Establishing In-House Cutoffs of CSF Alzheimer's Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort.

BACKGROUND: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. METHODS: We quantified CSF Aß1-42, Aß1-40, t-Tau, and p181Tau with standard INNOTEST® ELISA and Lumipulse G® chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for Aß1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and Aß1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and Aß1-42/Aß1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). RESULTS: Cutoff values of Aß1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for Aß1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for Aß1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the Aß1-42/Aß1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815-27). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. CONCLUSIONS: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.

Pain and recurrent falls in the older and oldest-old non-institutionalized population.

BACKGROUND: Recurrent falls represent a priority in geriatric research. In this study we evaluated the influence of pain as a risk factor for recurrent falls (two or more in 1 year) in the older (65-79 years) and oldest-old (80 or more years) non-institutionalized population. METHODS: Prospective cohort study. 772 non-institutionalized individuals with ages of 65 years or older (with overrepresentation of people aged 80 years or older [n = 550]) were included through randomized and multistage sampling, stratified according to gender, geographic area and habitat size. Basal evaluation at participant's home including pain evaluation by Face Pain Scale (FPS, range 0-6) and then telephonic contact every 3 months were performed until complete 12 months. Multivariate analysis by logistic regression (recurrent falls as outcome variable) for each age group (older and oldest-old group) were developed considering pain as a quantitative variable (according to FPS score). Models were adjusted for age, gender, balance, muscle strength, depressive symptoms, cognitive decline, number of drugs and number of drugs with risk of falls. RESULTS: 114 (51.35%) and 286 (52%) participants of older and oldest-old group, respectively, reported pain; and recurrent falls occurred in 6.93% (n = 12) of the older group and 12.06% (n = 51) of the oldest-old group. In the older group, pain was associated with recurrent falls, with an associated odds ratio (OR) of 1.47 (95% CI 1.08-2.00; beta 0.3864) for each unit increase in pain intensity (thus, participants with the most severe pain [FPS 6] had OR of 10.16 regarding to participants without pain [FPS 0]). In the oldest-old group, pain was not associated with recurrent falls. CONCLUSIONS: Pain, a potentially modifiable and highly prevalent symptom, is a risk factor for recurrent falls in the older people (65-79 years). However, we have not been able to demonstrate that this relationship is maintained in the oldest-old population (80 or more years).

Prevalence and treatment of pain in non-institutionalized very old population: transversal study at national level.

BACKGROUND: In Europe, there is no conclusive data at national level about pain prevalence in non-institutionalized very old population. In USA, it has recently been reported a high prevalence (56 %); however, this data can not be extrapolated to other regions because the known influence of geographical and ethnic differences. Furthermore there are few data on use of treatments for pain in this population. AIMS: To explore prevalence and considered pharmacological treatments for pain in this population. METHODS: Transversal study on 551 participants aged 80 or more living in Spain (non-institutionalized). Probabilistic multistage sampling was carried out, stratified by sex and place of residence. All Spanish regions were considered for recruitment process. Pain (last 4 weeks), intensity (Face Pain Scale), localization and pharmacological treatments were evaluated by in-person interviews. RESULTS: Pain's prevalence was 52.5 % (CI 95 % 48.28-56.80) and 38.5 % experienced pain of at least moderate intensity. The most frequently involved body regions were lower limbs (26.6 %) and dorso-lumbar region (21.9 %). Only 40 % of participants with pain and 43.2 % with moderate or severe pain used analgesics, and paracetamol was less frequently used than non-steroidal anti-inflammatory drugs at any pain intensity. Age was not associated with higher prevalence [odds ratios 0.97 (CI 95 % 0.93-1.02) in females and 0.99 (CI 95 % 0.92-1.06) in males]. CONCLUSIONS: The prevalence of pain in non-institutionalized very old people is high. Pain is probably being undertreated, even moderate or severe pain. Guideline's recommendations are probably not being considered to select the analgesic therapy.

Association with and predictive capacity of self-perceived risk of falling in recurrent falls in older people: a prospective study.

