Different types of abstract concepts: evidence from two neurodegenerative patients.

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

Electroencephalographic upper/low alpha frequency power ratio relates to cortex thinning in mild cognitive impairment.

OBJECTIVE: Temporoparietal cortex thinning is associated with mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase in EEG upper/low α frequency power ratio has been associated with AD converter MCI subjects. We investigated the association of the EEG upper/low α frequency power ratio with patterns of cortical thickness in MCI. METHODS: 74 adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalography (EEG) recording and high-resolution 3-dimensional magnetic resonance imaging (MRI). The EEG upper/low α frequency power ratio as well as cortical thickness were computed for each subject. Three MCI groups were detected according to increasing tertile values of EEG upper/low α frequency power ratios, and the difference of cortical thickness among the groups was estimated. RESULTS: The EEG high upper/low α frequency power ratio group had a total cortical grey matter volume reduction of 471 mm(2), greater than that of the EEG low upper/low α frequency power ratio group (p < 0.001). The EEG high upper/low α frequency power ratio group showed a similar but less marked pattern (160 mm(2)) of cortical thinning when compared to the EEG middle upper/low α frequency power ratio group (p < 0.001). Moreover, the EEG high upper/low α frequency power ratio group had wider cortical thinning than other groups, mapped to the supramarginal gyrus and precuneus bilaterally. No significant regional cortical thickness differences were found between middle and low EEG upper/low α frequency power ratio groups. CONCLUSION: A high EEG upper/low α frequency power ratio was associated with temporoparietal cortical thinning in MCI subjects. The combination of upper/low α frequency power ratio and cortical thickness measurement could be useful for identifying individuals at risk for progression to AD dementia and may be of value in the clinical context.

EEG markers are associated to gray matter changes in thalamus and basal ganglia in subjects with mild cognitive impairment.

BACKGROUND: Gray matter (GM) changes of thalamus and basal ganglia have been demonstrated to be involved in Alzheimer's disease (AD). Moreover, the increase of two EEG markers, alpha3/alpha2 and theta/gamma ratio, have been associated with, respectively, AD converter and non-AD converter subjects with mild cognitive impairment (MCI). OBJECTIVE: To study the association of prognostic EEG markers with specific GM changes of thalamus and basal ganglia in subjects with MCI to identify different MCI populations. METHODS: 74 adult subjects with mild cognitive impairment underwent EEG recording and high resolution 3D magnetic resonance imaging (MRI). The theta/gamma and alpha3/alpha2 ratio was computed for each subject. Three groups were obtained according to increasing tertile values of both alpha3/alpha2 and theta/gamma ratio. Gray matter density differences between groups were investigated using a voxel-based morphometry technique. RESULTS: Subjects with higher a3/a2 ratios when compared to subjects with lower and middle a3/a2 ratios showed minor atrophy in the ventral stream of basal ganglia (head of caudate nuclei and accumbens nuclei bilaterally) and of the pulvinar nuclei in the thalamus; subjects with higher t/g ratio showed minor atrophy in putamina nuclei bilaterally than subjects with middle ratio. CONCLUSION: The integrated analysis of EEG and morpho-structural markers could be useful in the comprehension of anatomo-physiological underpinning of the MCI entity.

The CST3 B haplotype is associated with frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene (CST3) was genetically associated with FTLD. METHODS: Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion. RESULTS: In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P = 0.002)] and of AB/BB genotypes (OR = 1.704, P = 0.008) in FTLD patients. CONCLUSIONS: The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD.

Mapping the effect of APOE epsilon4 on gray matter loss in Alzheimer's disease in vivo.

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) epsilon4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (epsilon4+, age: 72+/-10 SD years, MMSE: 20+/-3 SD) and 14 non-carriers (epsilon4-, age: 69+/-9, MMSE: 20+/-5) of the epsilon4 allele and compared them to 29 age-and-sex matched controls (age: 70+/-9, MMSE: 28+/-1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. epsilon4+ and epsilon4- patients showed similar performance on neuropsychological tests (p>.05, t-test). Diffuse cortical atrophy was detected for both epsilon4+ (p=.0001, permutation test) and epsilon4- patients (p=.0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5-15% greater loss in non-carriers). APOE effect in AD was not significant (p>.74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p=.002, ANOVA), in both early and late-onset patients (p<.05, ANOVA). We conclude that the epsilon4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.

