Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer's disease.

Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.

Common variants of human TERT and TERC genes and susceptibility to sporadic Alzheimers disease.

Studies investigating telomere length in association with cognitive decline, dementia, and sporadic Alzheimer's disease (AD) have frequently found shorter telomeres to be associated with the development of AD and telomerase expression with pathological processes in AD. Human telomerase is constituted by two components: the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). Genetic variation at the two loci has been investigated in relation to telomere length, longevity, and common diseases of advanced age, but not in relation to AD. We examined three polymorphisms of the TERT gene (VNTR MNS16A, rs2853691, rs33954691) and three polymorphisms of the TERC gene (rs12696304, rs3772190, rs16847897) in a sample of 220 AD patients and 146 controls. MNS16A LL genotype was found to be associated with an increased risk of AD only in males [interaction term adjusted OR=3.55 (95% CI 1.2-10.2)]. The three TERC single nucleotide polymorphisms are in strict linkage disequilibrium and their genotype combinations influenced the age at AD onset (AAO). The combined genotype GG-TT-CC was associated with a mean AAO six years lower (70.5±6.7) than that associated with the other genotype combinations (76.04±6.7, p=0.01). The fact that the MNS16 L allele has been reported to lower TERT expression, and that the TERC alleles G, T, C (rs12696304, rs3772190, rs16847897 in this order have been repeatedly found associated with shorter LTL, seems to corroborate the hypothesis of a role of telomere length and telomerase in AD susceptibility.

The Italian validation of the Anosognosia Questionnaire for Dementia in Alzheimer's disease.

Although the Anosognosia Questionnaire-Dementia (AQ-D) is one of the main instruments for assessing awareness in Alzheimer's disease (AD), the normative data were until now limited to people from Argentina and Japan. This study aims to validate this instrument in an European context, in particular in an Italian sample. In a multicenter project (Verona, Padova, and Trapani), 130 patients with AD and their caregivers participated in the study. Psychometric characteristics of AQ-D are confirmed indicating that the scale permits the early identification of anosognosia and the correct care management of patients. Indeed, anosognosia results to be present also in patients with very mild AD (moderate: 44.44%; mild: 47.17%; and very mild: 23.73%). Moreover, the results indicate that deficits in awareness may vary in severity and that different types of anosognosia may be identified.

Cognitive stimulation of executive functions in mild cognitive impairment: specific efficacy and impact in memory.

Executive functions play an important role in the maintenance of autonomy in day-to-day activities. Nevertheless, there is little research into specific cognitive training for Mild Cognitive Impairment (MCI). We present the results of a program which aims to teach specific strategies and metacognitive abilities in order for patients to be able to carry out attentional and executive tasks. Two groups (A and B) were compared in a cross-over design. After the first evaluation, Group A (but not B) participated in a six month cognitive stimulation program. After a second assessment, only Group B received treatment and then a final evaluation was carried out on both groups. The results show that: i) both groups improved their performance as an effect of training; ii) improvements generalized to memory and general cognitive tasks; iii) in the interval without training, Group B's performance worsened and iv) Group A partially maintained their results over time.

Awareness of cognitive deficits and clinical competence in mild to moderate Alzheimer's disease: their relevance in clinical practice.

Awareness of cognitive deficits and clinical competence were investigated in 79 mild to moderate Alzheimer's disease patients. Awareness was assessed by the anosognosia questionnaire for dementia, and clinical competence by specific neuropsychological tests such as trail making test-A, Babcock story recall test, semantic and phonemic verbal fluency. The findings show that 66 % of the patients were aware of memory deficits, while the 34 % were unaware. Deficit in awareness correlated with lower scores on the Mini Mental State Examination test that, in the score range from 24.51 to 30 and from 19.50 to 24.50, appeared to be a significant predictor of level of awareness. None of the AD patients had fully preserved clinical competence, only 7 patients (9 %) had partially preserved clinical competence and 72 patients (91 %) had completely lost clinical competence. All the patients with partially preserved clinical competence (9 %) were aware of their memory deficit. The study indicates that neuropsychological tests used for the assessment of executive functions are not suitable for investigating clinical competence. Therefore, additional and specific tools for the evaluation of clinical competence are necessary. Indeed, these might allow clinicians to identify AD patients who, despite their deficits in selected functions, retain their autonomy of choice as well as recognize those patients who should proceed to the nomination of a legal representative.

