The m6A-epitranscriptome in brain plasticity, learning and memory.

Activity-dependent gene expression and protein translation underlie the ability of neurons to dynamically adjust their synaptic strength in response to sensory experience and during learning. The emerging field of epitranscriptomics (RNA modifications) has rapidly shifted our views on the mechanisms that regulate gene expression. Among hundreds of biochemical modifications on RNA, N6-methyladenosine (m6A) is the most abundant reversible mRNA modification in the brain. Its dynamic nature and ability to regulate all aspects of mRNA processing have positioned m6A as an important and versatile regulator of nervous system functions, including neuronal plasticity, learning and memory. In this review, we summarise recent experimental evidence that supports the role of m6A signalling in learning and memory, as well as providing an overview of the underlying molecular mechanisms in neurons. We also discuss the consequences of perturbed m6A signalling and/or its regulatory networks which are increasingly being linked to various cognitive disorders in humans.

IL-1ß and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer's disease.

BACKGROUND: Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer's disease. With advancing age, the progressive increase in the body's pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer's disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases. METHODS: To examine the impacts of periodontitis on the onset and progression of Alzheimer's disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer's disease, interleukin 1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice. RESULTS: Here, we show that IL-1ß and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer's disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer's disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer's disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice. CONCLUSIONS: Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer's disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer's disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer's disease.

ß-Hydroxybutyric acid attenuates heat stress-induced neuroinflammation via inhibiting TLR4/p38 MAPK and NF-κB pathways in the hippocampus.

Heat stress causes many pathophysiological responses in the brain, including neuroinflammation and cognitive deficits. ß-Hydroxybutyric acid (BHBA) has been shown to have neuroprotective effects against inflammation induced by lipopolysaccharide. The aim of the present study was to evaluate the effects of BHBA on neuroinflammation induced by heat stress, as well as the underlying mechanisms. Mice were pretreated with vehicle, BHBA or minocycline (positive control group) and followed by heat exposure (43°C) for 15 min for 14 days. In mice subjected to heat stress, we found that treatment with BHBA or minocycline significantly decreased the level of serum cortisol, the expressions of heat shock protein 70 (HSP70), and the density of c-Fos+ cells in the hippocampus. Surprisingly, the ethological tests revealed that heat stress led to cognitive dysfunctions and could be alleviated by BHBA and minocycline administration. Further investigation showed that BHBA and minocycline significantly attenuated the activation of microglia and astrocyte induced by heat stress. Pro-inflammatory cytokines were attenuated in the hippocampus by BHBA and minocycline treatment. Importantly, compared with the heat stress group, mice in the BHBA treatment group and positive control group experienced a decrease in the expressions of toll-like receptor 4 (TLR4), phospho-p38 (p-p38), and nuclear factor kappa B (NF-κB). Our results elucidated that BHBA inhibits neuroinflammation induced by heat stress by suppressing the activation of microglia and astrocyte, and modulating TLR4/p38 MAPK and NF-κB pathways. This study provides new evidence that BHBA is a potential strategy for protecting animals from heat stress.

Risk factors for post-COVID cognitive dysfunctions: the impact of psychosocial vulnerability.

BACKGROUND: Cognitive dysfunction is a well-established manifestation of the post-COVID syndrome. Psychological vulnerability to stressors can modify disease trajectories, causing long-term risk for negative outcomes. Nonetheless, how premorbid risk factors and response to stressor affect neuropsychological changes is still incompletely understood. In this study, we explored the impact of psychosocial variables on cognitive functioning in a post-COVID sample. METHODS: All subjects were submitted to a comprehensive neuropsychological battery and an assessment of perceived loneliness, post-traumatic stress, and changes in anxiety and depression levels. A social vulnerability index was also calculated. The set of psycho-social variables was reduced to two Principal Component Analysis (PCA) components: distress and isolation. RESULTS: Forty-five percent of individuals showed cognitive impairments, with predominant memory and executive deficits. Post-traumatic stress disorder was clinically relevant in 44% of the sample. Social vulnerability scores of the sample were comparable to those of general population. The individual performance in learning and response initiation/suppression was directly related to distress component, encasing anxiety, stress, and depression measures. CONCLUSION: These findings suggest that psychosocial assessment of post-COVID patients can detect fragile individuals at risk of cognitive impairments. Dedicated psychological support services may play a useful role in the prevention of post-COVID cognitive dysfunction.

