Memorization test and resting state EEG components in mild and subjective cognitive impairment

BACKGROUND: Mild (MCI) and Subjective Cognitive Impairment (SCI) are conditions at risk of developing Alzheimer's disease (AD). Differential between normal aging at early stages can be really challenging; available biomarkers need to be combined and can be quite invasive and expensive. OBJECTIVE: The aim of this pilot study is to examine possible EEG alterations in MCI and SCI compared to controls, analyzing if a cognitive task could highlight early AD hallmarks. METHOD: We recruited 11 MCI, 8 SCI and 7 healthy subjects as controls (CS), all matched for age and education. Neuropsychological assessment and EEG recording, at resting state and during a mental memory task, were performed. Classical spectral measures and nonlinear parameters were used to characterize EEGs. RESULTS: During cognitive task, \u3b1-band power reduction was found predominantly in frontal regions in SCI and CS, diffused to all regions in MCI; moreover, decreased EEG complexity was found in SCI compared to controls. The \u3b1 -band power attenuation restricted to frontal regions in SCI during a free recall task (involving frontal areas), suggests that MCI patients compensate for encoding deficit by activating different brain networks to perform the same task. Furthermore, EEG complexity reduction - that has been found already in SCI - could be a possible early hallmark of AD. CONCLUSION: This study draws attention on the importance of nonlinear approach in EEG analysis and the potential role of cognitive task in highlighting EEG alterations at very early stages of cognitive impairment; EEG could therefore have a practical impact on dementia diagnosis

Neuropsychological, Behavioral, and Anatomical Evolution in Right Temporal Variant Frontotemporal Dementia: A Longitudinal Single Case Analysis

We examine longitudinal clinical and anatomical data for a patient with the right temporal variant of frontotemporal dementia. The patient received comprehensive clinical evaluations and structural MRI scans over three years. She presented with early behavioral deficits and ultimately developed semantic impairments consistent with the semantic variant of primary progressive aphasia. Imaging revealed early atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that right and left temporal variants reflect early asymmetry of atrophy that may become more bilateral over time, resulting in a mixed clinical picture

Versican G3 Promotes Mouse Mammary Tumor Cell Growth, Migration, and Metastasis by Influencing EGF Receptor Signaling

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis

Blood transcriptomics of drug-na\uefve sporadic Parkinson's disease patients

BACKGROUND: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD. METHODS: Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set"). RESULTS: Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR. CONCLUSIONS: Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention

Processi fisiopatologici e possibili strategie terapeutiche nella neurodegenerazione. Studi clinici e di base.

