Blood biomarkers of Alzheimer's disease in the community: Variation by chronic diseases and inflammatory status.

INTRODUCTION: We explored the variations of blood biomarkers of Alzheimer's disease (AD) by chronic diseases and systemic inflammation. METHODS: We explored the association of AD blood biomarkers with chronic diseases and systemic inflammation (interleukin-6 [IL-6]), in 2366 dementia-free participants of the Swedish National Study on Aging and Care-in Kungsholmen, using quantile regression models. RESULTS: A greater number of co-occurring chronic diseases was associated with higher concentrations of phosphorylated-tau 181 (p-tau181), total-tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) (p < 0.01). Anemia, kidney, cerebrovascular, and heart diseases were associated with variations in the levels of AD blood biomarkers. Participants in the highest (vs. lowest) interleukin-6 (IL-6) tertile had higher NfL concentration. Systemic inflammation amplified the associations between several chronic diseases and p-tau181, t-tau, NfL, and GFAP. DISCUSSION: In the community, the concentration of AD blood biomarkers varies in relation to medical conditions and systemic inflammation. Recognizing these influences is crucial for the accurate interpretation and clinical implementation of blood biomarkers. HIGHLIGHTS: Participants with a complex clinical profile (i.e., multiple co-occurring diseases or specific disease combinations) display elevated levels of AD blood-biomarkers. Anemia, heart, cerebrovascular, and kidney diseases are associated with variations is the levels of AD blood biomarkers in cognitively intact older adults. Systemic inflammation amplifies the association between several chronic diseases and AD blood biomarkers.

Association of mild and complex multimorbidity with structural brain changes in older adults: A population-based study.

INTRODUCTION: We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults. METHODS: We included 390 dementia-free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes. RESULTS: Compared to non-multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (ß*time -0.03, 95% CI -0.05, -0.01) and hippocampal (ß*time -0.05, 95% CI -0.08, -0.03) volumes, the greatest ventricular enlargement (ß*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (ß*time 0.04, 95% CI 0.01, 0.07). DISCUSSION: Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology. HIGHLIGHTS: Multimorbidity accelerates structural brain changes in cognitively intact older adults These brain changes encompass both neurodegeneration and cerebrovascular pathology The complexity of multimorbidity is associated with the rate of brain changes' progression.

Sundowning in Patients with Dementia: Identification, Prevalence, and Clinical Correlates.

BACKGROUND: The term sundowning is used to describe the emergence or worsening of neuropsychiatric symptoms in late afternoon or early evening in people with dementia. OBJECTIVE: Our aim was to evaluate sundowning's prevalence and clinical manifestations among patients attending a tertiary memory clinic and to investigate its clinical and neuropsychological correlates. METHODS: Patients with dementia attending our memory clinic were enrolled in the study. Sundowning was identified through a specifically designed questionnaire. Sociodemographic and clinical features of sundowners and non-sundowners were compared, and a logistic regression was performed to identify the variables associated with the phenomenon. A subgroup of patients underwent a complete neuropsychological assessment. RESULTS: Among 184 recruited patients, 39 (21.2%) exhibited sundowning, mostly expressed as agitation (56.4%), irritability (53.8%), and anxiety (46.2%). Sundowners were significantly older, had a later dementia onset, exhibited more severe cognitive and functional impairment, more frequent nocturnal awakenings, and hearing loss relative to non-sundowners. They were also more likely to use anticholinergic medications and antipsychotics, and less likely to use memantine. In a multi-adjusted model, the factors significantly associated with sundowning were the Clinical Dementia Rating score (OR 3.88; 95% CI 1.39-10.90) and the use of memantine (OR 0.20; 95% CI 0.05-0.74). Participants with and without sundowning obtained similar results in single domain neuropsychological tests. CONCLUSION: Sundowning is commonly experienced by patients with dementia and appears as a multiply determined condition. Its presence should always be evaluated in clinical practice and a multidimensional approach should be adopted to identify its predictors.

Multimorbidity patterns and 18-year transitions from normal cognition to dementia and death: A population-based study.

