Maria Laura Manca

Daytime sleepiness in mild and moderate Alzheimer's disease and its relationship with cognitive impairment

The increased tendency to fall asleep during the daytime together with increased wakefulness during the night has been demonstrated in patients with advanced Alzheimers disease (AD). The aim of this study was to assess daytime sleep propensity in a cohort of patients with mild/moderate AD and to correlate it with cognitive impairment. Twenty drug‐free AD patients meeting the NINCDS‐ADRDA criteria for probable AD were evaluated. According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n = 11) and moderate (CDR2; n = 9) dementia patients. A group of 12 healthy subjects was taken as controls. The subjects were evaluated by the multiple sleep latency test (MSLT) after their nocturnal sleep pattern had been assessed by a polysomnographic recording throughout the night before. Both groups of AD patients showed a higher level of daytime sleepiness, which was statistically significant for mean daytime sleep latency (MDSL) (controls versus CDR1 and versus CDR2, CDR1 versus CDR2) and for 10:00 and 12:00 hour naps (controls versus CDR1, controls versus CDR2). In the entire group of AD patients, MDSL was significantly related with MMSE, De Renzis Token test, verbal fluency, verbal digit span, story recall, Ravens Progressive Matrices, Weigl test and Bentons three‐dimensional test. These data indicate that an increased sleep propensity during daytime occurs also in patients with mild/moderate AD detected by objective neurophysiological techniques.

Decreased platelet cytochrome c oxidase activity is accompanied by increased blood lactate concentration during exercise in patients with Alzheimer disease

Increasing evidence indicates that mitochondrial dysfunction occurs in the central nervous system as well as in the peripheral tissues from Alzheimers disease (AD) patients. We have recently shown that mitochondrial cytochrome c oxidase (COX) activity is significantly reduced in brain and platelets from AD patients compared to controls. In the present study we investigated whether impaired COX activity could have functional consequences on energy metabolism. Blood lactate concentration was monitored at rest and during incremental exercise in 22 AD patients in whom COX activity in platelets was decreased compared to controls (35.7 +/- 11.4 vs 48.4 +/- 1.4 nmol/min/mg, P < 0.01). In both resting and exercising conditions, blood lactate was significantly higher in AD patients than in controls. Although the magnitude of exercise-related lactate accumulation was not different between the two groups, an anticipated anaerobic lactate threshold during the incremental forearm exercise was found in AD patients (50% of maximal voluntary contraction MVC compared to 60% in controls). COX activity was inversely related to lactate at a significant level for resting condition (r = -0.65) and borderline for anaerobic threshold exercise level. These results support the hypothesis of a systemic impairment of the mitochondrial function in AD and indicate that decreased COX activity could have functional consequences on metabolism.

Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.

Serotoninergic Polymorphisms (5-HTTLPR and 5-HT2A): Association Studies with Psychosis in Alzheimer Disease

Patients with Alzheimer disease (AD) often exhibit psychotic symptoms associated with cognitive impairment. A few association studies have been carried out to determine if the serotonin transporter and receptor genes are potential risk factors for AD and/or associated psychopathology. The aim of this study was to investigate the association of a serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the 5-HT2A receptor T102C polymorphism with the risk of developing dementia and/or psychotic symptoms in a group of sporadic AD patients from Italy. No significant differences in the distribution of allele and genotype frequencies of 5-HTTLPR and 5-HT2A T102C were found between patient and control groups. However, a significant association between the C102/C102 5-HT2A genotype and psychotic symptoms (p < 0.001) was observed. Our data strongly confirm results from previous studies suggesting that the C102 allele of the 5-HT2A receptor is associated with the occurrence of psychotic symptoms in AD. On the contrary, the serotonin transporter does not appear to be a major susceptibility factor in the pathophysiology of the disease.

A Ser326Cys polymorphism in the DNA repair gene hOGG1 is not associated with sporadic Alzheimer's disease

Oxidative damage accumulates in the DNA of the human brain over time, and is supposed to play a critical role in the pathogenesis of Alzheimers disease (AD). It has been suggested that the brain in AD might be subjected to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for the removal of oxidized bases. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the base excision repair (BER) pathway, and a decrease in BER activity was observed in post-mortem brain regions of AD individuals, especially in the activity of 8-oxoguanine DNA glycosylase. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. However, although a deficient BER was proposed in the etiology of AD by several authors, polymorphisms of BER genes have not been studied in AD yet. We performed a case-control study including 178 patients with sporadic AD (sAD) and 146 matched controls to evaluate the role of the Ser326Cys polymorphism as a risk factor for sAD. In the present study we failed to find any association between allele (chi2=0.03, p=0.86) or genotype (chi2=0.25, p=0.882) frequencies of hOGG1 Ser326Cys and the risk of sAD. Present results suggest that the Ser326Cys polymorphism of the hOGG1 gene is not an independent risk factor for sAD.