2009/2010Study background: Alzheimer’s (AD) and Parkinson’s Disease (PD) represent the most frequent clinical expressions of neurodegeneration. Great genetic heterogeneity characterizes neurodegenerative diseases: there are cases with Mendelian transmission and complete penetrance, and others in which genetics predispose to greater disease susceptibility. In this scenery, the influence of environmental factors plays a fundamental role in contributing to disease development. The increasing focus on genetic etiology of diseases over the past 20 years has resulted in a significant body of knowledge for neurological pathologies, providing great insight not only into the role of genetics in sporadic PD, but also into the molecular pathways and disease mechanisms involved in the pathogenesis. AD wise, positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 responsible for early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. It is however interesting how during the course of only three years, genome-wide association studies (GWAS) in AD have yielded more reproducible, consistent and thus likely more relevant findings than three decades of candidate-gene-driven research. Recent GWAS have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. Project 1: Genome-wise association study - Genetic Park Project Friuli Venezia Giulia The first study, whose core is the whole genome analysis, involves all inhabitants of six isolated populations of Friuli Venezia-Giulia. Potentially, it offers a powerful opportunity for evaluating and understanding the relative contribution of genes and environment in the development of complex or multifactorial diseases, including AD. Research performed in isolated populations might offer unique information, thanks to favourable characteristics such as reduced genetic heterogeneity secondary to “founder effect” and endogamia, and greater environmental uniformity, as compared with large continental populations. This study can be subdivided into three phases: 1) data collection of possible risk factors, family recurrence and personal history of cognitive impairment; 2) brief neurological and neuropsychological screening, aiming at identification of possible AD cases (NINDS-ADRDA criteria); 3) blood collection and genome analysis in the group of subjects with clinical suspicion of AD with/without cerebrovascular disease. Epidemiological data analysis evidenced greater dementia prevalence in isolated populations if compared to prevalence in Italian population (9% versus 5%, in people >65 years). After whole genome analysis and comparisons of genetic data of healthy and affected subjects, possible correlations between dementia and some specific risk factors (low education, atrial fibrillation and diabetes) have been found. Finally, Genome Wise Association Study found a really interesting gene differently expressed in demented patients: PTPRD gene on chromosome 9, that is already know to play an important role in Long Term Potentiation mechanisms in mice. To our knowledge, this is the first report of possible PTPRD involvement in humans with cognitive decline, and the first from GWAS to be somehow not related to A! hypothesis. Project 2: Gene expression profiling in de novo Parkinson’s Disease patients This study intends to analyze gene expression profiling in patients with a clinical diagnosis of PD, confirmed by DaTSCAN, naïve from any specific therapy, in order to find out potential biomarkers for PD, easily detectable in peripheral blood through noninvasive methods, and possibly allowing a pre-clinical diagnosis. We performed a transcriptome-wide scan in 40 idiopatic PD patients, looking for molecular processes alteration in their blood cells, and comparing the results with those of 20 healthy controls, matched for age, sex and environmental factors. After clinical diagnosis and instrumental confirmation of PD, the experimental design includes RNA isolation from venous whole blood, microarray analysis, data processing, Real-Time PCR, functional classification process. According to preliminary results of gene expression profiling in PD patients, some specific pathways seem to be related to PD pathological processes, in particular: hypoxia, axonal guidance, calcium signaling, inflammation, diabetes, glycosphingolipid metabolism, neurotransmitters pathways, neurodegenerative diseases. Further studies and replication of these findings are obviously mandatory for their validation, but we think this could be a starting point for understanding physiopathological mechanisms and developing new therapeutical strategies in PD. "Background: La malattia di Alzheimer (AD) e la malattia di Parkinson (PD) rappresentano le piu’ frequenti espressioni cliniche di neurodegenerazione. Le patologie neurodegenerative si caratterizzano per un’importante eterogeneita’ genetica: esistono casi a trasmissione mendeliana e penetranza completa, ed