OBJECTIVE: Given the impact of recurrent falls in older people, risk evaluation for falling is an important part of geriatric assessment. Available clinical tools usually do not include patients' self-perceived risk of falling. The objective of this study was to evaluate association with and predictive capacity of self-perceived risk of falling in recurrent falls. METHODS: Prospective cohort study. Patients attending a geriatric outpatients' clinic were recruited (Pfeiffer score <5). A baseline assessment and follow-up over 14 months was scheduled for each patient. Self-perceived risk of falling was assessed through four questions. Association with falls was evaluated through relative risk, survival curves (Kaplan-Meier), and Cox regression (recurrent falls as outcome variables). Predictive capacity was evaluated through sensitivity, specificity, and predictive values. RESULTS: 52 participants answered all 4 questions, and 15 participants (27.2 %) presented recurrent falls. Question 1 (Do you think you may fall in the next few months?) was associated with the occurrence of recurrent falls according to relative risk [3.88 (CI95 %:1.48-10.09)] and survival curves (log Rank, p 0.004). Such relationship is maintained over time. Cox-regression also showed significant difference in relation to the answer for question 1 and recurrent falls [hazard ratio 4.044 (CI: 1.410-11.597); p 0.009]. Sensitivity, specificity, positive and negative predictive values (question 1) were 53.3 % (CI95 %:28.1-78.6), 84.2 % (CI95 %:72.6-95.8), 57.1 % (CI95 %:31.2-83.1), and 82.1 % (CI95 %:70.0-94.1), respectively. CONCLUSIONS: Patients' self-perceived risk of falling is related to recurrent falls amongst people with a high risk of falling and this parameter might be useful in falling risk evaluation.

Mortality in Elderly Patients Taking Furosemide: Prospective Cohorts Study.

Objectives: Low blood pressure (BP) has been proposed as a risk factor of death in elderly patients. However, this association could be partially accounted for by the deleterious effects of BP-lowering drugs. We analyzed whether these drugs are associated to an increased risk of death in elderly patients taking multiple potential confounders into account. Design: This is a prospective cohort study. Setting and Participants. Probabilistic sample of 772 community-dwelling patients aged >65 years living in Spain, who were appointed for an initial clinical visit and followed up through telephone calls 4, 6, 9, 12, and 60 months afterwards. Methods: At baseline visit, BP was measured using standardized methods, and BP medications and risk factors of death in elderly patients (BMI, oxygen saturation, toxic habits, comorbidity, muscular strength, and functional and cognitive capacity) were collected. During the follow-up, the vital status of patients and the date of death were ascertained. Results: During a median 5-year follow-up, 226 all-cause deaths occurred among the 686 participants included in the analysis. In a Cox regression model that included all the BP drug classes, diuretics and nitrites were significantly associated with mortality (p < 0.005). Within diuretics, furosemide was found to be responsible for the association of the group. In multivariable Cox regression models adjusted for BP and the rest of the mortality risk factors, furosemide remained as the only BP drug that was independently associated with mortality (hazard ratio 2.34; p < 0.01). Conclusions: Furosemide was prospectively associated with increased mortality in older people. If confirmed, this drug should be taken into account by prescribers and considered a confounder in BP studies.

Sex, Neuropsychiatric Profiles, and Caregiver Burden in Alzheimer's Disease Dementia: A Latent Class Analysis.

BACKGROUND: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) can be disruptive for patients and their families. OBJECTIVE: We aimed to classify patients based on NPS and to explore the relationship of these classes with sex and with caregiver burden. METHODS: The study cohort comprised individuals with AD dementia diagnosed at Ace Alzheimer Center in Barcelona, Spain, between 2011-2020. NPS were ascertained by using the Neuropsychiatric Inventory-Questionnaire. Latent class analysis was used to identify clusters of individuals sharing a similar NPS profile. We evaluated the caregiver burden using the Zarit Burden Interview. Multivariable regression models were used to obtain adjusted estimates of the association between sex, NPS classes, and caregiver burden. RESULTS: A total of 1,065 patients with AD dementia and their primary caregivers were included. We classified patients into five different classes according to their NPS profile: "Affective", "High-behavioral-disturbance", "Negative-affect", "Affective/deliriant", and "Apathy". We found that age, sex, and type of AD diagnosis differed greatly across classes. We found that patients from the "High-behavioral-disturbance" (OR = 2.56, 95% CI: 1.00-6.56), "Negative-affect" (OR = 2.72, 95% CI: 1.26-3.64), and "Affective/deliriant" (OR = 2.14, 95% CI: 1.26-3.64) classes were over two times more likely to have a female caregiver than those in "Apathy" class. These three classes were also the ones associated to the greatest caregiver burden in the adjusted analyses, which seems to explain the increased burden observed among female caregivers. CONCLUSION: Caregiver burden is highly dependent on the patient's NPS profiles. Female caregivers provide care to patients that pose a greater burden, which makes them more susceptible to become overwhelmed.