Implications of metal exposure and liver function in Parkinsonian patients resident in the vicinities of ferroalloy plants.

Valcamonica is an Italian valley where ferro-manganese industries have been active for a century and where an increased prevalence of parkinsonism was observed. A group of 93 patients (65 from Valcamonica, 28 from the reference area of Brescia city) and 76 controls (52 from Valcamonica, 24 from Brescia) were screened for serum Cu, Zn, Fe, Mn in blood (MnB) and urine (MnU), transferrin, peroxides, alanine (ALT) and aspartate (AST) transaminases and direct bilirubin. Test results were compared among groups according to the residential area and related to the disease severity. Valcamonica patients had a serum-increase of Cu, as well as of AST/ALT ratio, and a serum-decrease of Zn and Fe compared with other subgroups of cases and controls. Cases and controls from Valcamonica had higher MnB and MnU levels compared to cases and controls from Brescia. After controlling for the duration of illness, the Unified Parkinson's Disease Rating Scale III domain correlated with serum Cu and AST/ALT ratio. Our results suggest the possibility that, in this area, a lifetime exposure to neurotoxicants and to Mn in particular, when accompanied to a subclinical liver dysfunction, may pose an increased risk for neurodegenerative disorders via metal metabolism (Cu, Zn, Fe) abnormalities.

The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND AIMS: Neuronal nitric oxide synthase (NOS)1 C276T polymorphism was shown to increase the risk for frontotemporal lobar degeneration (FTLD). In the brain, both NOS1 and NOS3 (endothelial isoform) have been detected. The distribution of NOS3 G894T (Glu298Asp) and T-786C single nucleotide polymorphisms (SNPs) was analyzed in a population of 222 patients with FTLD compared with 218 age-matched controls to determine whether they could influence the susceptibility to develop the disease. RESULTS: A statistically significant increased frequency of the NOS3 G894T SNP was observed in patients as compared with controls (40.0 vs. 31.4%, P = 0.011, OR: 1.65, CI: 1.13-2.42). Conversely, the distribution of the T-786C SNP was similar in patients and controls. No differences were observed stratifying according to gender. DISCUSSION: The NOS3 G894T polymorphism likely acts as risk factor for sporadic FTLD, but studies in larger populations are needed to confirm these preliminary findings.

DCUN1D1 is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is considered as a proteinopathy; therefore, it is conceivable that genes encoding for factors involved in protein misfolding and/or degradation could play a role in its pathogenesis. METHODS: An association study of defective in cullin neddylation 1 (DCN-1)-domain containing 1 (DCUN1D1), which is involved in protein degradation, was carried out in a population of 220 patients with FTLD as compared with 229 age-matched controls. RESULTS: A statistically significant increased frequency of the GG genotype of the DCUN1D1 rs4859146 single nucleotide polymorphism (SNP) was observed in patients compared with controls (6.9 vs. 1.7%, P = 0.011, adjusted OR: 4.39, 95% CI: 1.40-13.78). Stratifying according to the clinical syndrome, significant differences were observed between the behavioral variant of frontotemporal dementia and controls (GG frequency: 6.3 vs. 1.7%, P = 0.02, OR:4.0, 95%, CI = 1.24-12.92), as well as between patients with progressive aphasia compared with controls (15.4 vs. 1.7%, P = 0.014, OR = 11.30, 95%, CI = 1.63-78.45), but not in patients with SD versus controls (8.3 vs. 1.7%, P = 0.18, OR = 5.24, 95% C.I. = 0.45-60.63). No significant differences in allelic and genotypic frequencies of the DCUN1D1 rs4859147 SNP were found. CONCLUSIONS: The GG genotype of the DCUN1D1 rs4859147 SNP represents a risk factor for the development of FTLD, increasing the risk of about fourfold.

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study.

High plasma concentration of homocysteine is an independent risk factor for Alzheimer's disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346(7):476-483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI- and AD-, homocysteine level <11 micromol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level >or=11 micromol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD- group. Instead, no difference was found between MCI- and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.

Vascular damage and EEG markers in subjects with mild cognitive impairment.