Neurosyphilis manifesting with rapidly progressive dementia: report of three cases.

Neurosyphilis is rather an unusual cause of dementia characterized by a rapidly progressive course and psychiatric symptoms. Diagnosis of neurosyphilis should be suspected in the presence of a global cognitive impairment consisting in disorientation, amnesia and severe impairment of speech and judgement and psychiatric symptoms such as depression, mania and psychosis, with a subacute onset. More commonly, clinical manifestations of neurosyphilis include general PARESIS (involvement of Personality, Affect, Reflexes, Eye, Sensorium, Intellect and Speech). Upon clinical suspicion, diagnosis of neurosyphilis is confirmed by a reactive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory. Here we report three Human Immunodeficiency Virus (HIV)-negative male patients presenting with psychiatric symptoms and a rapidly evolving dementia. Although magnetic resonance imaging did not address to diagnosis, CSF examination was mandatory in neurosyphilis diagnosis. Other diagnostic tools such as neuropsychology and single-photon emission computed tomography resulted supportive in the diagnosis. We showed that a prompt antibiotic treatment might stop disease progression. Therefore, neurosyphilis should be always considered even in HIV-negative patients in the presence of unexpected psychiatric symptoms accompanied by a rapidly evolving cognitive decline.

P21 gene variation and late-onset Alzheimer's disease in the Italian population.

BACKGROUND: Variation at the cyclin-dependent kinase inhibitor gene P21 in a patient sample of the Italian population was investigated in search of genetic factors potentially involved in sporadic late-onset Alzheimer's disease (AD). METHODS: Two single nucleotide polymorphisms (SNPs) were studied in this gene: a C>A transversion at codon 31 (ser>arg) in exon 2 (RS1801270) and a C>T transition occurring 20 bp downstream from the stop codon of exon 3 (RS1059234). RESULTS: The odd ratios were: RS1801270 A allele = 0.62 (95% CI = 0.33-1.18; p = 0.14); RS1059234 T allele = 0.57 (95% CI = 0.33-0.98; p = 0.04). In addition, a longer duration of disease was found with genotypes carrying the RS1059234 T allele (4.3 ± 2.5 years) than with those not carrying it (3.3 ± 2.1 years) (p = 0.001). CONCLUSION: In the present sample, one of the two SNPs seems in some way related to AD, since carriers of one allele were slightly protected against AD onset.

Cognitive stimulation in a-MCI: an experimental study.

Nowadays, preventing the effects of mental decline is an international priority, but there is little research into cognitive training in mild cognitive impairment (MCI). We present the results of a program aimed at teaching memory strategies and improving metacognitive abilities. This was associated with training to ameliorate caregivers' assistance. Two groups (A and B) were compared in a crossover design. After the first evaluation, group A (but not B) participated in a 6-month cognitive stimulation program. After a second assessment, only B received treatment and then a final evaluation was carried out on both the groups. The results show that (1) both the groups improved their performance as an effect of training; (2) improvements are specific to the functions trained; (3) in the interval without intervention, performance of group B worsened; and (4) group A has maintained their results over time. In conclusion, our results show that specific training may reduce memory impairment in MCI.

Screening of two mutations at exon 3 of the apolipoprotein E gene (sites 28 and 42) in a sample of patients with sporadic late-onset Alzheimer's disease.

The search for further variation at the APOE gene in a sample of patients with sporadic late-onset Alzheimer's disease (AD) and related controls revealed two different mutations in the exon 3 of the gene. One, the Leu28-->Pro, always found on an APOE e(*)4 allele, was present in five of the 94 patients and in 1 of the 157 controls. The other, Thr42-->Ala, found on an e(*)3 allele, was observed in only one AD patient, who also carried the Leu28-->Pro, but in none of the controls. In the AD patient group the allele e(*)4(-), corresponding to Leu28-->Pro, showed a frequency of 0.027, compared with only 0.003 in the controls. Compared to E3/3 and E3/2 genotypes, the risk of developing AD associated with the genotypes carrying the e(*)4 allele, the well-established risk allele for AD onset, was observed to be high (OR=3.16; 95% CI=1.62-6.20; P=0.0009), but the risk associated with genotypes carrying the Leu28-->Pro mutation was higher still (OR=10.95; 95% CI=1.25-95.75; P=0.015). The higher risk associated with this mutation was assessed by meta-analysis carried out using the data of three patient groups from a previously published study Kamboh et al. and from our study. The results indicated that, compared with all the other APOE genotypes, those carrying the Leu28-->Pro mutation were at a substantially higher risk of developing AD (OR=4.25; 95% CI=1.21-14.97).