Differences in macular vessel density in the superficial plexus across cognitive impairment: the NORFACE cohort.

Optical coherence tomography angiography (OCT-A) allows the detection of retinal vessel density (VD) loss, which is a reflection of brain vascular pathology. We aimed to investigate differences in macular VD in the superficial plexus in a large cohort of individuals cognitively unimpaired (CU), with mild cognitive impairment due to Alzheimer´s disease (MCI-AD), MCI due to cerebrovascular pathology (MCI-Va), probable Alzheimer´s disease dementia (ADD) and Vascular Dementia (VaD). Clinical, demographical, ophthalmological and OCT-A data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences of macular VD in four quadrants (superior, nasal, inferior and temporal) among the five diagnostic groups were assessed in a multivariate regression model, adjusted by age, sex, education, hypertension, diabetes mellitus, heart disease and stroke. The study cohort comprised 672 participants: 128 CU, 120 MCI-AD, 111 MCI-Va, 257 ADD and 56 VaD. Regression analysis showed a significantly higher VD in the temporal quadrant in MCI-AD compared to CU participants (49.05 ± 4.91 vs 47.27 ± 4.17, p = 0.02, d = 0.40), and a significantly lower VD in the inferior quadrant in MCI-Va compared to CU participants (48.70 ± 6.57 vs 51.27 ± 6.39, p = 0.02, d = 0.40). Individuals with heart disease presented significantly lower VD in the inferior quadrant than those without (p = 0.01). The interaction of sex and diagnosis had no effect in differentiating VD. Mini-Mental State Examination (MMSE) scores were not correlated to VD (all r < 0.16; p > 0.07). In conclusion, our study showed that the MCI-AD and MCI-Va groups had significant differences in macular VD in opposite directions in the temporal and inferior quadrants, respectively, compared to CU participants, suggesting that macular VD might be able to differentiate two pathogenic pathways (AD- and cerebrovascular-related) in early stages of cognitive decline.

The spatial parameters of gait and their association with falls, functional decline and death in older adults: a prospective study.

Association between spatial gait parameters and adverse health outcomes in the elderly has not been sufficiently studied. The goal of this study is to evaluate whether the stride length or the step width predict falls, functional loss and mortality. We conducted a prospective cohort study on a probabilistic sample of 431 noninstitutionalized, older-than-64-years subjects living in Spain, who were followed-up for five years. In the baseline visit, spatial gait parameters were recorded along with several control variables, with special emphasis on known medical conditions, strength, balance and functional and cognitive capacities. In the follow-up calls, vital status, functional status and number of falls from last control were recorded. We found that a normalized-to-height stride length shorter than 0.52 predicted recurrent falls in the next 6 months with 93% sensitivity and 53% specificity (AUC: 0.72), and in the next 12 months with 81% sensitivity and 57% specificity (AUC: 0.67). A normalized stride length <0.5 predicted functional loss at 12 months with a sensitivity of 79.4% and specificity of 65.6% (AUC: 0.75). This predictive capacity remained independent after correcting for the rest of risk factors studied. Step-with was not clearly related to functional loss or falls. Both shorter normalized stride length (OR1.56; AUC: 0.62; p < 0.05) and larger step width (OR1.42; AUC: 0.62; p < 0.05) were associated with risk of death at 60 months; however, none of them remained as independent predictor of death, after correcting for other risk factors. In summary, spatial gait parameters may be risk markers for adverse outcomes in the elderly. Step length is independently associated with functional loss and falls at one year, after correction for numerous known risk factors.

Normal limits of home measured spatial gait parameters of the elderly population and their association with health variables.