OBJECTIVE: We evaluated the changes induced by cerebrovascular (CV) damage on brain rhythmicity recorded by electroencephalography (EEG) in a cohort of subjects with mild cognitive impairment (MCI). METHODS: We enrolled 99 MCI subjects (Mini-Mental State Examination [MMSE] mean score 26.6). All subjects underwent EEG recording and magnetic resonance imaging (MRI). EEGs were recorded at rest. Individual EEG frequencies were indexed by the theta/alpha transition frequency (TF) and by the individual alpha frequency (IAF) with power peak in the extended alpha range (5-14 Hz). Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands on the basis of the TF and IAF values. Subsequently, we divided the cohort in four sub-groups based on subcortical CV damage as scored by the age-related white matter changes scale (ARWMC). RESULTS: CV damage was associated with 'slowing' of TF proportional to its severity. In the spectral bandpower the severity of vascular damage was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with IAF and alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. CONCLUSIONS: EEG analysis may show physiological markers sensitive to CV damage. The appropriate use of this EEG index may help the differential diagnosis of different forms of cognitive decline, namely primary degenerative and secondary to CV damage. SIGNIFICANCE: The EEG neurophysiological approach, together with anatomical features from imaging, could be helpful in the understanding of the functional substrate of dementing disorders.

Hippocampal atrophy and EEG markers in subjects with mild cognitive impairment.

OBJECTIVE: The present study evaluates the potential relationship between hippocampal atrophy and EEG brain rhythmicity, as assessed by relative band power and alpha frequency indices in a cohort of subjects with mild cognitive impairment (MCI). METHODS: Eighty-eight subjects falling within the definition of MCI patients were enrolled. All subjects underwent EEG recording and magnetic resonance imaging (MRI). Volumetric morphometry estimates of the hippocampal region were computed. Individual EEG frequencies were indexed by the theta/alpha transition frequency (TF) and the individual alpha frequency (IAF). The relative power was separately computed for delta, theta, alpha1, alpha2 and alpha3 frequency bands. The MCI cohort was classified into four subgroups, based on the mean and standard deviations of the hippocampal volume of a normal elderly control sample. RESULTS: The group with moderate hippocampal atrophy showed the highest increase in the theta power on frontal regions, and of the alpha2 and alpha3 powers on frontal and temporo-parietal areas. The analysis of the individual alpha frequency markers showed that the values for the alpha markers were highest in the group with the smallest hippocampal volume, whereas in the group with moderate hippocampal atrophy, these values were lower than in the group with severe atrophy. CONCLUSIONS: The relationship between hippocampal atrophy and EEG activity changes in MCI subjects is not proportional to the hippocampal atrophy. Therefore, EEG markers could represent a new tool for differential diagnosis. SIGNIFICANCE: The hippocampal atrophy induces different brain synchronization/desynchronization patterns. EEG changes model the brain activity induced by a discrete change of the hippocampal volume. The changes in the EEG rhythmicity differ greatly from those in MCI patients with subcortical vascular damage.

Dementia, delusions and seizures: storage disease or genetic AD?

We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended.

[Metals and oxidative stress in Parkinson's disease from industrial areas with exposition to environmental toxins or metal pollution]. / Dismetabolismo dei metalli e stress ossidativo in pazienti con in Parkinson's disease di un'area industriale esposta ad inquinamento da metalli.

BACKGROUND: Parkinson's disease (PD) is characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway resulting in movement disorders. PD is a complex disease, in which and environmental factors, as exposure to toxins or metals coul be involved. OBJECTIVE: To assess if serum metals (Cu, Fe, Zn), biological variables of their metabolism, total peroxides and antioxidants were abnormal in PD, in relation to environmental exposure. METHODS: We compared levels of serum copper, iron, zinc, ceruloplasmin and transferrin, peroxides, antioxidants (TRAP) in 65 PD patients coming from an Industrial zone highly exposed to metal pollution (Valcamonica) with measures from 28 PD patients from no metal pollution areas of the province of Brescia and 52 healthy controls coming from Valcamonica and 24 from the province of Brescia. RESULTS: PD patients had higher serum concentration of zinc than controls. Only in PD patients coming from Valcamonica levels of Cu were higher than in subjects coming from the province of Brescia. Moreover, In patients with PD levels of sieric Cu significantly correlated with score of the Unified Parkinson's Disease Rating Scale (UDPRS). CONCLUSIONS: Zinc seems to be higher in PD independently from the exposition to metal pollution. Perturbation of copper metabolism in PD seems to be related to exposition to environmental toxins or metal pollution and coul be involved in the progression of the disease itself.

