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.

Land/Water Aerobic Activities: Two Sides of the Same Coin. A Comparative Analysis on the Effects in Cognition of Alzheimer's Disease.

 Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer's disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se, independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-ß accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions.

The funnel effect of reserves prompted by leisure activities across the Alzheimer's disease continuum.

BACKGROUND: Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves. OBJECTIVE: This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum. METHODS: 35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses. RESULTS: Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls. CONCLUSIONS: This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.

Clinical validity of the Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB) in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD. METHODS: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses. RESULTS: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI. CONCLUSIONS: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD.

A Long Term Recurrent Case of Acute Retinal Pigment Epithelitis.

PURPOSE: To describe the case of a young adult who developed two episodes of Acute Retinal Pigment Epithelitis (ARPE) in the same eye 7 years apart, describing retinal morphologic changes using SD-OCT scan. OBSERVATIONS: ARPE is an acute, self-limiting macular disorder characterized by a stippled dark macular lesion surrounded by a hypopigmented halo under fundus examination, corresponding to a foveal disruption of the outer retinal layers and an hyperreflective lesion under SD-OCT scan. Despite ARPE lesions usually appearing to be situated within the macula, a diffuse involvement of the RPE has been suggested1. SD-OCT scan in our patient showed multiple focal lesions involving the whole posterior pole of the affected eye. CONCLUSIONS AND IMPORTANCE: We report the first case where a diffuse involvement of the RPE in the disease is supported by an OCT finding and the case with the longest period between two recurrent self-limited episodes described so far.

Prospective, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial comparing the safety and efficacy of intranasal dexmedetomidine to oral midazolam as premedication for propofol sedation in pediatric patients undergoing magnetic resonance imaging: the MIDEX MRI trial.

BACKGROUND: Children under 6 years who need magnetic resonance imaging usually require sedation to obtain best quality images, but the optimal sedation protocol remains to be determined. In 2018, we showed a 22% interruption in image acquisition during magnetic resonance imaging when performing a propofol-based sedation using a bolus approach. As non-pharmacological premedication is often insufficient to reduce the anxiety of children related to parental separation, pharmacological premedication may be useful to facilitate the induction of anesthesia. In our institution, effective premedication is obtained oral intake of midazolam, though its administration relies on patients' compliance and could also lead to paradoxical reaction. Dexmedetomidine has a safe profile in the pediatric population and can therefore represent an interesting alternative. The primary objective of this trial is to demonstrate the superiority of intranasal dexmedetomidine compared to oral midazolam as premedication in reducing the occurrence of any event requiring temporary or definitive interruption of the examination to allow anesthesiologist intervention in children undergoing magnetic resonance imaging under propofol sedation. METHODS: In this single-center, prospective, randomized, double-blind, double-dummy, active comparator-controlled, superiority trial, we planned to include 250 patients, aged 6 months to 6 years, undergoing a scheduled magnetic resonance imaging requiring the presence of an anesthesiologist. After informed consent, the patients will be randomized to receive either oral midazolam or intranasal dexmedetomidine as premedication. The data will be analyzed in intention to treat, using Kolmogorov-Smirnov Z, chi-square, Wilcoxon, and Mann-Whitney U tests. A P-value < 0.05 will be considered statistically significant. DISCUSSION: The MIDEX MRI study will assess the efficacy of intranasal dexmedetomidine compared to oral midazolam to improve the quality of a propofol-based sedation prior to magnetic resonance imaging, without negative repercussion on the postoperative period. TRIAL REGISTRATION: ClinicalTrial.gov NCT05192629 . Registered on 14 January 2022. Protocol version 2.1.

Preclinical Brain Network Abnormalities in Patients with Subjective Cognitive Decline.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. OBJECTIVE: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. METHODS: 23 SCD and 33 healthy subjects (HS) underwent an extensive neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. RESULTS: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. CONCLUSIONS: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term.

Italian adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB 1.0): development and normative data.

BACKGROUND: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue. METHODS: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms. RESULTS: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward. CONCLUSIONS: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings.

Recall and Recognition in Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall, performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance. OBJECTIVE: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia. METHODS: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer's disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs). RESULTS: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance. CONCLUSION: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks.

Forgetting Rates on the Recency Portion of a Word List Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer's disease (AD). Consistent with AD patients' distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients' conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD.

Forgetting Rate on the Recency Portion of a Word List Differentiates Mild to Moderate Alzheimer's Disease from Other Forms of Dementi.

Patients with Alzheimer's disease (AD) demonstrate a disproportionately larger forgetting rate in episodic memory tasks. Previous studies documented that, in comparison with healthy controls, the increased forgetting manifested by AD patients in word list recall tasks is confined to the recency portion of the list with normal forgetting rates on the primacy and mid-list portions. In this study we compared the primacy, mid-list, and recency ratios, obtained by dividing the immediate and delayed recall of words in position 1-4, 5-11, and 12-15 of a 15-word list, in different groups of demented patients, i.e., AD, frontal variant of frontotemporal dementia (fvFTD), Lewy body disease (LBD), subcortical ischemic vascular dementia (SIVD), and a group of normal controls (NC). The aim was to investigate whether the above reported forgetting pattern would differentiate AD performance from that of other dementia groups. Results of the statistical analysis showed that only the recency ratio differentiated AD from patients in the other dementia groups. Consistently, hierarchical logistic regression analyses demonstrated that the recency ratio discriminated between AD patients and individuals affected by other forms of dementia. In particular, the discrimination power was high in differentiating AD from fvFTD patients but was less accurate in differentiating AD from LBD and SIVD patients. We assume that the increased forgetting in AD patients is due to a deficit in memory consolidation mechanisms (specific to AD) that prevent the terminal items in a list from being transferred from a temporary short-term memory store to a stable long-term memory store.

Neuropsychological correlates of cognitive, emotional-affective and auto-activation apathy in Alzheimer's disease.

Apathy symptoms include different dimensions: cognitive (C), emotional-affective (E-Aff) and auto-activation; they have been related to dysfunctions of the dorsolateral, orbito-basal prefrontal cortex and the subcortical frontal connections to the basal ganglia, respectively. In Alzheimer's disease (AD), an association has been found between apathy severity and both executive deficits and atrophy of the dorso-lateral prefrontal cortex; however, it is not clear whether these associations concern only the cognitive aspects of apathy. Furthermore, whether there is an association in AD between E-aff apathy and theory of mind (ToM),the cognitive functions subsumed by the orbito-basal prefrontal cortex, has not been investigated. Aim of the study was to investigate the relationship between C, E-Aff and auto-activation apathy and performance on tasks investigating executive and ToM cognitive functions in AD. For this purpose, 20 AD patients with apathy and 20 matched controls were submitted to an executive and ToM neuropsychological assessment. Apathy was assessed with a weekly diary (ApD) created specifically to assist caregivers in quantifying the C, E-Aff and auto-activation symptomatology of apathy. Correlational analyses showed that AD patients' scores on the Modified Card Sorting Test (MCST) and Emotion Attribution tasks were correlated with most ApD scores. However, regression analyses showed that C diary scores were predicted by MCST performance, E-Aff diary scores by performance on the E-Attribution task and ApD scores measuring auto-activation apathy were predicted by both the MCST and the Emotion Attribution scores. These results confirm the co-occurrence of apathy and executive-function deficits in AD and suggest a specific association between AD patients' executive deficits and the cognitive component of apathy. Furthermore, they document, for the first time, an association between poor performance on tests assessing ToM abilities and the emotional-affective component of apathy in AD patients. Finally, these results are in line with the view that auto-activation apathy reflects the sum of emotional and cognitive processing deficits.