altri in cui la componente genetica predispone ad una maggiore suscettibilita’ alla malattia. In questo scenario, l’influenza dei fattori ambientali gioca un ruolo fondamentale, contribuendo allo sviluppo della malattia. Il crescente interesse sulla componente genetica delle malattie negli ultimi 20 anni ha comportato ad un aumento delle conoscenze circa le patologie neurologiche, aprendo nuove prospettive nell’ambito dei meccanismi patogenetici molecolari (es.PD idiopatico). Per quanto concerne l’AD, i metodi di “positional cloning” hanno portato all’identificazione di rare mutazioni nei geni APP, PSEN1, and PSEN2, responsabili di forme familiari ad esordio giovanile di AD. e successivamente alla scoperta dell’APOE quale principale fattore di rischio per AD ad esordio tardivo. E’ tuttavia molto interessante notare come durante il corso di soli tre anni, gli studi di genome-wide association (GWAS) nell’AD abbiamo portato a risultati coerenti e probabilmente più rilevanti rispetto a 10 anni di ricerca fondata sui geni candidati. Recenti studi GWAS hanno portato alla scoperta di loci aggiuntivi di suscettibilità’ all’AD, molto frequenti nella popolazione generale, ma on solo un modesto effetto sul rischio di malattia. Di conseguenza, un’ampia proporzione di AD “ereditario” continua a rimanere inspiegato dai geni a ora noti. Progetto 1: Genome-wise association study – Progetto Parco Genetico Friuli Venezia Giulia Il primo studio, il cui nucleo è l’analisi dell’intero genoma, coinvolge gli abitanti di sei popolazioni isolate del Friuli Venezia - Giulia. Potenzialmente, fornisce una consistente opportunità’ di valutare e comprendere il contributo di geni ed ambiente nello sviluppo delle patologie complesse o multifattoriali, AD incluso; la ricerca svolta nell’ambito delle popolazioni isolate può infatti offrire informazioni uniche, grazie alla ridotta eterogeneità genetica secondaria all’”effetto fondatore” e all’endogamia, e ad una maggiore uniformità ambientale, rispetto alle vaste popolazioni continentali. Questo studio può essere suddiviso in tre fasi: 1) raccolta di informazioni circa possibili fattori di rischio, familiarità e storia personale di disturbo cognitivo; 2) breve screening neurologico e neuropsicologico, con l’obiettivo di identificare possibili casi di AD (criteri NINDS-ADRDA); 3) prelievo ematico e analisi genomica nel gruppo di soggetti con sospetto clinico di AD con/senza malattia cerebrovascolare. L’analisi dei dati epidemiologici ha evidenziato una maggiore prevalenza di demenza negli isolati, rispetto alla prevalenza nella popolazione italiana (9% versus 5%, in soggetti >65 anni); dall’analisi dell’intero genoma e dal confronto fra soggetti sani ed ammalati, e’ stata trovata un possibile correlazione fra demenza ed alcuni fattori di rischio (bassa scolarità, fibrillazione atriale, diabete). Infine, GWAS ha evidenziato un gene particolarmente interessante, differentemente espresso nei soggetti con demenza: il gene PTPRD sul cromosoma 9, già noto per avere un ruolo importante nei meccanismi di Long Term Potentiation nei topi. Ci risulta che questo sia il primo riscontro di un possibile coinvolgimento del gene PTPRD in soggetti con deterioramento cognitivo, ed il primo proveniente da GWAS in qualche modo no correlato all’ipotesi dell’amiloide. Progetto 2: Profilo di espressione genica in pazienti con malattia di Parkinson de novo Questo studio intende analizzare il profilo di espressione genica in pazienti con diagnosi clinica di PD, confermata dal DaTSCAN, naïve da terapia specifica; lo scopo di e’ l’individuazione di potenziali biomarkers per PD, facilmente identificabili nel sangue periferico attraverso metodiche non invasive, e possibilmente utili per la diagnosi preclinica. E’ stata quindi eseguita un’analisi genomica in 40 soggetti affetti da PD idiopatico, con lo scopo di trovare alterazioni molecolari nelle cellule del sangue periferico, e paragonare i risultati ottenuti con quelli di 20 soggetti di controllo sani, paragonabili per sesso, età e fattori ambientali. Dopo la diagnosi clinica e la conferma strumentale di PD, il disegno sperimentale include l’estrazione del RNA da un prelievo di sangue venoso periferico, analisi mediante microarrays, elaborazione dei dati, Real-Time PCR, e procedimento di classificazione funzionale. Secondo i risultati preliminari dei profili di espressione genica, alcune specifiche pathways sembrano essere correlate al processo patologico nel PD, in particolare ipossia, orientamento assonale, segnale Ca-mediato, infiammazione, diabete, metabolismo glicosfingolipidico, pathways neurotrasmettitoriali e patologie neurodegenerative. Ulteriori studi e la replicazione dei risultati sono ovviamente indispensabili per la loro validazione, ma riteniamo che questo sia un buon punto di partenza per comprendere i meccanismi fisiopatologici e sviluppare nuove strategie terapeutiche nel PD. "XXIII Cicl

