A comparison of 4 different machine learning algorithms to predict lactoferrin content in bovine milk from mid-infrared spectra.

Lactoferrin (LF) is a glycoprotein naturally present in milk. Its content varies throughout lactation, but also with mastitis; therefore it is a potential additional indicator of udder health beyond somatic cell count. Condequently, there is an interest in quantifying this biomolecule routinely. First prediction equations proposed in the literature to predict the content in milk using milk mid-infrared spectrometry were built using partial least square regression (PLSR) due to the limited size of the data set. Thanks to a large data set, the current study aimed to test 4 different machine learning algorithms using a large data set comprising 6,619 records collected across different herds, breeds, and countries. The first algorithm was a PLSR, as used in past investigations. The second and third algorithms used partial least square (PLS) factors combined with a linear and polynomial support vector regression (PLS + SVR). The fourth algorithm also used PLS factors, but included in an artificial neural network with 1 hidden layer (PLS + ANN). The training and validation sets comprised 5,541 and 836 records, respectively. Even if the calibration prediction performances were the best for PLS + polynomial SVR, their validation prediction performances were the worst. The 3 other algorithms had similar validation performances. Indeed, the validation root mean squared error (RMSE) ranged between 162.17 and 166.75 mg/L of milk. However, the lower standard deviation of cross-validation RMSE and the better normality of the residual distribution observed for PLS + ANN suggest that this modeling was more suitable to predict the LF content in milk from milk mid-infrared spectra (R2v = 0.60 and validation RMSE = 162.17 mg/L of milk). This PLS +ANN model was then applied to almost 6 million spectral records. The predicted LF showed the expected relationships with milk yield, somatic cell score, somatic cell count, and stage of lactation. The model tended to underestimate high LF values (higher than 600 mg/L of milk). However, if the prediction threshold was set to 500 mg/L, 82% of samples from the validation having a content of LF higher than 600 mg/L were detected. Future research should aim to increase the number of those extremely high LF records in the calibration set.

Genetics of Alzheimer's Disease and Frontotemporal Dementia.

The genetics of neurodegenerative diseases has an important role to clarify the pathogenetic mechanism, the diagnosis and finally the therapeutic and ethical implications. Moreover, the genetic approach to the study of the main clinical forms of dementia (Alzheimer's disease-AD and Frontotemporal Dementia-FTD) suggests clinical guidelines for helping families to navigate through these complexities. AD and FTD are multifactorial, genetically complex diseases involving many candidate genes. Mutations in three genes (i.e. Amyloid Precursor Protein, APP; presenilin 1, PSEN1; presenilin 2, PSEN2) have been linked to 50% of all familial forms of AD (FAD). Genome wide association studies (GWAS) have involved an increasing number of genes with a possible role in the disease pathogenesis. Up to now, the genetics of familial forms of FTD is related to 7 genes: the microtubule-associated protein tau (MAPT) progranulin (GRN), the valosin-containing protein (VCP), chromatin-modifying 2B (CHMP2B), the TARDNA binding protein 43 encoding gene (TARBDP), fused in sarcoma (FUS) and the last hexanucleotide expansion repeats in the open reading frame of chromosome 9 (C9orf72). Pre-test counseling and the identification of genetic defects are important in both patients and asymptomatic at risk family members.

Large deletion mutation of SPAST in a multi-generation family from Sardinia.

BACKGROUND AND PURPOSE: The hereditary spastic paraplegias (HSP) are characterized by progressive spasticity of the lower limbs, mostly inherited as an autosomal dominant trait. Analyses of large HSP pedigrees could help to better characterize the phenotype due to a single causative mutation. Patients in a seven-generation kindred carrying a large deletion in SPAST/SPG4 are described. METHODS: Individuals originating from Sardinia were clinically and genetically studied. RESULTS: Sixty-seven subjects carried a heterozygous deletion encompassing exons 2-17 of SPAST. Fifty patients (53.2 ± 15.4 years) presented a pure form of spastic paraparesis characterized by mild impairment and slow progression. Most patients showed spasticity, increased tendon reflexes in the lower limbs and Babinski sign, whilst weakness was rarely detected and urinary disturbances occasionally reported. Amongst the 17 asymptomatic carriers of the mutation, minimal neurological signs were detected in 11 cases. CONCLUSIONS: A focus on spasticity, increased tendon reflexes and Babinski sign, more than on weakness, could help clinicians to promote early diagnosis in asymptomatic carriers of SPAST deletions.

Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder. The majority of cases are sporadic ALS (SALS), with 5-10% being familial ALS (FALS), and are inherited mostly as autosomal dominant. Mutations in Cu/Zn superoxide dismutase (SOD1) and the TAR DNA-binding protein (TARDBP) gene are the most commonly known cause of ALS. We analyzed these genes in 61 Italian ALS patients using high-resolution melting analysis to confirm the role of SOD1 and TARDBP in the physiopathology of ALS. The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients. This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis. The different genotype-phenotype correlations suggest the implication of other factors possibly influencing clinical manifestation of the disease, such as an epigenetic or epistatic effect with other genes not yet identified.

