk individuals, and that there is a relationship between ALF and the pathophysiological processes underlying AD. [ABSTRACT FROM AUTHOR]

Background: Abnormal cholesterol metabolism changes the neuronal membrane and interferes with amyloidogenesis. Oxysterols in CSF are related to Alzheimer's disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. We aim to demonstrate that the association of oxysterols, biomarkers and WM microstructure occurs early in asymptomatic individuals. Method: We studied the association of inter‐individual variability of CSF 24‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), 7‐ketocholesterol (7‐KC), 7β‐hydroxycholesterol (7β‐OHC), β‐amyloid1‐42 (Aβ42), total‐tau (t‐tau), phosphorylated‐tau (p‐tau), neurofilament (NfL) and WM microstructure in cognitive regions, using diffusion tensor imaging (DTI), generalized lineal models and moderation/mediation analyses in 153 healthy adults. Result: 7‐KC levels were related to Aβ42 (B = ‐1.41; p = 0.041). Higher 7‐KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD) and radial (RD) diffusivity in cognitive regions. 7‐KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017) and genu (B = 68.64, p = 0.000) and fornix (B = 10.97, p = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD and RD in the fornix, corpus callosum, inferior longitudinal fasciculus and hippocampus. The association between AxD and Aβ42 was moderated by 7K‐C (p= 0.048). Conclusion: This study adds clinical evidence to support the role of 7K‐C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process. [ABSTRACT FROM AUTHOR]

Background: GOIZ ZAINDU ("caring early" in Basque) is a pilot study to adapt FINGER methodology to the Basque Population and evaluate feasibility and adherence to a FINGER‐like multimodal intervention program. Additional exploratory aims included assessment of efficacy on cognition and collection of necessary data to design a large efficacy trial. Method: GOIZ ZAINDU is a one year, randomized, controlled trial of a multimodal intervention in persons aged 60+ with increased CAIDE score (≥ 6), no dementia, and below‐than‐expected performance in at least one of three cognitive screening tests. Participants were recruited from a previous program on early diagnosis and risk awareness (GOIZ‐ALZHEIMER). Randomization to a Multimodal intervention (MI) or to Regular Health Advice (RHA) was stratified by cognitive status (MCI/normal) and age (>/≤ 75). MI included cardiovascular risk factors control, nutritional counseling, physical activity and cognitive training. Primary outcome was adherence to intervention program. Cognitive outcomes included Neuropsychological Test Battery z scores change. Analyses were carried out by intention to treat. Result: 125 participants were recruited (mean age: 75.64 (6.46); 58% women). MI (n=61) and RHA (n=64) groups were balanced in demographics and cognition (Table 1). 52 (85%) participants from RHA and 56 (88%) from MI group completed the study. 55% of participants had attended all intervention activities; 70% attended more than half of cognitive sessions; and 55% attended more than half of cardiovascular, nutritional and physical activity program sessions Risk of cognitive decline was higher in RHA group compared with MI in executive Function (EF)(p=.019) and Processing Speed (PS) scores (p=.026) (Table 2). 32 (64%) participants In the RHA and 22 (40%) in the MI group declined in EF; 30 persons (61%) in the RHA and 22 (39%) in the MI declined in PS, Conclusion: The GOIZ‐ZAINDU study has proved that the FINGER methodology is adaptable and feasible in a different socio‐cultural environment. Exploratory efficacy results show lower risk of decline in EF and PS. These results support the design of a large‐scale efficacy FINGER‐like trial in Southern Europe, the GO‐ON study. [ABSTRACT FROM AUTHOR]

Introduction: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). Methods: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging‐Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. Results: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. Discussion: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to study motor and nonmotor symptoms and striatal dopaminergic denervation, as well as the relationship between them, in a cohort of asymptomatic relatives of patients with Parkinson's disease (PD) with the R1441G-leucine-rich repeat kinase 2 mutation. Methods: Asymptomatic relatives of patients with PD and this mutation were tested for the presence of the mutation and evaluated for striatal, putamenal, and caudate dopaminergic transporters using (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single-photon emission computed tomography binding ratios. Clinical and neuropsychological evaluations including timed motor tests, a smell identification test, and global cognition, attention, executive, visuospatial, and memory functions as well as depression, constipation, and rapid eye movement sleep behavior disorder were also assessed. Results: Twenty-seven carriers and 19 noncarriers were studied. Compared with noncarriers, mutation carriers had significantly lower (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan mean striatal (P = 0.03), mean putamenal (P = 0.01), and lowest putamenal (P = 0.01) binding ratios. Multiple linear regression analysis showed that the carrier status and the execution of timed tests significantly predicted striatal (123)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane binding. The proportion of variation accounted for by the regression model of these variables was 69% for the putamen and 53% for the caudate nucleus. Conclusions: Asymptomatic carriers of the R1441G-leucine-rich repeat kinase 2 mutation have evidence of dopaminergic nigrostriatal denervation, mainly in the putamen, which is associated with a decline in the execution of complex motor tests. These tests could be early indicators of the ongoing dopaminergic deficit in this group at risk of PD. [ABSTRACT FROM AUTHOR]

ABSTRACT An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population-based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD-G2019S carriers (20%) than in PD-R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non-skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Previous trials in Europe (FINGER, MAPT and PreDIVA) have shown that interventions on risk and protective factors represent a window of opportunity for dementia prevention, especially in participants with increased risk. To fully understand the potential impact of these interventions, their feasibility and efficacy needs to be explored in contexts worldwide. GOIZ ZAINDU ("caring early" in Basque language) is a pilot study to adapt FINGER methodology in Southern Europe with the aim to evaluate the feasibility of a lifestyle intervention program in this cultural and social context. An additional exploratory aim is to assess the efficacy of the intervention on cognition. Method: GOIZ ZAINDU is a one year controlled, randomized, multimodal intervention. Inclusion criteria were: age 60+; CAIDE dementia risk score of 6 points or higher; no dementia; and below‐than‐expected cognitive performance in at least one of three brief cognitive screening tests. Cognitive status (MCI or normal) and age were accounted for randomization to a multidomain intervention (MI) or to Regular Health Advice (RHA). MI includes cardiovascular risk control, nutritional counseling, physical activity program, and cognitive training. Cognitive outcomes include the modified Neuropsychological Test Battery (mNTB) composite score change, and domain Z score change for executive function, processing speed, and memory. Mixed‐effects regression models with maximum likelihood estimation to analyze change in cognitive scores as a function of randomization group, time and groupxtime interaction will be performed. Result: 125 participants were recruited. 64 people were assigned to MI and 61 to RHA. The study started in June 2018, last patient first visit was in March 2019. Up to date 94 participants have completed the study that will end in April 2020. Exploratory results of the efficacy analysis of the intervention on cognition change will be presented. Conclusion: The GOIZ‐ZAINDU study has proved that the FINGER methodology is adaptable and feasible in a different socio‐cultural environment. Exploratory efficacy results will support the design of the large‐scale efficacy FINGER‐like trial in the Basque Country. [ABSTRACT FROM AUTHOR]