The role of somatosensory feedback in dystonia: a psychophysical [correction of psycophysical] evaluation.

Ten patients with idiopathic dystonia and twelve healthy controls were tested with pairs of non-noxious electrical stimuli separated by different time intervals. Stimuli were delivered (i) to the pad of the index finger (same-point condition), (ii) to the pad and to the base of the index finger (same-finger condition) and (iii) to the pad of the index and ring fingers (different-fingers condition). Subjects were asked to report if they perceived single or double stimuli in the first condition and synchronous or asynchronous stimuli in the second and third conditions. STDTs were significantly higher in dystonic than control subjects in all three conditions. Results extend current knowledge on deficits of somesthetic temporal discrimination in dystonia by showing that temporal deficits are not influenced by spatial variables.

Plasma alpha1-antichymotrypsin in Alzheimer's disease; relationships with APOE genotypes.

Inflammatory processes are thought to be important contributors to the pathogenesis of Alzheimer's disease (AD). alpha1-antichymotrypsin (ACT) is a proteinase inhibitor characteristic of acute-phase inflammation and has been identified in amyloid plaques. We analyzed the plasma ACT levels in a sample of subjects with late-onset AD and correspondent controls. Plasma ACT was higher in AD patients (62.8 +/- 20.2 mg/dl) than in controls (58.8 +/- 18.1 mg/dl), but not significantly (P = 0.13). In the AD patients regression analysis showed a positive linear relationship between ACT levels and duration of the disease (P = 0.037). Increased ACT concentrations (64.6 +/- 21.2 mg/dl) were also found in patients with greater cognitive impairment (MMSE scores < 20), but since this factor depends on the duration of the disease as well, our present data seem to indicate a complex relationship involving elevated ACT levels, disease duration and cognitive impairment. Plasma ACT was found to differ significantly according to APOE genotypes (P = 0.017), the highest levels being associated to E3-E3 homozygotes (66.1 +/- 17.8 mg/dl) and the lowest to E4-E3 subjects (53.1 +/- 18.2 mg/dl). In patients not carrying APOE*4 allele the ACT levels were higher than in controls (P = 0.014), and the relationship between ACT and disease duration was stronger than that observed in the total AD sample (P = 0.003), but it was absent in those carrying APOE*4 (P = 0.67). Taken together our results seem to suggest that inflammation is a relevant factor in AD pathogenesis for subjects with E3-E3 and E3-E2 genotypes but less important for APOE*4 carrying subjects.

Polymorphisms of the apolipoprotein E gene regulatory region and of the LDL receptor gene in late-onset Alzheimer's disease in relation to the plasma lipidic pattern.

Two new polymorphisms in the regulatory region of the apolipoprotein E gene, -491 A/T and -427 T/C, have been reported to be associated with the risk of Alzheimer's disease (AD). Moreover, in vitro studies suggest that the two polymorphisms modulate the levels of apoE protein expression. We examined these two polymorphisms, as well as the MspI polymorphism in the LDL receptor gene, in a series of elderly patients with late-onset sporadic AD and in an age-matched control group but failed to find any kind of association between these genetic features and an increased risk of AD. In the same samples we investigated the relationships between various genotypes and plasma lipid levels. Since the well-known effect of the three-allelic APOE polymorphism on plasma lipid levels could mask the effect of other polymorphisms, the analyses were performed taking into account the APOE genotype. The two regulatory region polymorphisms had significant effects only on the apoE levels. The -427 TT homozygotes had lower, and the -491 AA homozygotes had higher levels of apoE than other genotypes. This result confirmed in vivo the already observed in vitro effects of -491 A/T and -427 T/C polymorphisms on APOE promoter transcription activity.

Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer's disease.