Neurological and neuropsychological features in Parkinsonian patients exposed to neurotoxic metals.

BACKGROUND: Environmental exposure to heavy metals and especially manganese (Mn) took place in Valcamonica, Italy, where a high prevalence of Parkinsonism was observed (age and sex standardized 407/100,000; 95% CI: 393.87-420.12), and the Standardized Morbidity Ratios was associated with environmental Mn levels. METHODS: A cross sectional study compared Parkinsonian patients residents in Valcamonica with patients from Brescia, Italy. Age- and sex-matched healthy individuals were recruited as controls. The protocol included information on clinical, occupational, residential history and life habits, neuro-psychological testing, and assessment of genetic polymorphism. RESULTS: The target group included 65 patients and 52 controls from Valcamonica, 28 patients and 14 controls from Brescia. Age at onset of the disease was lower in women from both areas. After adjusting for age and age at onset, patients from Valcamonica showed more severe motor impairment at the UPDRS scale, higher damage of cognitive and motor functions at MMSE, Token and Trial Making tests. Genetic variables showed a different allelic distribution of DRD4 gene between cases and controls, outside Valcamonica, where a less frequent familiarity for parkinsonism was reported. CONCLUSIONS: Parkinsonian patients with previous exposure to metals showed a more severe neuropsychological phenotype, without detectable contribution from genetic factors.

Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.

Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment.

BACKGROUND: The diagnosis of mild cognitive impairment (MCI) is clinically unhelpful, as many patients with MCI develop dementia but many do not. OBJECTIVE: To identify clinical instruments easily applicable in the clinical routine that might be useful to predict progression to dementia in patients with MCI assessed in the outpatient facility of a memory clinic. PARTICIPANTS AND METHODS: 52 dementia-free patients (mean (standard deviation) age 70 (6) years; 56% women) with MCI, and 65 healthy controls (age 69 (6) years; 54% women) underwent brain magnetic resonance scan with standardised visual assessment of medial temporal atrophy (MTA) and subcortical cerebrovascular lesions (SVLs). Follow-up assessment occurred 15.4 (SD 3.4) months after baseline to detect incident dementia and improvement, defined as normal neuropsychological performance on follow-up. RESULTS: Patients were classified into three groups according to the presence of memory disturbance only (MCI Mem), other neuropsychological deficits (MCI Oth) or both (MCI Mem+). MCI Mem and Mem+ showed MTA more frequently (31% and 47% v 5% and 14% of controls and MCI Oth, p<0.001). 11 patients developed dementia (annual rate 16.5%) and 7 improved on follow-up. The only independent predictor of progression was MTA (odds ratio (OR) 7.1, 95% confidence interval (CI) 1.4 to 35.0), whereas predictors of improvement were the absence of memory impairment (OR 18.5, 95% CI 2.0 to 171.3) and normal MRI scan (OR 10.0, 95% CI 1.7 to 60.2). CONCLUSION: Neuropsychological patterns identify groups of patients with MCI showing specific clinical features and risk of progression to dementia. MTA clinically rated with a visual scale is the most relevant predictor of progression and improvement.

Action and object naming in frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.

Action naming has been reported to be disproportionately impaired in comparison to object naming in patients with frontotemporal dementia (FTD). This finding has been attributed to the crucial role of frontal cortex in action naming. The investigation of object and action naming in the different subtypes of FTD, as well as in the related conditions of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), may thus contribute to the elucidation of the cerebral correlates of the action-object discrepancy as well as provide clues to the underlying cognitive mechanisms. The results indicated that, with the exception of semantic dementia, action naming was more impaired than object naming in all patient groups. The discrepancy was similar in frontal variant of FTD and Alzheimer's disease patients, whereas patients with nonfluent primary progressive aphasia, PSP, and CBD were significantly more impaired in the oral production of actions than of objects. These findings indicate that action naming impairment is not a general feature of FTD, but rather is associated with conditions that affect the frontoparietal-subcortical circuits involved in action knowledge and action representation.