BACKGROUND: Several chronic diseases accelerate cognitive decline; however, it is still unknown how different patterns of multimorbidity influence individuals' trajectories across the cognitive continuum. OBJECTIVES: We aimed to investigate the impact of multimorbidity and of specific multimorbidity patterns on the transitions across cognitive stages (normal cognition, cognitive impairment, no dementia [CIND], dementia) and death. METHODS: We included 3122 dementia-free individuals from the Swedish National study on Aging and Care in Kungsholmen. Using fuzzy c-means cluster analysis, multimorbid participants were classified into mutually exclusive groups characterized by commonly coexisting chronic diseases. Participants were followed up to 18 years to detect incident CIND, dementia, or death. Transition hazard ratios (HRs), life expectancies, and time spent in different cognitive stages were estimated using multistate Markov models. RESULTS: At baseline, five multimorbidity patterns were identified: neuropsychiatric, cardiovascular, sensory impairment/cancer, respiratory/metabolic/musculoskeletal, and unspecific. Compared to the unspecific pattern, the neuropsychiatric and sensory impairment/cancer ones showed reduced hazards of reverting from CIND to normal cognition (HR 0.53, 95% CI 0.33-0.85 and HR 0.60, 95% CI 0.39-0.91). Participants in the cardiovascular pattern exhibited an increased hazard of progression from CIND to dementia (HR 1.70, 95% CI 1.15-2.52) and for all transitions to death. Subjects with the neuropsychiatric and cardiovascular patterns showed reduced life expectancy at age 75, with an anticipation of CIND (up to 1.6 and 2.2 years, respectively) and dementia onset (up to 1.8 and 3.3 years, respectively). CONCLUSIONS: Multimorbidity patterns differentially steer individual trajectories across the cognitive continuum of older adults and may be used as a risk stratification tool.

Prevalence and Safety of COVID-19 Vaccination in Community-Dwelling People with Dementia: Findings from a Tertiary Memory Clinic in Italy.

This study aimed to explore the prevalence and safety of SARS-CoV-2 vaccination in individuals with dementia. Patients with mild cognitive impairment or dementia were recruited at a tertiary memory clinic, from March 15 to September 15, 2021. Information on COVID-19 vaccination and adverse events experienced after vaccine administration were collected from caregivers. Two-hundred-seventy subjects were finally recruited. Among them, 253 (93.7%) had received the vaccine and only 69 (27.3%) experienced adverse events. Cognitive and behavioral changes following immunization were only rarely reported. COVID-19 vaccination is safe and well-tolerated in patients with cognitive impairment who should be prioritized in the vaccination campaign.

A nationwide survey of Italian Centers for Cognitive Disorders and Dementia on the provision of care for international migrants.

BACKGROUND: More than 500,000 dementia cases can be estimated among migrants living in Europe. There is the need to collect "real world" data on the preparedness of healthcare services to support the inclusion of migrants in the public health response to dementia. The present study aimed (i) to estimate the number of migrants referred to Italian memory clinics (Centers for Cognitive Disorders and Dementia [CCDDs]) and (ii) to identify possible barriers and resources for the provision of diversity-sensitive care. METHODS: A survey of all Italian CCDDs was conducted between December 2020 and April 2021. An online questionnaire was developed to obtain information on the number of migrants referred to Italian CCDDs in 2019, the challenges encountered in the diagnostic approach, and possible facilitators in the provision of care. RESULTS: Overall, 343 of the 570 contacted CCDDs completed the survey questionnaire (response rate: 60.2%). Nearly 4527 migrants were referred to these services in 2019. Migrants accounted for a median 1.1% (IQR: 0.9%-2.8%) of overall CCDD referrals. More than one-third of respondents reported that the number of migrants referred to their facilities had increased in the last 5 years. The overall quality of the migrants' cognitive assessment was deemed to be very poor or insufficient in most cases. A minority of CCDDs had translated information material on dementia and reported the possibility to contact cultural mediators and interpreters. CONCLUSIONS: A relevant number of migrants are being referred to Italian CCDDs that are still not adequately prepared to deliver diversity-sensitive care and support.

Supporting and Protecting People with Dementia in the COVID-19 Pandemic.