Besides apolipoprotein E (APOE) polymorphism, whose association with Alzheimer's disease (AD) has been confirmed in most of the numerous population samples studied, other markers have been investigated. In most cases the association firstly described was not confirmed in subsequent works. Since it is important to examine these associations in as many populations as possible, we investigated APOE, APOC1, APOC2, alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphisms in a series of elderly patients with late-onset sporadic AD from Northern Italy and in a sex and age-matched control group. We could not confirm the significantly higher frequency of the ACT*A allele among carriers of APOE e*4 allele described elsewhere, although a similar trend was observed. The APOC2 and the PS-1 distributions were similar between patients and controls. However, we observed a significant difference in the genotype and allele frequencies of APOE and APOC1: patients had higher e*4 and C1*2 allele frequencies. This finding confirms the important role for APOE in AD occurrence. In addition, APOC1 seems to be an interesting marker because, though in strict linkage disequilibrium with APOE, it seems to play an independent role in AD risk. In contrast to previously reported data, plasma apoE concentrations were similar in patients and in controls. An interaction between APOE and APOC1 polymorphisms and apoE levels was observed in patients: subjects carrying the APOE E3/E2 or the APOC1 2-2 genotype have higher apoE concentrations than those who do not.

The spatial distribution of visual attention in hemineglect and extinction patients.

We studied the visual field distribution of speed and accuracy of manual responses to small brief light flashes, in patients with left hemineglect or extinction resulting from right hemisphere vascular lesions and in brain-damaged and healthy control subjects. All patients with right hemisphere lesions showed a greater impairment in both the speed of response and the detection rate in the contralesional than in the ipsilesional hemifield. This interfield difference increased with the eccentricity of stimulus presentation and was especially pronounced in neglect patients who showed a paradoxical increase in speed of response and detection rate at increasingly larger eccentricities in the ipsilesional hemifield. We hypothesize that both the contralesional slowing down and the ipsilesional speeding up of the response depends upon an exaggerated gradient of attention towards the ipsilesional hemifield. To assess whether these abnormalities concern automatic or controlled attentional processes, in a second experiment, we manipulated the predictability of the side of the stimulus presentation by using blocked rather than randomized stimulus presentations. This resulted in a speeding up of responses in both hemifields thus showing that the patients were able to focus attention to the side of stimulus presentation voluntarily. However, there was no modification of the contra-ipsilesional differences which, therefore, are likely to be related to abnormal automatic processes rather than controlled attention.

Familial cavernous hemangioma with atypical neuroimaging.

Three members of the same family were studied, all of whom had multiple intracerebral cavernous angiomas for which a dominant autosomal inheritance was hypothesised. The proband suffered from headaches, and physical examination revealed evident right hemiparesis. The second case started with a hemorrhagic cerebral stroke and the third was asymptomatic on neurological examination. Nuclear magnetic resonance (NMR), performed in two of the three cases, showed lesions whose number and extent were not radiologically characteristic of cavernous angioma. A cerebral biopsy of the proband enabled the diagnosis to be made. Despite the recent introduction of NMR, the nosological classification of familial forms can be difficult when the radiological lesions are atypical. In such cases, cerebral biopsy is not only a valid diagnostic aid, but is also indispensable for obtaining adequate genetic information.

Implicit redundant-targets effect in visual extinction.

Patients with left visual extinction as a result of unilateral right hemisphere damage were tested on a redundant-targets effect paradigm (RTE). LED-generated brief flashes were lateralized either to the left or to the right visual hemifield or presented bilaterally. Subjects were asked to press a key as fast as possible following either unilateral or bilateral stimuli and immediately afterwards to report on the number of stimuli presented. As previously found in normal subjects, bilateral stimuli were responded to faster than unilateral ones, and this was evidence of a RTE. The main thrust of this study was that extinction patients showed a RTE not only for correctly perceived bilateral stimuli but also in trials in which they extinguished the stimulus on the field contralateral to the lesion. This result is compatible with a preserved processing of the extinguished input at least up to the stage at which it may interact with the input from the normal side to yield a speeded motor response. Interestingly, the implicit redundancy gain of extinction patients was found to fit a coactivation (i.e. neural) rather than a probabilistic model.

Reversible cerebral ischemias: a comparative analysis of risk factors in TIAs and in RINDs.

A retrospective study in which 709 patients, 522 with RIND and 187 with TIA, were compared in respect of common risk factors (RFs) for acute cerebrovascular disease. The two forms of the disease differed significantly in respect of smoking, hematocrit, hypercholesteremia, hypertriglyceridemia and hyperuricacidemia. Although these RFs do not seem to be determinants of or discriminants between the two forms of acute cerebrovascular disease, it is nonetheless highly probable that, together with all the other RFs, they have a facilitatory role.