The pathogenic effects of particulate matter on neurodegeneration: a review.

The increasing amount of particulate matter (PM) in the ambient air is a pressing public health issue globally. Epidemiological studies involving data from millions of patients or volunteers have associated PM with increased risk of dementia and Alzheimer's disease in the elderly and cognitive dysfunction and neurodegenerative pathology across all age groups, suggesting that PM may be a risk factor for neurodegenerative diseases. Neurodegenerative diseases affect an increasing population in this aging society, putting a heavy burden on economics and family. Therefore, understanding the mechanism by which PM contributes to neurodegeneration is essential to develop effective interventions. Evidence in human and animal studies suggested that PM induced neurodenegerative-like pathology including neurotoxicity, neuroinflammation, oxidative stress, and damage in blood-brain barrier and neurovascular units, which may contribute to the increased risk of neurodegeneration. Interestingly, antagonizing oxidative stress alleviated the neurotoxicity of PM, which may underlie the essential role of oxidative stress in PM's potential effect in neurodegeneration. This review summarized up-to-date epidemiological and experimental studies on the pathogenic role of PM in neurodegenerative diseases and discussed the possible underlying mechanisms.

Serum neurofilament light reflects cognitive dysfunctions in children with obstructive sleep apnea.

BACKGROUND: In children, obstructive sleep apnea (OSA) can cause cognitive dysfunctions. Amyloid-beta and tau are elevated in OSA. Neurofilament light (NfL) is a marker of neuro-axonal damage, but there are no reports of NfL for OSA. The objective was to investigate the serum levels of NfL and tau in children with or without OSA and explore their relationship with cognitive dysfunctions caused by OSA. METHODS: This retrospective case-control study included children diagnosed with adenoid tonsil hypertrophy from July 2017 to September 2019 at the Second Affiliated Hospital of Xi'an Jiaotong University. Correlations between cognitive scores and tau and NfL were examined. RESULTS: Fifty-six OSA and 49 non-OSA children were included. The serum NfL levels were higher in the OSA group (31.68 (27.29-36.07) pg/ml) than in the non-OSA group (19.13 (17.32-20.95) pg/ml) (P < 0.001). Moreover, NfL was correlated with the course of the disease, apnea-hypopnea index (AHI), obstructive apnea index (OAI), obstructive apnea-hypopnea index (OAHI), average oxygen saturation (SaO2), respiratory arousal index (RAI), and cognitive dysfunctions evaluated by the Chinese Wechsler Intelligence Scale for Children (C-WISC) (all P < 0.05). The area under the receiver operating characteristics curve (AUC) of NfL was 0.816 (95%CI: 0.736-0.897). Multiple regression analysis revealed that NfL was significantly associated with verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ) and full-scale intelligence quotient (FIQ) (P < 0.001, respectively). CONCLUSIONS: Serum NfL levels are associated with the severity of cognitive dysfunctions in children diagnosed with adenoid tonsil hypertrophy and might be a candidate noninvasive, objective marker to identify cognitive dysfunctions in children with OSA.

Sleep Disorders and Cognitive Dysfunctions in Parkinson's Disease: A Meta-Analytic Study.