Cholinesterase inhibition as a possible therapy for delirium in vascular dementia: a controlled, open 24-month study of 246 patients.

The goal of this study was to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effect on delirium in vascular dementia (VaD). The results from this follow-up study suggest that although delirium is frequent in elderly, cognitively impaired patients, it might not be a simple consequence of acute disease and hospitalization. Rather, delirium can be secondary to brain damage and to metabolic disturbances. According to the Lewy body dementia model, delirium could be induced by a lack of acetylcholine in the brain. Rivastigmine may help reduce the frequency of delirium episodes and help shorten their duration. Additional studies are required to better define the causes of delirium, which currently has no definitive treatment

FRONTAL LOBE DEMENTIA AND SUBCORTICAL VASCULAR DEMENTIA: A NEUROPSYCHOLOGICAL COMPARISON

We compared the performance of 40 patients with frontal lobe dementia to that of 40 patients with subcortical vascular dementia (80 patients including, 46 men and 34 women) in a set of tasks assessing attentional, executive, and behavioural tasks. The frontal lobe dementia represents an important cause for degenerative disruption and is increasingly recognised as an important form (up to 25%) of degenerative dementia among individuals of late-middle-age. The main involvement is the frontal-subcortical pathway, which is the final target of impairment even in subcortical vascular dementia. A wider involvement of the cortical (decisional) layers in frontal dementia, in contrast with the prominent and widespread involvement of the subcortical pathways (refinement and corrections programs) creates the different profiles of the two groups. Frontal patients have more difficulties in abstract reasoning, focusing attention, and implementing strategies to solve problems. They exhibit more profound behavioural alterations in personality and social conduct and show only moderate depression, and a total lack of insight concerning their clinical condition. In contrast, the patients with subcortical vascular dementia have poor general cognitive functions, high insight, and important depression and apathy as the principal and most salient characteristic of their behavioral conduct

Vitamin B12 and folate depletion in cognition: a review

In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly) pathological features will be necessary to better understand this fascinating biochemical riddle

Using the ATN system as a guide for the neuropsychological assessment of Alzheimer’s disease

Many studies have attempted to determine whether Alzheimer’s disease (AD) in-vivo biomarkers can predict neuropsychological performance since pathophysiological changes precede cognitive changes by several years. Nonetheless, neuropsychological measures can also detect cognitive deterioration in cognitively normal individuals with AD-positive biomarkers. Recent studies have investigated whether cognitive measures can be used as a proxy for biomarkers. This is a crucial issue since biomarker analysis is expensive, invasive, and not yet widespread in clinical practice. However, these studies have so far considered only one or two classes of AD biomarkers. Here, we aim at preliminarily evaluating whether and which neuropsychological measures can discriminate individuals that have been classified according to the full scheme of biomarkers known as ATN system. This scheme groups biomarkers as a function of the three main AD-related pathologic processes they measure (i.e., β-amyloidosis, tauopathy, and neurodegeneration) to provide an unbiased and descriptive definition of the Alzheimer’s continuum

Connected speech deficit as an early hallmark of CSF-defined Alzheimer\u2019s disease and correlation with cerebral hypoperfusion pattern

Background: Diagnosis of prodromal Alzheimer's disease (AD) still represents a hot topic and there is a growing interest for the detection of early and non-invasive biomarkers. Although progressive episodic memory impairment is the typical predominant feature of AD, communicative difficulties can be already present at the early stages of the disease. Objective: This study investigated the narrative discourse production deficit as a hallmark of CSFdefined prodromal AD and its correlation with cerebral hypoperfusion pattern. Method: Narrative assessment with a multilevel procedure for discourse analysis was conducted on 28 subjects with Mild Cognitive impairment (15 MCI due to AD; 13 MCI non-AD) and 28 healthy controls. The diagnostic workup included CSF AD biomarkers. Cerebral hypoperfusion pattern was identified by SPECT image processing. Results: The results showed that the discourse analysis of global coherence and lexical informativeness indexes allowed to identify MCI due to AD from MCI non-AD and healthy subjects. These findings allow to hypothesize that the loss of narrative efficacy could be a possible early clinical hallmark of the Alzheimer\u2019s disease. Furthermore, a significant correlation of global coherence and lexical informativeness reduction with the SPECT hypoperfusion was found in the dorsal aspect of the anterior part of the left inferior frontal gyrus, supporting the hypothesis that this area has a significant role in communicative efficacy, and in particular, in semantic selection executive control. Conclusion: This study therefore contributes to the understanding of neural networks for language processing and their involvement in prodromal Alzheimer's disease. It also suggests an easy and sensitive tool for clinical practice that can help identifying individuals with prodromal Alzheimer\u2019s disease