Cognitive functioning, cerebrospinal fluid Alzheimer's disease biomarkers and cerebral glucose metabolism in late-onset epilepsy of unknown aetiology: A prospective study.

Epilepsy is increasing, being more common in older adults, with more than 20% of late-onset cases with unknown aetiology (LOEU). Although epilepsy was associated with cognitive impairment, few studies evaluated the trajectories of cognitive decline in patients with LOEU. The present study aimed at assessing biomarkers of Alzheimer's disease (AD) in patients with LOEU and evaluating their cognitive performance for 12 months. For this study, 55 patients diagnosed with LOEU and 21 controls were included. Participants underwent cognitive evaluation and cerebrospinal fluid (CSF) biomarker analysis (ß-amyloid42 , tau proteins) before starting anti-seizure medication and then repeated the cognitive evaluation at the 12-month follow-up. A subgroup of LOEU patients and controls also performed 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET) before starting anti-seizure medication. At baseline, LOEU patients showed lower Mini-Mental State Examination (MMSE) score, worse cognitive performance in several domains, lower ß-amyloid42 and higher tau proteins CSF levels than controls. Significantly reduced glucose consumption was observed in the right posterior cingulate cortex and left praecuneus areas in LOEU patients than controls, and this finding correlated with memory impairment. In the longitudinal analysis, a significant decrease in MMSE and an increase in verbal fluency scores were found in LOEU patients. These findings evidence that LOEU patients have a significant cognitive impairment, and alteration of cerebral glucose consumption and CSF AD biomarkers than controls. Moreover, they showed a progressive global cognitive decline at follow-up, although verbal fluency was preserved. Further studies are needed to better understand the pathophysiological aspects of LOEU and its association with AD.

A narrative review on the potential of tomato and lycopene for the prevention of Alzheimer's disease and other dementias.

Oxidative stress is a major factor in aging and is implicated in the pathogenesis of tumors, diabetes mellitus, cardiovascular and neurodegenerative diseases, including Alzheimer Disease (AD). Bioactive constituents of tomato as polyphenols and carotenoids, among which lycopene (LYC) are effective in reducing markers of oxidative stress, and appear to have a protective modulator role on the pathogenetic mechanisms, cognitive symptoms and behavioral manifestations of these diseases in cell cultures and animal models. Epidemiological evidence indicates a consistent association between the intake of tomatoes and reduced cardiovascular and neoplastic risk. LYC deficiency is common in elders and AD patients and it is strongly predictive of mortality and poor cardiovascular (CV) outcomes. Dietary intake of tomatoes seems to be more effective than tomato/LYC supplementation. Limited evidence from human intervention trials suggests that increasing tomato intake, besides improving CV markers, enhances cognitive performances. In this narrative review, we analyze the existing evidence on the beneficial effects of tomatoes on AD-related processes or risk factors. Results support the development of promising nutritional strategies to increase the levels of tomato consumption for the prevention or treatment of AD and other dementias. Extensive well-structured research, however, is mandatory to confirm the neuroprotective effects of tomato/LYC in humans.

Acceptance and Usability of Immersive Virtual Reality in Older Adults with Objective and Subjective Cognitive Decline.

BACKGROUND: Virtual reality (VR) has recently emerged as a promising means for the administration of cognitive training of seniors at risk of dementia. Immersive VR could result in increased engagement and performances; however, its acceptance in older adults with cognitive deficits still has to be assessed. OBJECTIVE: To assess acceptance and usability of an immersive VR environment requiring real walking and active participants' interaction. METHODS: 58 seniors with mild cognitive impairment (MCI, n = 24) or subjective cognitive decline (SCD, n = 31) performed a shopping task in a virtual supermarket displayed through a head-mounted display. Subjective and objective outcomes were evaluated. RESULTS: Immersive VR was well-accepted by all but one participant (TAM3 positive subscales > 5.33), irrespective of the extent of cognitive decline. Participants enjoyed the experience (spatial presence 3.51±0.50, engagement 3.85±0.68, naturalness 3.85±0.82) and reported negligible side-effects (SSQ: 3.74; q1-q3:0-16.83). The environment was considered extremely realistic, such as to induce potentially harmful behaviors: one participant fell while trying to lean on a virtual shelf. Older participants needed more time to conclude trials. Participants with MCI committed more errors in grocery items' selection and experienced less "perceived control" over the environment. CONCLUSION: Immersive VR was acceptable and enjoyable for older adults in both groups. Cognitive deficits could induce risky behaviors, and cause issues in the interactions with virtual items. Further studies are needed to confirm acceptance of immersive VR in individuals at risk of dementia, and to extend the results to people with more severe symptoms.