A relationship between sleep disorders and cognitive dysfunctions was reported in Parkinson's Disease (PD), however, some studies did not confirm the link. A meta-analytic study was performed to investigate the relationship between sleep disorders and cognitive dysfunctions, and to clarify the evolution of cognitive status in PD patients with sleep disorders.The systematic literature search was performed up to November 2020 using PubMed, Scopus, and PsycINFO databases. We included studies published in peer-reviewed journals in English providing results about neuropsychological comparison between patients with or without sleep disorders. Meta-analysis on cross-sectional data included 54 studies for REM Sleep Behavior Disorder (RBD), 22 for Excessive Daytime Sleepiness (EDS), 7 for Obstructive Sleep Apnea (OSA), 13 for Restless Legs Syndrome (RLS), and 5 for insomnia, the meta-analysis on longitudinal data included 7 studies.RBD was related to deficits of global cognitive functioning, memory, executive functions, attention/working memory, language, and visuospatial abilities. EDS was associated with deficits of global cognitive functioning and attention and working memory abilities, whereas RLS and OSA were related to global cognitive dysfunction. Moreover, we revealed that PD patients with RBD and those with EDS performed worse than PD patients without sleep disorders at follow-up rather than baseline evaluation. Our results suggest that sleep disorders are associated with cognitive deficits supporting indirectly that these, especially the REM Sleep Behavior Disorder, reflect abnormalities of frontal networks and posterior cortical areas. Sleep disorders in patients with PD seem to also increase the risk for long-term cognitive decline.

TIMP-1: A key cytokine released from activated astrocytes protects neurons and ameliorates cognitive behaviours in a rodent model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by two pathologic species, extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles. Astrocytes that maintain normal homeostasis in the brain undergo a set of molecular, cellular and functional changes called reactive astrogliosis in various neurological diseases including AD. It is hypothesized that reactive astrocytes initially tend to protect neurons by reducing Aß load and by secreting a plethora of cytokines, however, their functions have only been poorly investigated. Our studies on the kinetics of activation of cortical astrocytes following Aß-exposure revealed significant level of activation as early as in 6 h. The astrocyte conditioned medium (ACM) from 6 h Aß-treated astrocytes (Aß-ACM) provided significant neuroprotection of cultured cortical neurons against Aß insults. Analysis of the secreted proteins in Aß-ACM revealed a marked increase of Tissue inhibitor of Metalloproteinase-1 (TIMP-1) within 6 h. Interestingly, we found that neutralization of TIMP-1 with antibody or knockdown with siRNA in astrocytes abolished most of the neuroprotective ability of the 6 h Aß-ACM on Aß-treated cultured neurons. Furthermore addition of exogenous rat recombinant TIMP-1 protein protects primary neurons from Aß mediated toxicity. In a well characterized Aß-infused rodent model of AD, intra-cerebroventricular administration of TIMP-1 revealed a reduction in Aß load and apoptosis in hippocampal and cortical regions. Finally, we found that TIMP-1 can ameliorate Aß-induced cognitive dysfunctions through restoration of Akt and its downstream pathway and maintenance of synaptic integrity. Thus, our results not only provide a functional clarity for TIMP-1, secreted by activated astrocytes, but also support it as a major candidate in cytokine-mediated therapy of AD especially at the early phase of disease progression.

Apathy as a herald of cognitive changes in multiple sclerosis: A 2-year follow-up study.

BACKGROUND: Behavioral symptoms, such as apathy and depression, are common in multiple sclerosis (MS) but their relationship with cognitive and clinical characteristics often remains underinvestigated and not monitored over time. OBJECTIVE: The aim of this study was to assess the evolution of cognitive profile of patients affected by MS in relation to apathy and depression using a 2-year follow-up study. METHODS: Two years after the first assessment, 100 of 125 MS patients were re-evaluated on a comprehensive neuropsychological battery, and on specific scales for assessment of apathy (Apathy Evaluation Scale-Self-reported) and depression (Hamilton Depression Rating Scale). RESULTS: After 2 years (T1), we found a relatively consistent prevalence of apathy (about 40%) and a reduction in prevalence of depression (from 44% to 30%). Higher level of apathy at baseline predicted the progressive cognitive changes at follow-up; and patients with apathy without depression ("pure" apathy) than patients without apathy had poorer performance on the interference task of the Stroop test assessing inhibitory control. CONCLUSION: The present results suggested that apathy in MS was associated with more severe executive dysfunctions (in particular cognitive control). Apathy rather than depression predicted cognitive impairment in MS over time.