Gait studies in the elderly population have been always conducted in gait labs or spacious clinical facilities, which influence gait parameters, and also implies that the participants have to be able to move to these facilities. Indoors gait characteristics of the elderly population have been very little studied. In this study, we aim to define the normal limits of the spatial gait parameters of the elderly, when walking at home, and to analyze relationship existing between the spatial gait parameters to other health variables. For such purpose, we conducted a transversal study on a probabilistic sample of 431 Spanish community-dwelling older, in which the spatial gait parameters were recorded by using an ink footprints method. We found that the mean stride length indoors was 88.47 cm (SD:26.05 cm; mean CI95%:85.52-91.41 cm), and the mean step width was 10.34 cm (SD:4.37 cm; mean CI95%:9.84-10.83 cm). Stride length was shorter in women and the oldest group, and was significantly influenced by the strength, balance, and physical activity. Stride width was larger in the oldest group and mainly affected by balance. A composite parameter including width and normalized stride length was independent from sex, and strongly differentiated between age groups. This parameter was affected by strength.

A two-question tool to assess the risk of repeated falls in the elderly.

INTRODUCTION: Older adults' perception of their own risk of fall has never been included into screening tools. The goal of this study was to evaluate the predictive validity of questions on subjects' self-perception of their own risk of fall. METHODS: This prospective study was conducted on a probabilistic sample of 772 Spanish community-dwelling older adults, who were followed-up for a one year period. At a baseline visit, subjects were asked about their recent history of falls (question 1: "Have you fallen in the last 6 months?"), as well as on their perception of their own risk of fall by using two questions (question 2: "Do you think you may fall in the next few months?" possible answers: yes/no; question 3: "What is the probability that you fall in the next few months?" possible answers: low/intermediate/high). The follow-up consisted of quarterly telephone calls, where the number of falls occurred in that period was recorded. RESULTS: A short questionnaire built with questions 1 and 3 showed 70% sensitivity (95% CI: 56%-84%), 72% specificity (95% CI: 68%-76%) and 0.74 area under the ROC curve (95% CI: 0.66-0.82) for prediction of repeated falls in the subsequent year. CONCLUSIONS: The estimation of one's own risk of fall has predictive validity for the occurrence of repeated falls in older adults. A short questionnaire including a question on perception of one's own risk of fall and a question on the recent history of falls had good predictive validity.

[Falls in the Spanish elderly population: Incidence, consequences and risk factors]. / Caídas en la población anciana española: incidencia, consecuencias y factores de riesgo.

INTRODUCTION: Falls in the elderly constitute a public health concern. The objective of the present study was to collect updated data on the frequency of falls in the Spanish elderly population, as well as to analyse their consequences and associated risk factors. MATERIAL AND METHODS: This prospective study was conducted on a probabilistic sample of 772 Spanish, community dwelling, older adults. During the baseline visit, data were collected on functional capacity, history of falls, disease background, number of medications used, balance impairment, use of walking aids, cognitive capacity and depression symptoms. Participants were followed up for one year by means of quarterly phone calls, where they were asked about the number of falls occurred in that period, as well as their consequences and associated use of healthcare resources. RESULTS: During the one-year follow up period, 28.4% (95%CI 24.9-32.1) of participants suffered one or more falls, while 9.9% (95%CI 7.4-11.4) suffered multiple falls. One-third of the falls were due to accidental extrinsic causes. Among participants who had suffered falls, 9.3% suffered a fracture (3.1% hip fracture), and 55.4% required healthcare services (29% were managed in the hospital emergency room, and 7.3% were admitted to hospital). Risk factors identified through multivariate analysis were: advanced age (>79 years), not having a companion, using more than 2 drugs, dependency in BADLs, impaired strength or balance, and use of walking aids. CONCLUSIONS: Falls continue to be a major public health concern in Spain. Given that some of the associated risk factors may be modified, introducing programs aimed at tackling this problem should be regarded as a priority.

Innovations in health care services: the CAALYX system.