Serum lipoproteins and cancer.

BACKGROUND AND AIMS: In haematological and solid tumours the blood lipoprotein profile has been reported to be altered; while decreased levels of total cholesterol and increased values of triglycerides have been observed. The mechanism and meaning of these changes are, however, not fully understood. The aim of the present study was to determine relationships between cancer progression and serum lipoproteins. METHODS AND RESULTS: We performed a case-control study. We included cancer patients admitted to the 1st Division of Medical Oncology, Businco Hospital of Cagliari, Italy, between 1984 and 1998; 519 patients with any type of solid tumours and 928 healthy controls. We considered total cholesterol (C), high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, triglycerides and apolipoprotein A-1; other parameters examined were glycaemia, insulinaemia, body mass index (BMI), homeostasis model assessment-estimated insulin resistance (HOMA-IR), C reactive protein (CRP) and tumour necrosis factor-alpha (TNF-alpha). In the cancer group HDL-C and apolipoprotein A-1 were lower (p<0.05) and triglycerides were higher (p<0.05) than in controls; HDL-C (mg/dl) females: 48 vs. 64; males, 40 vs. 52; Apo-A-1 (mg/dl) females: 125 vs. 173; males, 120 vs. 152; triglycerides (mg/dl) females: 133 vs. 96; males, 152 vs. 117. Glucose (mg/dl) was lower in the cancer group (p<0.05); females, 72.3 vs. 80.0; males, 75.7 vs. 78.4. CONCLUSION: Using multivariate analysis we were able to rule out cardiovascular and inflammatory diseases as causes of low HDL-C, and also demonstrate that these alterations can be shown as a specific consequence of the presence of a malignant tumour with a diagnostic and prognostic significance.

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease.

OBJECTIVES: Declines in brain glucose metabolism have been described early in Alzheimer's disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon 4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods. METHODS: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected). RESULTS: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers. CONCLUSIONS: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients.

Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy.

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.

Genetic risk factors in familial Alzheimer's disease.

In the last 10 years significant progress has been made to describe and identify the underlying biological mechanisms that cause the different manifestation of Alzheimer's disease. Since the first report of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD), considerable progress has been made. Results from linkage analysis and gene sequencing has provided evidence that a minority of early onset FAD families develops the disease as a result of mutations in the gene coding for the Abeta-amyloid precursor protein, and that mutations in presenilin 1 and 2 genes account for a larger subgroup of early onset families. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other genetic risk factors may exist. Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, on chromosome 19, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families.

Association between 5-HT(2A) receptor polymorphism and psychotic symptoms in Alzheimer's disease.

BACKGROUND: The aim of this study is to analyze the segregation of the 102T/C polymorphism in the serotonin 2A receptor gene in patients affected by sporadic and familial Alzheimer's disease (FAD) with and without psychotic symptoms. METHODS: The polymorphism was analyzed in 275 subjects. A semistructured interview was used to obtain information about delusions, hallucinations, and other specific behavioral signs occurring during the disease. RESULTS: Fifty-two percent of AD patients with psychotic symptoms were homozygous for the C102 allele, as compared with 6.9% of AD patients without psychosis. Similarly, the C102/C102 genotype was significantly more frequent in FAD patients with psychosis than in FAD patients without (46.5% vs. 7.8%). CONCLUSIONS: Our data strongly confirm and extend to FAD previous studies suggesting that the genetic variation at this locus is associated with prominent psychotic features in AD and that the 102C allele could play an important role in late-onset AD.

Alpha2-macroglobulin polymorphisms in Italian sporadic and familial Alzheimer's disease.

A 5-bp deletion and a Val1000 polymorphism at the alpha(2)-macroglobulin (A2M) gene have recently been reported to be associated with late onset Alzheimer's disease (AD). As recently it has been suggested that the effect of the A2M gene on AD susceptibility may be limited to certain populations or families, we analyzed the segregation of A2M and apolipoprotein E polymorphisms in Italian sporadic and familial AD. We analyzed the two polymorphisms in a total of 346 subjects including 98 controls by polymerase chain reaction-restriction fragment length polymorphism method. Our data do not confirm these associations, in particular we found a significant decrease of the deletion allele in AD with respect to controls. Our data do not support a role for the A2M gene as genetic risk factor for AD.