Effects of estrogens on cognition and brain morphology: involvement of the cerebellum.

OBJECTIVES: Sex steroid hormones are implicated in the cognitive processes of the adult brain. Among studies reporting a positive effect of estrogen replacement therapy (ERT) on cognition, the most consistent evidence is that it enhances verbal memory and visuospatial functions. In the present study we investigated the effect of ERT on cognition and on brain morphology in healthy postmenopausal women, taking into account the distinction in current and past ERT users. METHODS: Participants were postmenopausal nondemented women recruited from the community: ERT users were 40 (23 current users, 17 past users), while never users were 43. Forty of recruited subjects gave consent to undergo 3D high resolution MRI (16 current users, 7 past users and 17 never users). Participants underwent MMSE and a battery of neuropsychological tests measuring memory, language, intelligence, attention and visuo-spatial abilities. RESULTS: The past users group outperformed the never users in four tests: Token test, WCST categories, attentional matrices and Rey's delayed list; the current users group outperformed the never users in the Rey's list test. ERT users had greater grey matter volumes mainly in the cerebellum, but an increase was observed also in the parietal and occipital cortex. CONCLUSIONS: ERT use appears to improve linguistic, attentive and planning abilities. Interestingly, the beneficial effects on cognition were detected mainly in the past users subgroup. Here we propose that the trophic effect of estrogens on cerebellum might account for the observed improvement in cognition.

Patient classification and outcome prediction in IgA nephropathy.

OBJECTIVE: IgA Nephropathy (IgAN) is a common kidney disease which may entail renal failure, known as End Stage Kidney Disease (ESKD). One of the major difficulties dealing with this disease is to predict the time of the long-term prognosis for a patient at the time of diagnosis. In fact, the progression of IgAN to ESKD depends on an intricate interrelationship between clinical and laboratory findings. Therefore, the objective of this work has been the selection of the best data mining tool to build a model able to predict (I) if a patient with a biopsy proven IgAN will reach ESKD and (II) if a patient will reach the ESKD before or after 5 years. MATERIAL AND METHODS: The largest available cohort study worldwide on IgAN has been used to design and compare several data-driven models. The complete dataset was composed of 1174 records collected from Italian, Norwegian, and Japanese IgAN patients, in the last 30 years. The data mining tools considered in this work were artificial neural networks (ANNs), neuro fuzzy systems (NFSs), support vector machines (SVMs), and decision trees (DTs). A 10-fold cross validation was used to evaluate unbiased performances for all the models. RESULTS: An extensive model comparison based on accuracy, precision, recall, and f-measure was provided. Overall, the results indicate that ANNs can provide superior performance compared to the other models. The ANN for time-to-ESKD prediction is characterized by accuracy, precision, recall, and f-measure greater than 90%. The ANN for ESKD prediction has accuracy greater than 90% as well as precision, recall, and f-measure for the class of patients not reaching ESKD, while precision, recall, and f-measure for the class of patients reaching ESKD are slightly lower. The obtained model has been implemented in a Web-based decision support system (DSS). CONCLUSIONS: The extraction of novel knowledge from clinical data and the definition of predictive models to support diagnosis, prognosis, and therapy is becoming an essential tool for researchers and clinical practitioners in medicine. The proposed comparative study of several data mining models for the outcome prediction in IgAN patients, using a large dataset of clinical records from three different countries, provides an insight into the relative prediction ability of the considered methods applied to such a disease.

Calcium responses in human fibroblasts: a diagnostic molecular profile for Alzheimer's disease.

We have previously identified alterations of K+ channel function, IP3-mediated calcium release, and Cp20 (a memory-associated GTP binding protein) in fibroblasts from AD patients vs. controls. In the present study we introduce a scoring system based on these response alterations that integrates two or more alterations (and their degree) in AD vs. control fibroblasts. This scoring system generates an index that distinguishes AD patients from controls with both high specificity and sensitivity. We also show that low doses of bradykinin elicit intracellular calcium release almost exclusively in AD cell lines in an all or none fashion that provide a clear measurement of enhanced IP3-mediated function in AD vs. controls.