The Effects of COVID-19 and Quarantine Measures on the Lifestyles and Mental Health of People Over 60 at Increased Risk of Dementia.

Background: The lockdown strategies adopted to limit the spread of COVID-19 infection may lead to adopt unhealthy lifestyles which may impact on the mental well-being and future risk of dementia. Older adults with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) may suffer important mental health consequences from measures of quarantine and confinement. Aims: The study aimed to explore the effects of COVID-19 and quarantine measures on lifestyles and mental health of elderly at increased risk of dementia. Methods: One hundred and twenty six community-dwelling seniors with MCI or SCD were phone-interviewed and assessed with questions regarding variables related to COVID-19 pandemic, lifestyle changes and scales validated for the assessment of depression, anxiety, and apathy. Results: The sample included 55.6% patients with MCI and 56 people with SCD. Over 1/3 of the sample reduced their physical activity and nearly 70% reported an increase in idle time. Adherence to the Mediterranean diet decreased in almost 1/3 of respondents and over 35% reported weight gain. Social activities were abolished and 1/6 of participants also decreased productive and mental-stimulating activities. 19.8% were depressed, 9.5% anxious, and 9.5% apathetic. A significant association existed between depression and living alone or having a poor relation with cohabitants and between anxiety and SCD, cold or flu symptoms, and reduction in productive leisure activities. Conclusions: Seniors with SCD and MCI underwent lifestyle changes that are potentially harmful to their future cognitive decline, even if, with the exception of leisure activities, they do not appear to be cross-sectionally associated with psychiatric symptoms.

Sedentary Behaviors and Physical Activity Habits Independently Affect Fat Oxidation in Fasting Conditions and Capillary Glucose Levels After Standardized Glucose-Rich Meal in Healthy Females.

PURPOSE: Sedentary behaviors and muscle inactivity are being growingly recognized as important risk factors for health, adjunctively and independently from a scarce physical activity (PA), although the metabolic mechanism underneath is barely clear. To explore the relation between sedentary behaviors (SBs) and metabolism, we measured the metabolic profile in fasting condition and after oral glucose overload in a group of women, along with objective monitoring of their PA/sedentary lifestyle habits. SUBJECTS AND METHODS: Thirteen women (age: 32.5 ± 16.1 years; BMI: 24.0 ± 3.3 kg/m2), recruited among university students and research staff, underwent indirect calorimetry to assess fat and carbohydrate contribution to energy metabolism, in fasting conditions and after a glucose-rich standard meal (about 45 g of glucose). Glucose concentration in capillary blood was determined in fasting state and 15 and 30 min after meal. Habitual PA and SBs in the previous week were continuously monitored with Actigraph accelerometers. RESULTS: After adjustment for age, the contribution of fat oxidation to metabolic energy sources, normalized for fat-free mass, in fasting conditions was significantly correlated with time spent in sitting/lying position during wake hours (p < 0.001), independent from PA habits, whereas capillary blood peak and change of glucose concentration after the meal were significantly and inversely correlated with average daily moderate to vigorous PA (p = 0.025 and p = 0.019, respectively), independent from average daily sitting/lying time. CONCLUSIONS: Here, we report for the first time a direct effect of muscle inactivity on increased fat oxidation in fasting conditions, which can be hypothesized as a preliminary condition for the development of insulin resistance. We also report the direct independent effect of PA on the capacity to respond to a glycemic load, so that SBs and reduced PA appear to concur, although independently, to the increased health risk, as elsewhere observed on an epidemiological ground.

Sleep-Wake Cycle in Alzheimer's Disease Is Associated with Tau Pathology and Orexin Dysregulation.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. OBJECTIVE: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. METHODS: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. RESULTS: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. CONCLUSION: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

Cognitive performances in patients affected by late-onset epilepsy with unknown etiology: A 12-month follow-up study.