The role of the motor subtypes on the relationship between anxiety and cognitive dysfunctions in Parkinson's disease.

Anxiety is a common neuropsychiatric symptom in Parkinson's disease (PD). Until now, anxiety has been consistently related to cognitive deficits and severity of motor symptoms, whereas the association between anxiety and motor subtypes (TD-PD, tremor dominant and PIGD-PD, postural instability/gait disturbances dominant) revealed contrasting results. The present study aims to investigate the relationship between PD motor subtypes and anxiety and to explore whether the relationship between anxiety and cognitive deficits occurs in a specific PD motor subtype. Consecutive PD outpatients were recruited and divided into TD-PD and PIGD-PD groups according to Jankovic et al.'s criteria. All participants underwent a neuropsychological battery to evaluate anxiety, apathy, the global cognitive functioning, memory abilities, executive and visuo-constructional functions. Thirty-six patients with TD-PD and 35 patients with PIGD-PD were enrolled. The two groups did not differ on demographical and clinical variables. As for the severity of anxiety, no significant difference between the two groups was found. Regression analysis revealed that higher anxiety score was associated with poorer performance on constructional visuospatial test in both TD-PD and PIGD-PD. Clinical variables were not associated with anxiety in the two groups. Our findings indicated that the severity of anxiety was not associated with any PD motor subtypes. Moreover, regression analysis revealed that impaired visuo-constructional abilities are related to anxiety independently of PD motor subtypes. Since altered fronto-parietal network might be one of the pathogenetic mechanisms underpinning anxiety and constructional visuospatial deficits, the treatment of cognitive dysfunctions might reduce anxious symptoms.

The impact of obstructive apnea sleep syndrome on chemical function.

OBJECTIVE/HYPOTHESIS: To investigate the impact of obstructive sleep apnea syndrome (OSAS) on the olfactory and gustatory functions, and the potential mechanisms affecting olfactory and gustatory functions. MATERIALS AND METHODS: A total of 120 men between the ages of 41 and 70 (mean age (SD) = 56 ± 7.5) were divided into three groups according to polysomnography results: snoring group, mild to moderate OSAS group, and severe OSAS group. Olfactory and gustatory functions were evaluated by the Sniffin' Sticks test and the triple-drop method, respectively. Otorhinolaryngologic examination, as well as sleep and quality of life questionnaires, were completed by all subjects one day before or after polysomnography. RESULTS: There was a significant difference in odor thresholds (THR), odor discrimination (OD), odor identification (OI), thresholds-discrimination-identification (TDI) (p < 0.001, p < 0.001, p = 0.003, p < 0.001), and total taste score (p = 0.004, p = 0.021, p = 0.006) in all three groups. Of the subjects in the OSAS group, 43 (54%) exhibited olfactory dysfunction, including 18 subjects (45%) in the mild to moderate group and 25 subjects (63%) in the severe group. Significant negative correlations were found between all olfactory parameters and polysomnography parameters. Furthermore, a negative correlation was present between the total taste scores and the apnea-hypopnea index (AHI). CONCLUSION: Men with OSAS exhibited impairment in olfactory and gustatory functions. Significant correlations were found between AHI and olfactory parameters, as well as between AHI and total taste scores.

Systemic inflammation linking chronic periodontitis to cognitive decline.

Persistent inflammation in the systemic immune system can impose detrimental effects on the central nervous system (CNS). Neuroinflammation might be a result of this to accelerate the progressive deterioration of neuronal functions during aging. In this regard, controlling inflammation through delaying and/or preventing chronic inflammatory diseases may be a potential strategy to prevent or modify the progression of Alzheimer's Disease (AD). Periodontitis is a chronic inflammatory disease of the oral cavity that is common among the elderly, especially for those who have decline in cognitive functions. While epidemiological findings support the association of chronic periodontitis and cognitive decline, whether they have causal relationship remains unclear. Nonetheless, the possibility that periodontopathogens, systemic immune cells and inflammatory cytokines could reach the CNS should not be overlooked. The impacts of periodontitis on CNS homeostasis and inflammation as a pathophysiological factor concerning the association between periodontitis and AD will be discussed in this review. Future work should elucidate the pathological pathways involved in periodontitis-induced cerebral infections and inflammation, and define the role of the latter in AD progression.

Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory.

A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2 ±â€¯0.01 µM) compared to standard donepezil (AChE, IC50: 0.1 ±â€¯0.002 µM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ±â€¯1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93 ±â€¯0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.

[Specific markers of neuropsychiatric systemic lupus erythematosus with mental disorders - review of the literature].

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease belonging to spectrum of interest of many medical specialties. Wide range of patients 14-75% with SLE suffers from neuropsychiatric disorders. The problematic diagnosis of neuropsychiatric SLE has generated many studies focusing on etiology of the disease with the presence of specific autoantibodies, abnormalities which can be detected by imaging examinations or correlation with catecholamine levels. The aim of this review paper is to discuss the frequency of neuropsychiatric disturbances in patients with SLE and their potential association with immunological abnormalities and specific disease markers. So far published literature regarding this topic indicates the usefulness of autoantibodies specificity. The use of the specific antibodies may be helpful in targeting diagnostics towards psychiatric disorders, especially depressive ones. Imaging scanning techniques such as computed tomography (CT) have limited value in psychiatric disorders diagnosis but can be useful in neurological symptoms and complains. Therapeutic use of systemic glucocorticosteroids due to anti-inflammatory properties with multidirectional action, may also significantly influence the course of neuropsychiatric diseases, especially in patients with SLE. Awareness of the morbidity of neuropsychiatric disorders and the possibilities of their diagnosis are important in the management of patients with systemic lupus erythematosus, which significantly affects the quality of life of patients, treatment efficacy and psyche.

Cognitive Impairments in Unipolar Depression: The Impact of Rumination.

BACKGROUND: Major depressive disorder (MDD) is associated with impairments in several cognitive domains. People with depression also tend to focus on and think about their problems ("ruminate") more than people without depression. Recent studies indicate that depressive rumination is connected to cognitive impairments in MDD. However, there is little scientific understanding of the role of rumination in these deficits. SAMPLING AND METHODS: The current study examined the performance of 62 outpatients suffering from unipolar major depression with a low tendency to ruminate versus outpatients with a high tendency to ruminate using a neuropsychological battery covering the 5 cognitive domains: attention, memory, working memory, executive functions and processing speed. RESULTS: The results indicated that high ruminators show a lower performance than low ruminators with regard to processing speed and executive function tasks with low effect sizes. However, these findings were not significant after Bonferroni correction. Hierarchical linear regression revealed that the effect on processing speed could be partially attributed to rumination, but an effect on executive functions was not established. CONCLUSIONS: The current study is the first to systematically investigate the impact of rumination on cognitive impairments in MDD, exploring a broad range of cognitive domains. The results partially support the hypothesis that rumination has an impact on single cognitive domains and highlight the necessity for further investigations in order to generalize these findings.

Neuropsychological correlates of Pisa syndrome in patients with Parkinson's disease.

BACKGROUND: A complex relationship exists between postural control and cognition in the elderly. Namely, neural mechanisms that are required for the regulation of posture have been variably associated with cognitive dysfunctions. Parkinson's disease (PD) is the second most common neurodegenerative disease among the elderly, and it has been associated with both cognitive and postural abnormalities such as Pisa syndrome (PS). Although its onset has been considered to be multifactorial, the pathophysiological mechanisms underpinning PS are still not fully explained. Until now, no study investigated the possible contribution of cognitive dysfunction to occurrence of PS in PD. PATIENTS AND METHODS: Twenty PD patients with PS and 20 PD patients without PS were enrolled. All patients with PD underwent neuropsychological battery to assess behavioural disturbances, memory, attention, frontal/executive and visuospatial functions. RESULTS: The two groups did not differ on demographic features, age at PD onset and disease duration, whereas they significantly differed on UPDRS-Part III, and levodopa-equivalent daily dose (LEDD). MANCOVA with above-mentioned clinical variable as covariates revealed significant differences on tasks tapping verbal long-term memory, and attentional and visuoperceptual abilities between groups. The binary logistic regression revealed that higher LEDD and lower performance on visuospatial task (Benton Judgment of Lines Orientation test) significantly predicted occurrence of PS. CONCLUSION: Our results revealed a significant association of PS with altered attention and visuoperceptual functions in PD, suggesting that the occurrence of PS may be associated with alteration of both frontal-striatal systems and posterior cortical areas.