Lack of SOD1 gene mutations and activity alterations in two Italian families with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder, which results from the degeneration of motor neurons in the brain and spinal cord. Approximately 20% of the inherited autosomal dominant cases are due to mutations within the gene coding for Cu/Zn superoxide dismutase 1 (SOD1), a cytosolic homodimeric enzyme that catalyzes the dismutation of toxic superoxide anion. We investigated the presence of SOD1 gene mutations and activity alterations in two unrelated families of ALS patients from Elba, an island of central Italy. No mutation in SOD1 exon 1 to 5 and no activity alteration were observed in all members of the two analyzed ALS families (FALS). These data show an apparent heterogeneous distribution of ALS patients with SOD1 gene mutations among different populations and suggest that another genetic locus could be involved in the disease.

5-HT2A receptor gene polymorphisms in anorexia nervosa and bulimia nervosa.

To examine the distribution of different polymorphisms in genes of the 5-HT system in patients with anorexia nervosa (AN) and bulimia nervosa (BN), we analyzed the distribution of a polymorphism (-1438G/A) and the presence of known mutations in 5-HT2A and 5-HT2C receptor genes in 168 Italian female patients affected by AN and BN. Patients with AN restricting type (ANr) only, unlike those with AN binge eating/purging type (ANp) and BN purging type (BNp), showed a statistically significant difference in 5-HT2A-1438A/A genotype frequency with respect to controls. With regard to the other polymorphisms, no differences were found in the studied groups with respect to controls. 5-HT2A promoter polymorphism is probably implicated in the susceptibility to eating disorders and its involvement is more significant in ANr, when compared with ANp and BNp.

Implication of alpha1-antichymotrypsin polymorphism in familial Alzheimer's disease.

A common polymorphism in the alpha1-antichymotrypsin (ACT) gene has been shown to modify the Apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. Using the polymerase chain reaction, we analyzed the segregation of the ACT and ApoE polymorphisms in familial Alzheimer's disease (FAD) patients carrying mutations in Presenilin (PS) and APP genes and in both early onset (EO) and late onset (LO) FAD patients without known mutations. Our data suggest that ACT does not represent an additional risk factor for PS and APP mutated families. However, in LOFAD patients a high frequency of the combined ACT/AA and ApoE epsilon4/epsilon4 genotypes suggest that ACT may interact with ApoE and play a role in LOFAD.

No implication of apolipoprotein E polymorphism in Italian schizophrenic patients.

Numerous studies have provided evidence for a genetic association of the Apolipoprotein E (ApoE) epsilon4 allele and late onset familial and sporadic Alzheimer's disease (AD). Clinical observations show that a proportion of schizophrenic patients may suffer from severe cognitive impairment. That could reflect a particular clinical aspect of this mental disorder or a common, yet unknown, neurodegenerative mechanism. We analysed the ApoE gene polymorphism in a sample of 69 Italian patients with schizophrenia, 140 AD patients and 121 controls. In schizophrenic patients, the distribution of ApoE genotypes does not significantly differ from that of controls. No effect of the ApoE genotype on age of onset was found. The frequency of ApoE alleles in Italian schizophrenic patients is comparable with control values, suggesting that ApoE polymorphism does not represent a risk factor for schizophrenia.

Analysis of apolipoprotein E, alpha1-antichymotrypsin and presenilin-1 genes polymorphisms in dementia caused by normal pressure hydrocephalus in man.

Normal pressure hydrocephalus (NPH) is characterized by dementia, gait disorders and urinary incontinence. Apolipoprotein E (ApoE) epsilon4 allele has been associated with severity of dementia in Alzheimer's disease (AD) and in other forms of dementia. Moreover, homozygosity of the A allele of the alpha1-antichymotrypsin (ACT) gene and of allele 1 of the presenilin-1 (PS-1) gene was associated with an increased risk for late onset AD. We analyzed the distribution of ApoE, ACT and PS-1 genotypes and the corresponding allele frequencies in 13 NPH patients. No differences were found in ACT and PS-1 polymorphism distributions in the patients studied with respect to the control group. An increased ApoE epsilon4 allele frequency was observed in NPH patients with respect to controls, thus suggesting that epsilon4 allele may also be involved in the pathogenesis of the disease.

Presenilin-1 gene intronic polymorphism in sporadic and familial Alzheimer's disease.

A recent observation has shown a genetic association between an intronic polymorphism in the Presenilin-1 (PS-1) gene and late onset Alzheimer's disease (AD). The homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late onset AD. However, contrasting results have been published. We analyzed the distribution of the PS-1 intronic polymorphism in patients with sporadic AD and in seven familial AD (FAD) families carrying pathogenetic mutations in the amyloid precursor protein (APP) and Presenilin (PS-1 and PS-2) genes. Significant differences in PS-1 allele frequencies were observed in the Presenilin genes mutated families but not in late onset AD patients and in APP mutated families.

Apolipoprotein E and alpha1-antichymotrypsin polymorphism in Alzheimer's disease.

A recent observation has shown that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene modifies the apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes. The frequency of ApoE epsilon4/epsilon4 homozygosity in the AD sample resulted highest for the ACT/ TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE epsilon4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.