INTRODUCTION: Epilepsy has a growing frequency, particularly in the elderly. Several triggers may cause late-onset epilepsy; however, more than 20% of epilepsies, manifesting in the elderly, has an unknown etiology. Although cognition is frequently altered in patients affected by epilepsy, there is a paucity of studies specifically evaluating cognition in patients affected by late-onset epilepsy. The aim of the present study was to assess the cognitive profile of patients affected by late-onset epilepsy with an unknown etiology and followed for 12 months. METHODS: Patients affected by diagnosed late-onset epilepsy with unknown etiology were included in this observation. All patients were evaluated at the time of diagnosis (baseline) and at follow-up (12 months later). We distributed patients in subgroups based on seizure type (focal seizures [FS], secondarily generalized seizures [SGS], primarily generalized seizures [GS]) and antiepileptic drug (AED) regimen (mono- vs. polytherapy). Cognition was evaluated through standardized neuropsychological testing. RESULTS: Fifty-eight patients were included in this observation and distributed in three groups: 29 affected by FS, 14 affected by SGS, 15 affected by GS. Forty-five patients were in monotherapy, and 13 in polytherapy. The most frequent treatments were levetiracetam (n = 12), valproic acid (VPA) (n = 9), carbamazepine (n = 9), and oxcarbazepine (n = 7). We documented a significant decrease of Mini-Mental State Examination (MMSE) and memory scores at follow-up in the whole group. Verbal learning decreased exclusively in VPA users. CONCLUSION: Patients affected by late-onset epilepsy with unknown etiology showed a significant decline of cognition at follow-up, independently from number and efficacy of AEDs received. These results deserve verification in larger longitudinal cohorts.

The LIBRA Index in Relation to Cognitive Function, Functional Independence, and Psycho-Behavioral Symptoms in a Sample of Non-Institutionalized Seniors at Risk of Dementia.

BACKGROUND: Alzheimer's disease is the principal cause of dementia and is determined, in at least one third cases, by modifiable risk factors (MRF). The "Lifestyle for Brain Health (LIBRA)" index was recently developed to quantify the individual risk of progression to dementia ascribable to MRF. OBJECTIVE: The aim of this study was to investigate the association between LIBRA scores and markers of cognitive performance, functional independence, and psycho-behavioral symptoms in a community-based sample of Italian elders. METHODS: 308 senior participants with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) were evaluated with a complete neuropsychological battery and semi-structured interviews for the assessment of depression, apathy, and functional autonomy. All the 12 LIBRA MRF were available for the calculation of LIBRA scores. A modified version of the index (LIBRA-2) was calculated by removing depression weight from the LIBRA index. Partial correlation analyses, controlling for age and education, assessed the association between LIBRA indices and cognitive, functional, and behavioral outcomes. Separate analyses were repeated in the MCI and SCD subgroups. RESULTS: In participants with SCD (SCDp), significant correlations existed between LIBRA and markers of impairment in global cognition, visuo-spatial attention, and semantic fluency. LIBRA-2 associated with psycho-behavioral symptoms in the whole sample and in SCDp. LIBRA-2 only associated with apathy in the MCI subgroup. CONCLUSIONS: The LIBRA index might be useful to determine the lifestyle-attributable risk of cognitive and psycho-behavioral decline in Italian seniors at risk, while in those with overt cognitive impairment, these outcomes are presumably mainly associated with non-modifiable factors.

Neuropsychiatric symptoms differently affect mild cognitive impairment and Alzheimer's disease patients: a retrospective observational study.

Alzheimer's disease (AD) is the most common form of dementia characterized by the prevalent memory impairment. Mild cognitive impairment (MCI) may represent the early stage of AD, in particular when MCI patients show biomarkers consistent with AD pathology (MCI due to AD). Neuropsychiatric symptoms (NPS) frequently affect both MCI and AD patients. Cerebrospinal-fluid (CSF) tau and ß-amyloid42 (Aß42) levels are actually considered the most sensitive and specific biomarkers for AD neurodegeneration. In the present retrospective observational study, we evaluated CSF biomarkers and neuropsychological data (also including NPS measured by the neuropsychiatric inventory-NPI) in a population of patients affected by MCI due to AD compared with mild to moderate AD patients. We documented higher NPI scores in MCI compared with AD patients. In particular, sub-items related to sleep, appetite, irritability, depression, and anxiety were higher in MCI than AD. We also found the significant correlation between NPS and CSF AD biomarkers in the whole population of MCI and AD patients. Consistently, t-tau/Aß42 ratio correlated with NPS in all the MCI and AD patients. These results suggest the more prevalent occurrence of NPS in MCI patients showing AD pathology and converting to dementia than AD patients. Moreover, a more significant degree of AD neurodegeneration, featured by high t-tau/Aß42 ratio, correlated with more severe NPS, thus supposing that in MCI and AD patients a more extensive AD neurodegeneration is related to more severe behavioral disturbances.