We aimed to explore the awareness and preparedness of dementia caregivers and people with mild cognitive deficits on how to prevent COVID-19 infection and cope with the indirect consequences of the pandemic. A total of 139 patient-caregiver dyads received a telephone survey and 109 completed the survey. The majority of respondents reported having a moderate-to-good knowledge of the typical manifestations of COVID-19. Conversely, only few of them were informed of the atypical presentations and on how to recognize emergency warning signs. Filling the knowledge gaps on COVID-19 in the most vulnerable people may represent a significant resource to tackle the pandemic.

Use of Biomarkers in Ongoing Research Protocols on Alzheimer's Disease.

The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer's disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the "real world" remain to be clarified.

Counting deficits or diseases? The agreement between frailty and multimorbidity in subjects with cognitive disturbances.

In the present study, we explored the relationship between multimorbidity and frailty in a population of older individuals with cognitive disturbances attending a memory clinic. All subjects consecutively attending the Memory Clinic of the Department of Human Neuroscience, "Sapienza" University of Rome, between January 2017 and April 2018 for a first neurological evaluation were considered for the present analysis. Multimorbidity was defined as the simultaneous presence of two or more diseases in the same individual. A Frailty Index was computed by considering 44 age-related, multidimensional health deficits. Overall, 185 subjects were recruited in the study. A condition of multimorbidity was detected in 87.6% of the sample, whereas only the 44.6% of the study population was considered as frail. A poor agreement was observed between multimorbidity and frailty. The present findings confirm that counting diseases or health deficits may provide discordant information concerning the risk profile of older subjects.

Role of frailty in the assessment of cognitive functioning.

Neuropsychological tests, besides reflecting the cognitive reserves and deficits of the tested individual, might also be differently affected by his/her underlying biological asset. In this context, the construct of frailty may offer an opportunity for better weighting the results of traditional tests. We evaluated the relationships between a set neuropsychological measures and a 35-item Frailty Index (FI). The role played by the FI in the relationship between neuropsychological tests and global cognition was also explored. Data from the first neurological and neuropsychological assessments of 79 subjects attending our university memory clinic because complaining cognitive disturbances were considered for the present analysis. A statistically significant correlation between FI and Trail Making Test-B was observed (Spearman's rho 0.33; p = 0.02). The relationship between the performance at the Rey Complex Figure and global cognition (as measured by the Mini Mental State Examination) was influenced by the FI. In fact, participants with higher FI levels had a weakened association linking constructional/visual memory abilities and general cognitive functioning. The interpretation of the neuropsychological assessment can be biased by the frailty status of the tested individual. It can be hypothesized the need of developing new models of correction, that may better reflect the person's biology and complexity.

Race reporting and disparities in clinical trials on Alzheimer's disease: A systematic review.

INTRODUCTION: Race is an important health determinant and should adequately be considered in research and drug development protocols targeting Alzheimer's disease (AD). METHODS: A systematic review of available randomized controlled trials (RCTs) on the currently marketed treatments for AD was conducted with the aim of 1) documenting the reporting of race, and 2) exploring the impact of race on the efficacy and safety/tolerability of the considered medications. RESULTS: Overall, 59.2% of the 49 retained RCTs reported information concerning the race of participants. Only a striking minority of enrolled patients was constituted of blacks and Hispanics. None on the retained studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups nor performed sensitivity analyses accounting for the race of participants. DISCUSSION: Race has insufficiently been reported in previous interventional studies on AD. Its potential association with the effectiveness and safety/tolerability of the tested medications has completely been neglected.

Parkinson's disease among migrants in Europe: estimating the magnitude of an emerging phenomenon.

INTRODUCTION: The occurrence of age-related pathological conditions among subjects with a migration background and composing ethnic minorities is an emerging challenge for Western countries. Specifically, the onset of neurodegenerative diseases in these populations of individuals might assume special relevance and generate additional complexities for our healthcare systems. The aim of the present study was to estimate the number of Parkinson's disease (PD) cases in migrant subjects living in Europe. METHODS: The estimated cases of PD among ≥ 50-year-old migrants living in Europe, and in each of the 32 considered countries, were calculated by multiplying the number of migrants (derived by the Eurostat data) with the age-specific prevalence rates of PD (obtained by a recent meta-analysis). RESULTS: Nearly 20 million migrants ≥ 50 years lived in Europe in 2017. The application of the age-specific prevalence rates led to the estimation of 129,645 overall PD cases in this population, accounting for the 8% of overall PD cases in Europe. National estimates widely ranged from 36 cases in Iceland to 29,390 cases in France. CONCLUSION: The present findings suggest that the occurrence of PD in migrants and minority groups already constitutes an important issue for European healthcare systems and will assume further relevance given the rapidly evolving sociodemographic scenario. Characterizing the phenomenon at the "real world" level and implementing coordinated initiatives and strategies represent novel but pressing needs for our countries.