The Addenbrooke's Cognitive Examination Revised (ACE-R) and its sub-scores: normative values in an Italian population sample.

The Addenbrooke's Cognitive Examination Revised (ACE-R) is a rapid screening battery, including five sub-scales to explore different cognitive domains: attention/orientation, memory, fluency, language and visuospatial. ACE-R is considered useful in discriminating cognitively normal subjects from patients with mild dementia. The aim of present study was to provide normative values for ACE-R total score and sub-scale scores in a large sample of Italian healthy subjects. Five hundred twenty-six Italian healthy subjects (282 women and 246 men) of different ages (age range 20-93 years) and educational level (from primary school to university) underwent ACE-R and Montreal Cognitive Assessment (MoCA). Multiple linear regression analysis revealed that age and education significantly influenced performance on ACE-R total score and sub-scale scores. A significant effect of gender was found only in sub-scale attention/orientation. From the derived linear equation, a correction grid for raw scores was built. Inferential cut-offs score were estimated using a non-parametric technique and equivalent scores (ES) were computed. Correlation analysis showed a good significant correlation between ACE-R adjusted scores with MoCA adjusted scores (r = 0.612, p < 0.001). The present study provided normative data for the ACE-R in an Italian population useful for both clinical and research purposes.

Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study.

BACKGROUND AND PURPOSE: Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. METHODS: Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale (S-AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S-AES, a clinical interview and neuropsychological tests. RESULTS: According to the cut-off value of the S-AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A-A+), 37 patients never experienced apathy (A-A-) and eight patients showed apathy at the baseline only (A+A-). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A-A- on visuospatial and frontal tests; A-A+ had lower scores than A-A- on the interference task of the Stroop test (IT-ST). Regression analysis showed that poor performance on the IT-ST at baseline was the only independent predictor of onset of apathy at follow-up. CONCLUSIONS: The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT-ST may predict development of apathy in PD patients.

Subthreshold depression and subjective cognitive complaints in Parkinson's disease.

BACKGROUND AND PURPOSE: Subthreshold depression (SubD) is characterized by clinically relevant depressive symptoms not meeting criteria for major depression. The possible association of SubD with subjective cognitive complaints and/or objective cognitive impairments was investigated in a sample of consecutive, non-demented Parkinson's disease (PD) outpatients. METHODS: Amongst 115 patients, SubD was identified in 30 patients, major depression in 33; 36 patients were classified as non-depressed. Enrolled patients were administered tests and questionnaires validated in PD for assessing objective and subjective cognitive dysfunctions. RESULTS: On objective cognitive measures SubD patients did not differ from non-depressed patients, whereas depressed patients achieved significantly lower scores than the other two groups. SubD and depressed patients reported more cognitive complaints than non-depressed patients. CONCLUSIONS: SubD is a non-motor aspect of PD that is not related to objective cognitive deficits but is associated with subjective cognitive complaints, thus impacting on patients' well-being.

Intricacies of aging and Down syndrome.

Down syndrome is the most frequently occurring genetic condition, with a substantial escalation in risk associated with advanced maternal age. The syndrome is characterized by a diverse range of phenotypes, affecting to some extent all levels of organization, and its progeroid nature - early manifestation of aspects of the senile phenotype. Despite extensive investigations, many aspects and mechanisms of the disease remain unexplored. The current review aims to provide an overview of the main causes and manifestations of Down syndrome, while also examining the phenomenon of accelerated aging and exploring potential therapeutic strategies.