Effects of Combined Physical and Cognitive Virtual Reality-Based Training on Cognitive Impairment and Oxidative Stress in MCI Patients: A Pilot Study.

The growing elderly population and the increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) call for the improvement of the quality and the efficacy of the healthcare and social support services. Exercise and cognitive stimulation have been demonstrated to mitigate cognitive impairment and oxidative stress (OxS) has been recognized as a factor that contributes to the advancement of neurodegenerative diseases. Taking these aspects into account, the impact of a novel virtual reality (VR)-based program combining aerobic exercise and cognitive training has been evaluated in the pilot study proposed here. Ten patients (aged 73.3 ± 5.7 years) with MCI (Mini-Mental State Examination, MMSE: 23.0 ± 3.4) were randomly assigned to either 6 weeks physical and cognitive training (EXP) or control (CTR) group. Evaluations of cognitive profile, by a neuropsychological tests battery, and OxS, by collection of blood and urine samples, were performed before and at the end of the experimental period. The assessment of the patients' opinions toward the intervention was investigated through questionnaires. EXP group showed a tendency towards improvements in the MMSE, in visual-constructive test and visuo-spatial tests of attention, while CTR worsened. EXP group showed a greater improvement than CTR in the executive test, memory functions and verbal fluency. No statistical significance was obtained when comparing within and between both the groups, probably due to small number of subjects examined, which amplifies the effect of the slight heterogeneity in scores recorded. Despite a greater worsening of Daily Living Activities tests, all participants reported a better performance in real life, thanks to the elicited self-perceived improvement. After training intervention OxS (i.e., reactive oxygen species (ROS) production, oxidative damage of lipids and DNA) decreased resulting in significantly (range p < 0.05-0.001) lower in EXP vs. CTR group. Although not conclusive, the recorded effects in the present study are promising and suggest that this proposal would be a useful tool in support of cognitive training reducing OxS too. However, further studies on larger scale samples of patients are needed.

When Cognitive Decline and Depression Coexist in the Elderly: CSF Biomarkers Analysis Can Differentiate Alzheimer's Disease from Late-Life Depression.

Late-life depression (LLD) and Alzheimer's Disease (AD) are the two most frequent neuropsychiatric disorders affecting elderly. LLD and AD may clinically present with depressive and cognitive symptoms. Therefore, when cognitive decline is coupled with depression in the elderly, the differential diagnosis between LLD and AD could be challenging. The aim of the present study was to evaluate in a population of elderly patients affected by depression and dementia the usefulness of CSF AD biomarkers (tau proteins and ß-amyloid42-Aß42) and 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (18FFDG-PET) in early differentiating LLD from AD. Two hundred and fifty-six depressed and demented patients, after performing CSF AD biomarkers and 18FFDG-PET, were distributed in two groups on the basis of the current diagnostic guidelines for AD (n = 201) and LLD (n = 55). Patients were then observed for 2 years to verify the early diagnosis. After the 2 year follow-up we compared AD and LLD patients' CSF and 18FFDG-PET data obtained at baseline to a group of age- and sex-matched controls. We found CSF Aß42 levels significantly higher in LLD compared to AD patients. Remarkably, CSF Aß42 levels of LLD patients (range between 550 and 1204 pg/mL) did not overlap with those of AD patients (range between 82 and 528 pg/mL). Moreover, we documented no differences in CSF AD biomarkers (Aß42 and tau proteins) when comparing LLD patients to controls. In addition, AD patients showed the significant reduction of 18FFDG-PET uptake in temporo-parietal regions compared to both controls and LLD. Conversely, LLD and control groups did not differ at 18FFDG-PET analysis, although LLD patients showed heterogeneous patterns of glucose hypometabolism involving cortical and subcortical brain areas. It is noteworthy that at the end of the clinical follow-up, patients owing to AD group showed the expected significant decline of cognitive performances, whereas patients assigned to LLD group improved cognition as depressive symptoms recovered. Hence, in case of co-existence of cognitive impairment and depression in the elderly, we propose CSF AD biomarkers analysis to early differentiate LLD from AD and properly target the patient's therapeutic strategy and clinical follow-up.