Daytime Sleepiness in Epilepsy Patients Receiving Topiramate Monotherapy

Summary:  Purpose: Limited research has focused to date on objective neurophysiological evaluation of daytime sleepiness in patients treated with newer antiepileptic drugs (AEDs), especially when used as monotherapy. This study was aimed at assessing occurrence of daytime sleepiness in newly diagnosed, drug‐naïve patients with partial epilepsy receiving initial topiramate (TPM) monotherapy.

Lack of association between mtDNA haplogroups and Alzheimer’s disease in Tuscany

Mitochondrial DNA (mtDNA) haplogroup-specific polymorphisms were previously related to several neurodegenerative diseases, including Alzheimer’s disease (AD). However, the precise role of mtDNA haplogroups in the neurodegenerative cascade leading to AD is still unclear. In this work we have genotyped predefined European mtDNA haplogroups in 209 patients with AD and 191 matched controls. In order to minimise the risk of “genetic contamination”, which could lead to false associations between gene markers and disease, we were careful to enrol in the study only patients and controls of clear Tuscan origin (with at least three generations of Tuscanborn relatives). The frequency of the haplogroups did not differ between the two groups, and no correlation with gender, ApoE genotype, age of onset or disease status was observed. Further studies will be required to define the contribution of mtDNA haplogroups, if any, to the pathogenesis of AD. A correct population selection, in order to minimise the risk of genetic contamination, is essential in these studies.

Epidemiology of myotonic dystrophy in Italy: re-apprisal after genetic diagnosis

Before the discovery of the myotonic dystrophy (DM) gene, the DM epidemiological rates could not be accurately estimated. The aim of this study was to calculate the DM prevalence rates in Padova (North‐East Italy) and in four provinces of North‐West Tuscany (Central Italy) and, as of 30 June 1999, to do so using molecular genetic testing. 
A minimum prevalence rate of 9.31×10−5 inhabitants was found, consistent with epidemiological rates worldwide, and more than two times as high as those of two previous studies conducted in the same areas during the era prior to molecular genetic testing. 
This study, the first in Italy since the discovery of the DM gene, underlines the importance of direct genetic diagnosis of DM, especially in detecting mildly affected patients, a fundamental step in correctly estimating the risk of disease transmission in affected families.

Effects of aerobic training on lactate and catecholaminergic exercise responses in mitochondrial myopathies

The aim of this study was to evaluate the effects of an aerobic training program on the metabolic and sympathetic responses to exercise in 12 patients with mitochondrial myopathies. A 10-week course of aerobic training, consisting of supervised exercise every other day on an electrically braked pedal-rate bicycle ergometer was prescribed to each patient and four healthy controls. Venous lactate, epinephrine (EP) and norepinephrine (NEP) levels were assessed at baseline and after the aerobic training by means of constant-workload exercise performed at near lactate threshold (LT). In patients, a decrease in exercise peak values, significant for lactate (-38.6%, P < 0.01) but not for catecholamines (EP: -26.0%, NEP: -22.1%) was observed after training, findings confirmed by the lactate/EP and lactate/NEP area ratios. The results show that lactate accumulation during exercise is decreased after aerobic training in mitochondrial myopathies and that the effect is partially dissociated from the catecholaminergic response. This in turn suggests that the lactate decrease can be explained, at least in part, by the improved muscle oxidative metabolism consequent to the proposed training program.

Impaired oxidative metabolism in exercising muscle from ALS patients

The pathogenic mechanism of selective loss of motor neurones in amyotrophic lateral sclerosis (ALS) is still poorly understood. Recently, research evidence has suggested that mitochondrial dysfunction occurs in central nervous system as well as in peripheral tissues from ALS patients. The aim of our study was to indirectly investigate in vivo oxidative metabolism of exercising muscle in a case history of patients affected by ALS. To this purpose 11 patients, 8 male and 3 female, mean age+/-SD: 52.4+/-11.1 years, performed a bicycle incremental test for the assessment of lactate production. At rest, there was increased lactate concentration in patients: 2.77+/-0.79 vs. 1.48+/-0.49 mmol/l in normal controls (normal range: 0.67-2.47 mmol/l). Analysis of lactate curve during exercise showed a lactate production increase compared to controls. Furthermore, anaerobic lactate threshold was detected at 40-50% of the predicted normal power output, anticipated with respect to both normal subjects and non-ALS chronically denervated controls with comparable motor impairment (60-70%), suggesting that mitochondrial dysfunction can occur in exercising skeletal muscle from ALS patients.