PURPOSE: This paper describes proposed health care services innovations, provided by a system called CAALYX (Complete Ambient Assisted Living eXperiment). CAALYX aimed to provide healthcare innovation by extending the state-of-the-art in tele-healthcare, by focusing on increasing the confidence of elderly people living autonomously, by building on the knowledge base of the most common disorders and respective characteristic vital sign changes for this age group. METHODS: A review of the state-of-the-art on health care services was carried out. Then, extensive research was conducted on the particular needs of the elderly in relation to home health services that, if offered to them, could improve their day life by giving them greater confidence and autonomy. To achieve this, we addressed issues associated with the gathering of clinical data and interpretation of these data, as well as possibilities of automatically triggering appropriate clinical measures. Considering this initial work we started the identification of initiatives, ongoing works and technologies that could be used for the development of the system. After that, the implementation of CAALYX was done. FINDINGS: The innovation in CAALYX system considers three main areas of contribution: (i) The Roaming Monitoring System that is used to collect information on the well-being of the elderly users; (ii) The Home Monitoring System that is aimed at helping the elders independently living at home being implemented by a device (a personal computer or a set top box) that supports the connection of sensors and video cameras that may be used for monitoring and for interaction with the elder; (iii) The Central Care Service and Monitoring System that is implemented by a Caretaker System where attention and care services are provided to elders, where actors as Caretakers, Doctors and Relatives are logically linked to elders. Innovations in each of these areas are presented here. CONCLUSIONS: The ageing European society is placing an added burden on future generations, as the 'elderly-to-working-age-people' ratio is set to steadily increase in the future. Nowadays, quality of life and fitness allows for most older persons to have an active life well into their eighties. Furthermore, many older persons prefer to live in their own house and choose their own lifestyle. The CAALYX system can have a clear impact in increasing older persons' autonomy, by ensuring that they do not need to leave their preferred environment in order to be properly monitored and taken care of.

Caídas en la población anciana española: incidencia, consecuencias y factores de riesgo / Falls in the Spanish elderly population: incidence, consequences and risk factors

Introducción. Las caídas en los ancianos son un problema de salud pública. El objetivo de este estudio es obtener datos españoles y actualizados sobre la frecuencia de caídas en la población mayor, sus repercusiones y los factores de riesgo asociados a las mismas. Material y métodos. Estudio prospectivo sobre una muestra probabilística de 772 ancianos españoles, residentes en la comunidad, que fueron seguidos durante un año. En la visita basal se recogieron datos sobre su capacidad funcional, historia de caídas, antecedentes patológicos, número de fármacos, alteraciones del equilibrio, ayudas para la marcha, capacidad cognitiva y síntomas depresivos. El seguimiento se realizó mediante llamadas telefónicas trimestrales en las que se registraron el número de caídas del periodo, datos sobre sus consecuencias y sobre el uso de recursos sanitarios. Resultados. El 28,4% (IC95% 24,9-32,1) de los participantes presentaron una o más caídas anuales. El 9,9% (IC95% 7,4-11,4) tuvieron múltiples caídas. Un tercio de las caídas fueron por causa extrínseca accidental. El 9,3% de las personas que cayeron tuvieron fracturas (el 3,1% tuvieron fractura de cadera) y el 55,4% requirió asistencia médica (el 29% en urgencias hospitalarias; un 7,3% fueron ingresados). Los factores de riesgo identificados en análisis multivariante fueron: edad avanzada (> 79 años), no tener pareja, consumir más de 2 fármacos, dependencia para ABVD, disminución de fuerza o equilibrio y marcha con ayuda técnica. Conclusiones. Las caídas siguen siendo un problema de salud pública de primer orden. Algunos de los factores de riesgo asociados son modificables, por lo que impera la implantación de programas encaminados a reducir el problema (AU)

Introduction. Falls in the elderly constitute a public health concern. The objective of the present study was to collect updated data on the frequency of falls in the Spanish elderly population, as well as to analyse their consequences and associated risk factors. Material and methods. This prospective study was conducted on a probabilistic sample of 772 Spanish, community dwelling, older adults. During the baseline visit, data were collected on functional capacity, history of falls, disease background, number of medications used, balance impairment, use of walking aids, cognitive capacity and depression symptoms. Participants were followed up for one year by means of quarterly phone calls, where they were asked about the number of falls occurred in that period, as well as their consequences and associated use of healthcare resources. Results. During the one-year follow up period, 28.4% (95%CI 24.9-32.1) of participants suffered one or more falls, while 9.9% (95%CI 7.4-11.4) suffered multiple falls. One-third of the falls were due to accidental extrinsic causes. Among participants who had suffered falls, 9.3% suffered a fracture (3.1% hip fracture), and 55.4% required healthcare services (29% were managed in the hospital emergency room, and 7.3% were admitted to hospital). Risk factors identified through multivariate analysis were: advanced age (> 79 years), not having a companion, using more than 2 drugs, dependency in BADLs, impaired strength or balance, and use of walking aids. Conclusions. Falls continue to be a major public health concern in Spain. Given that some of the associated risk factors may be modified, introducing programs aimed at tackling this problem should be regarded as a priority (AU)