Migrants seeking help for cognitive disturbances: exploratory data from an Italian memory clinic.

INTRODUCTION: The phenomenon of dementia occurring in migrants and minority groups constitutes an emerging issue for Western countries. Nevertheless, it has been poorly explored from the perspective of "real-world" clinical services. We aimed to quantify the number of migrants from LMIC attending an Italian university memory clinic and to document its modifications over time. METHODS: All the subjects undergoing a first neurological and cognitive assessment between 2001 and 2017 were considered for the present analyses. RESULTS: The proportion of subjects from LMIC performing a first cognitive evaluation was found to remain substantially stable between 2001 and 2017. No statistically significant difference was found between "HIC" and "LMIC" individuals with regard to sociodemographic and clinical characteristics. CONCLUSION: These findings seem to indicate that cognitive disorders in LMIC migrants still constitute a marginal public health issues for Italian dementia services. Nevertheless, the identification of eventual sociocultural and healthcare barriers may help to understand the real magnitude and relevance of this phenomenon.

Estimating dementia cases in the immigrant population living in Italy.

INTRODUCTION: The phenomenon of dementia among immigrants and ethnic minorities represents an emerging challenge for Western countries. The aim of the present study was to estimate the number of dementia cases among immigrant subjects residing in Italy and in each Italian region to provide pivotal information on the magnitude of such public health issue. METHOD: The number of immigrant individuals, aged 65 years or older, living in Italy and in the 20 Italian regions was derived by the 2017 data of the National Institute for Statistics. The dementia prevalence rates were taken from the European data provided by the Neurologic Diseases in the Elderly Research Group. The estimated dementia cases were calculated by multiplying the number of immigrants with the age- and sex-specific prevalence rates. RESULTS:  Overall, 186,373 older immigrant subjects lived in Italy in January 2017. Nearly 7700 dementia cases were estimated in this population (5022 among women, 2725 among men). When considering each specific Italian region, the number of estimated cases ranged from 19 (Basilicata) to 1500 (Lombardia) with a marked inter-regional variability. DISCUSSION: Our findings indicate that the occurrence of dementia among immigrants and ethnic minorities constitutes a novel but already relevant issue for our healthcare systems. A non-negligible number of immigrant individuals is probably already seeking or might seek help for cognitive disturbances, thus potentially referring to general practitioners and/or to the Italian dementia services. The forecasted increasing magnitude of this phenomenon reinforces the need for tailored and locally oriented initiatives and policies.

Need to Recalibrate Research Outcomes in Alzheimer's Disease: Focus on Neuropsychiatric Symptoms.

OBJECTIVES: To determine whether neuropsychiatric symptoms (NPSs) are adequately considered in clinical research on Alzheimer's disease (AD). DESIGN: Systematic review. SETTING: Randomized controlled trials (RCTs) recruiting individuals with AD and published during the last 10 years in 16 major general medicine, neurology, psychiatry, and geriatric psychiatry journals and RCTs registered on clinicaltrials.gov and currently enrolling individuals with AD. PARTICIPANTS: Individuals with AD. MEASUREMENTS: Outcome measures adopted by the included studies. RESULTS: Only 21.4% of the included studies identified through the bibliographic searches had measures of NPSs as a primary outcome. Only 17.7% of the studies retrieved on clinicaltrials.gov made a specific effort to test the effect of pharmacological or nonpharmacological interventions on NPSs. CONCLUSION: These findings show how rarely previous and current research on AD has considered NPSs as primary research targets. Although these symptoms are widely recognized as the most-stressful and -challenging manifestations of dementia, they are addressed much less often than other research targets.

Sundowning in Dementia: Clinical Relevance, Pathophysiological Determinants, and Therapeutic Approaches.

Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non-pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice.