Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies.

INTRODUCTION: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. METHODS: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. RESULTS: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DISCUSSION: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Role of Sex and Age in Fatal Outcomes of COVID-19: Women and Older Centenarians Are More Resilient.

In the present paper, we have analysed the role of age and sex in the fatal outcome of COVID-19, as there are conflicting results in the literature. As such, we have answered three controversial questions regarding this aspect of the COVID-19 pandemic: (1) Have women been more resilient than men? (2) Did centenarians die less than the remaining older people? (3) Were older centenarians more resistant to SARS-CoV-2 than younger centenarians? The literature review demonstrated that: (1) it is women who are more resilient, in agreement with data showing that women live longer than men even during severe famines and epidemics; however, there are conflicting data regarding centenarian men; (2) centenarians overall did not die less than remaining older people, likely linked to their frailty; (3) in the first pandemic wave of 2020, centenarians > 101 years old (i.e., born before 1919), but not "younger centenarians", have been more resilient to COVID-19 and this may be related to the 1918 Spanish flu epidemic, although it is unclear what the mechanisms might be involved.

Expression pattern of perilipins in human brain during aging and in Alzheimer's disease.

AIMS: Perilipins are conserved proteins that decorate intracellular lipid droplets and are essential for lipid metabolism. To date, there is limited knowledge on their expression in human brain or their involvement in brain aging and neurodegeneration. The aim of this study was to characterise the expression levels of perilipins (Plin1-Plin5) in different cerebral areas from subjects of different age, with or without signs of neurodegeneration. METHODS: We performed real-time RT-PCR, western blotting, immunohistochemistry and confocal microscopy analyses in autoptic brain samples of frontal and temporal cortex, cerebellum and hippocampus from subjects ranging from 33 to 104 years of age, with or without histological signs of neurodegeneration. To test the possible relationship between Plins and inflammation, correlation analysis with IL-6 expression was also performed. RESULTS: Plin2, Plin3 and Plin5, but not Plin1 and Plin4, are expressed in the considered brain areas with different intensities. Plin2 appears to be expressed more in grey matter, particularly in neurons in all the areas analysed, whereas Plin3 and Plin5 appear to be expressed more in white matter. Plin3 seems to be expressed more in astrocytes. Only Plin2 expression is higher in old subjects and patients with early tauopathy or Alzheimer's disease and is associated with IL-6 expression. CONCLUSIONS: Perilipins are expressed in human brain but only Plin2 appears to be modulated with age and neurodegeneration and linked to an inflammatory state. We propose that the accumulation of lipid droplets decorated with Plin2 occurs during brain aging and that this accumulation may be an early marker and initial step of inflammation and neurodegeneration.

Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα.

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups.

BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.

Region-specific and age-related differences in astrocytes in the human brain.

Astrocyte heterogeneity and its relation to aging in the normal human brain remain poorly understood. We here analyzed astrocytes in gray and white matter brain tissues obtained from donors ranging in age between the neonatal period to over 100 years. We show that astrocytes are differently distributed with higher density in the white matter. This regional difference in cellular density becomes less prominent with age. Additionally, we confirm the presence of morphologically distinct astrocytes, with gray matter astrocytes being morphologically more complex. Notably, gray matter astrocytes morphologically change with age, while white matter astrocytes remain relatively consistent in morphology. Using regional mass spectrometry-based proteomics, we did, however, identify astrocyte specific proteins with regional differences in abundance, reflecting variation in cellular density or expression level. Importantly, the expression of some astrocyte specific proteins region-dependently decreases with age. Taken together, we provide insights into region- and age-related differences in astrocytes in the human brain.

What do we learn from the clinical and biological evaluation of the oral cavity in centenarians?

The number of centenarians is rapidly increasing worldwide and so are the studies on this segment of the population. A general consensus in the literature is that healthy longevity is an outcome of multiple factors, but the interrelationship between good oral health and healthy aging remains not fully understood. As part of the "CaT: Centenari a Trieste" study, a population-based cohort study set in Trieste, Italy, we report here the results of subjective self-reported oral health parameters and objective clinical and biological oral variables and their association with cognitive impairment in 25 centenarians enrolled in the study from September 2017 to May 2019. Oral health-related variables were recorded by means of a self-evaluation questionnaire and a comprehensive oral examination of teeth, prostheses and mucosae conducted by a trained dentist. In addition, 6-n-propylthiouracil (PROP) taste perception and salivary oxidative stress markers, specifically the Total Oxidative Status and Ferric Reducing Ability of Saliva, were measured. Finally, the oral data obtained were compared with the presence or absence of dementia in the enrolled subjects. The centenarians included in our study were generally satisfied with their oral health. Among the causes of discomfort, the most prevalent were difficulties in chewing and biting, with few subjects describing a correlation between their oral health and psycho-social issues. We evaluated possible relations of clinical and biological variables to the likelihood of being demented and did not find significant associations. We found a higher though not statistically significant mean salivary flow and antioxidant capacity of saliva in non-demented subjects. When evaluating the PROP taste perception profile, we found a higher proportion of supertasters compared with previous studies and different taste perception profiles according to dementia. Despite the relatively small number of participants, we believe that our study contributes to a better understanding of the clinical and biological profile of the oral cavity in subjects aged over 100 years, encouraging the inclusion of a comprehensive evaluation of the oral cavity in centenarian studies performed worldwide.

The role of diet on the risk of dementia in the oldest old: The Monzino 80-plus population-based study.

BACKGROUND & AIMS: Longevity also carries its dark side of age-related chronic diseases, dementia being one of the worst and the most prevalent. Since dementia lacks effective treatments, preventing or delaying it is highly desirable. Dietary habits and nutrition have been found to be important modifiable risk factors for many chronic diseases, but evidence on the role of diet on the risk of dementia is still limited, particularly among the very old. Aim of the present work is to study the association of the Mediterranean diet and its components with prevalent and incident dementia in the oldest-old. METHODS: We analyzed data from the Monzino 80-plus study, a population-based study in subjects 80 years or older in the Varese province, Italy. A validated food frequency questionnaire was used to collect information on 23 different foods consumed in the previous year. A Mediterranean diet score was calculated and its components were classified into tertiles. Multivariable models for dementia prevalence and incidence were adjusted for demographic and clinical characteristics. RESULTS: Information on nutrition was available for 1390 subjects in the cross-sectional study and 512 subjects in the longitudinal study, mean respective ages 93 and 92. Greater adherence to Mediterranean diet, greater consumption of eggs, fruits and vegetables, carbohydrates, and greater food intake were associated with a lower prevalence of dementia. Increasing number of portions per week and consumption of legumes significantly decreased the incidence of dementia during the 3.6 year mean follow-up: corresponding hazard ratios of highest vs. lowest tertiles (95% confidence intervals) were 0.66 (0.46-0.95) and 0.68 (0.47-0.97), respectively. CONCLUSION: Oldest-old eating less and having diets with less variety and nutrient density were more frequent among subjects with dementia. The longitudinal analysis confirmed oldest-old subjects who eat more portions, as well as those who have a higher intake of legumes, are at decreased risk of developing dementia even though reverse causality cannot be completely ruled out.

Is Parkinson's Disease a Very Rare Pathology in Centenarians? A Clinical Study in a Cohort of Subjects.

The number of people reaching old age is growing dramatically and centenarians are among the fastest growing age groups. Since no epidemiological study on Parkinson's disease (PD) in this age class is present in the medical literature, we estimated PD prevalence in the Centenari a Trieste (CaT) study. Participating centenarians were examined by a neurologist, who also retrieved their remote and pharmacological anamnesis. Ninety centenarians received a neurological examination. No subject had PD clinical signs. Moreover, none had a previous diagnosis of PD or had taken or was taking anti-Parkinson treatment. This simple but consistent clinical observation permits some physio-pathological hypotheses.

COVID-19 mortality in Lombardy: the vulnerability of the oldest old and the resilience of male centenarians.

Italy was the first European nation to be affected by COVID-19. The biggest cluster of cases occurred in Lombardy, the most populous Italian region, and elderly men were the population hit in the hardest way. Besides its high infectivity, COVID-19 causes a severe cytokine storm and old people, especially those with comorbidities, appear to be the most vulnerable, presumably in connection to inflammaging. In centenarians inflammaging is much lower than predicted by their chronological age and females, presenting survival advantage in almost all centenarian populations, outnumber males, a phenomenon particularly evident in Northern Italy. Within this scenario, we wondered if: a) the COVID-19 mortality in centenarians was lower than that in people aged between 50 and 80 and b) the mortality from COVID-19 in nonagenarians and centenarians highlighted gender differences.We checked COVID-19-related vulnerability/mortality at the peak of infection (March 2020), using data on total deaths (i.e. not only confirmed COVID-19 cases). Our conclusion is that excess mortality increases steadily up to very old ages and at the same time men older than 90 years become relatively more resilient than age-matched females.

Echocardiographic evaluation of centenarians in Trieste.

BACKGROUND: Population aging has increased together with the need for cardiovascular care. Understanding the relevance of cardiovascular conditions in the very old is crucial to developing a specific and rationale therapeutic approach. Centenarians can be considered a model of successful aging, although the impact of cardiovascular disease in this population is still unclear. AIM: To evaluate the cardiovascular health status of a subset of centenarians enrolled in the Centenari a Trieste study and living in the province of Trieste to describe the prevalence of cardiovascular conditions among them. METHODS: The current study included 20 individuals born before 1919 and living in the province of Trieste as of 1 May 2019. All centenarians were able to give consent and were subjected to an in-home complete clinical assessment focused on cardiovascular conditions, ECG and echocardiography. RESULTS: The majority of centenarians were women (85%) and were not taking any chronic cardiovascular medication (55%). No centenarians had a history of ischemic heart disease while about one-third had signs suggestive of heart failure at examination (20%). Atrial fibrillation was present in 20% of individuals and conduction disorders were uncommon. Although the majority of individuals had a preserved left ventricular function, diastolic function was abnormal in 80% of enrolled centenarians that, however, was mild in 73% of cases. CONCLUSION: This is the second study to perform in-home echocardiography in centenarians and the first to characterize the cardiovascular status of centenarians living in Trieste. The majority of centenarians had asymptomatic diastolic dysfunction and were naïve from cardiovascular therapy. The recruitment of new individuals from the Trieste area is continuing to perform analyses on clinical, genetic and environmental factors that may predict greater longevity in this geographical context and unveil mechanisms that regulate cardiac aging associated with increased lifespan.

A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype.

Presenilin mutations are the main cause of familial Alzheimer's disease. So far, more than 160 mutations in the Presenilin 1 gene (PSEN1) and approximately 10 mutations in the homologous Presenilin 2 gene (PSEN2) have been identified. Some PSEN1 mutations are associated with a phenotype fulfilling the clinical criteria of frontotemporal dementia. In PSEN2, T122P and M239V mutations presented with severe behavioral disturbances. We describe an Italian patient with a novel PSEN2 mutation (Y231C) who showed behavioral abnormalities and language impairment as presenting symptoms, with later involvement of other cognitive abilities, particularly of posterior functions.

Regression of chronic posterior leukoencephalopathy after stop of methotrexate treatment.

Posterior reversible leukoencephalopathy (PRLE) is a neurological disorder caused by a variety of pathological conditions such as high doses or long-term low-doses of immunosuppressive therapy. PRLE associated with methotrexate (MTX) is well known but it was rarely observed in adult patients submitted to long-term low-dose administration via the oral route. Here we report the case of a patient affected by psoriasis, treated by chronic oral low-dose of MTX, who presented with limb ideomotor apraxia. Magnetic resonance (MRI) of the brain showed, on T2-weighted images, a diffuse hyperintensity involving bilaterally the white matter of the occipital, parietal and frontal lobes. MTX treatment was stopped and, at the 6-month follow-up, the neuropsychological performances was improved. Two years later, the neuropsychological profile was normal and MRI showed a regression of the white matter abnormalities.

APE1/Ref-1 regulates PTEN expression mediated by Egr-1.

APE1/Ref-1, the mammalian ortholog of E. coli Xth, and a multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has dual role in controlling cellular response to oxidative stress. It is rate-limiting in repair of oxidative DNA damage including strand breaks and also has co-transcriptional activity by modulating genes expression directly regulated by Egr-1 and p53 transcription factors. PTEN, a phosphoinositide phosphatase, acts as an 'off' switch in the PI-3 kinase/Akt signalling pathway and regulates cell growth and survival. It is shown here that transient alteration in the APE1 level in HeLa cells modulates PTEN expression and that acetylatable APE1 is required for the activation of the PTEN gene. Acetylation of APE1 enhances its binding to distinct trans-acting complexes involved in activation or repression. The acetylated protein is deacetylated in vivo by histone deacetylases. It was found that exposure of HeLa cells to H(2)O(2) and to histone deacetylase inhibitors increases acetylation of APE1 and induction of PTEN. The absence of such induction in APE1-downregulated HeLa cells confirmed APE1's role in regulating inducible PTEN expression. That APE1-dependent PTEN expression is mediated by Egr-1 was supported by experiments with cells ectopically expressing Egr-1. Thus, the data open new perspectives in the comprehension of the many functions exerted by APE1 in controlling cell response to oxidative stress.

Cohort profile: 'Centenari a Trieste' (CaT), a study of the health status of centenarians in a small defined area of Italy.

PURPOSE: Centenarians, a segment of the population which some 50 years ago comprised only a few individuals, now count thousands in many countries, and demographic projections forecast that this growth will continue. The study of this new population will give us new information on extreme longevity and help prepare for their health and social needs. The aim of the Centenari a Trieste study is to describe the health and health service use by centenarians, with specific focus on cognitive status. PARTICIPANTS: This is a population-based study of centenarians living in the province of Trieste (Italy), a small area with a high prevalence of centenarians and a close network of health and social services, which makes it possible to conduct a study. Consenting individuals were visited by a clinician, tested by neuropsychologists and also gave a sample of their blood. Administrative data were retrieved as well. FINDINGS TO DATE: Of the 163 centenarians, 70 could be contacted and participated in the study. The main reasons for non-participation were impossibility to contact the subject (70) and death (20). Centenarians were mostly women (90%), tended to live in a nursing home (60%) and were generally severely functionally impaired (Barthel Index <50: 61%). Data from the administrative database showed that about one out of five needed hospitalisation in the preceding year and more than three out of four had at least one drug prescription. FUTURE PLANS: In 2017, we started a new wave of the study enrolling people who had just become centenarian and reassessing subjects already seen; we hope to extend this recruitment in the next years. Subjects are now examined also by cardiologists and dental specialists. We are collecting further different biological specimens to investigate new hypotheses on the cognitive function of the centenarians.

How experience modulates semantic memory for food: evidence from elderly adults and centenarians.

In order to make sense of the objects we encounter in everyday life we largely rely on previous knowledge stored in our semantic memory. Semantic memory is considered dependent on lifelong experience and cultural knowledge. So far, a few studies have investigated the role of expertise on the organization of semantic memory, whereas life-long experience has largely been overlooked. In this study, we investigated this issue using food concepts. In particular, we administered different semantic tasks using food (natural and transformed) and non-food (living and non-living things) as stimuli to participants belonging to three different age cohorts (56-74, 75-91, 100-108), who were also asked to report on the dietary habits held throughout their life. In addition, we investigated to what extent psycholinguistic variables influence the semantic performance of different age cohorts. Results showed that Centenarians recognized natural food better than transformed food, while the other two groups showed the opposite pattern. According to our analyses, experience is responsible for this effect in Centenarians, as their dietary habits seem to suggest. Moreover, significant correlations between picture naming and age of acquisition, familiarity and frequency were observed. This study indicates that lifelong experience can shape conceptual knowledge of food concepts, and that semantic memory is less resilient to aging than initially thought.

Role of circulating factors in cardiac aging.

Worldwide increase in life expectancy is a major contributor to the epidemic of chronic degenerative diseases. Aging, indeed, simultaneously affects multiple organ systems, and it has been hypothesized that systemic alterations in regulators of tissue physiology may regulate this process. Cardiac aging itself is a major risk factor for cardiovascular diseases and, because of the intimate relationship with the brain, may contribute to increase the risk of neurodegenerative disorders. Blood-borne factors may play a major role in this complex and still elusive process. A number of studies, mainly based on the revival of parabiosis, a surgical technique very popular during the 70s of the 20th century to study the effect of a shared circulation in two animals, have indeed shown the potential that humoral factors can control the aging process in different tissues. In this article we review the role of circulating factors in cardiovascular aging. A better understanding of these mechanisms may provide new insights in the aging process and provide novel therapeutic opportunities for chronic age-related disorders.

Risk of dementia and death in patients with atrial fibrillation: A competing risk analysis of a population-based cohort.

BACKGROUND: Previous studies have stated that atrial fibrillation (AF) is associated with a higher risk of dementia. However, none have examined the competition between death and incident dementia in patients with AF. We evaluated the risk of incident dementia in patients with AF in comparison to people without this arrhythmia, considering of the competing risk of death. METHODS: AF and non-AF cohorts were identified using the large administrative database of the Lombardy Region and followed for ten years. Patients with incident dementia were identified if they had an ICD 9 code referring to dementia at hospital discharge or a prescription for any anti-dementia drug. The association of AF with dementia or death was assessed with the multivariable Cox proportional-regression model, sensitivity analysis with a 1:1 propensity score matching and competing-risk analysis. RESULTS: In 2003 a total of 27,431 patients were hospitalized for AF in the Lombardy Region, while the cohort of non-AF counted 1,600,200 people. AF was associated with a higher risk of dementia (17%) and death (51%) at multivariable Cox analysis. These results were confirmed by the model fitted after propensity score matching. However, competing risk analysis found the association between AF and incident dementia was no longer significant (HR 0.99; 95% CI 0.94-1.04). CONCLUSIONS: In this real-world population the association between AF and dementia was no longer statistically significant when death was considered a competing risk.

Sporadic Creutzfeldt-Jakob disease: the extent of microglia activation is dependent on the biochemical type of PrPSc.

In prion-related encephalopathies, microglial activation occurs early and is dependent on accumulation of disease-specific forms of the prion protein (PrPSc) and may play a role in nerve cell death. Previously, we found that different types of PrPSc (i.e. type 1 and type 2) coexisted in approximately 25% of patients with sporadic Creutzfeldt-Jakob disease (CJD); and a close relationship was detected between PrPSc type, the pattern of PrP immunoreactivity, and extent of spongiform degeneration. To investigate whether microglial reaction is related to the biochemical type and deposition pattern of PrPSc, we carried out a neuropathologic and biochemical study on 26 patients with sporadic CJD, including all possible genotypes at codon 129 of the prion protein gene. By quantitative analysis, we demonstrated that strong microglial activation was associated with type 1 PrPSc and diffuse PrP immunoreactivity, whereas type 2 PrPSc and focal PrP deposits were accompanied by mild microglia reaction. These findings support the view that the phenotypic heterogeneity of sporadic CJD is largely determined by the physicochemical properties of distinct PrPSc conformers.

Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene.

Presenilin 1 and 2 are 2 highly homologous genes involved in familial Alzheimer disease. While more than 100 mutations in presenilin 1 are known to segregate with the disease in familial Alzheimer disease, only 9 mutations of presenilin 2 have been identified to date. We report the clinical and neuropathological phenotype of FLO10, the large Italian Alzheimer kindred associated with methionine to valine substitution at residue 239 of presenilin 2. The patients showed a remarkable variability in age of onset of symptoms, disease duration, and clinical presentation. The neuropathological study of 2 patients revealed peculiar features in addition to neurofibrillary changes and A beta amyloid deposits in the neuropil and vessel wall. Ectopic neurons in the subcortical white matter, often containing neurofibrillary tangles, were found in both patients, one of whom presented with epilepsy. Furthermore, 1 patient showed an unusually high number of ghost tangles in the cerebral cortex. These observations indicate that the Alzheimer kindred FLO10 associated with M239V mutation of presenilin 2 is characterized by some peculiarities of the clinical and neuropathologic phenotype compared to sporadic Alzheimer disease.