A functional 5HT2A receptor polymorphism (His452Tyr) and memory performances in Alzheimer's disease.

The functional His452Tyr polymorphism in the 5HT2A receptor has been described to be associated with verbal memory in healthy adults, with worse episodic memory performances in Tyr452 (T) carriers. The aim of our study was to investigate a possible effect of this polymorphism on memory performances in Alzheimer disease (AD). We enrolled 169 patients affected by probable AD. 5HT2A genotype was determined as previously described. According to their genotype, patients were divided in T carriers ( n = 111) and non-carriers ( n = 69). We evaluated the possible effect of 5HT2A polymorphism on verbal memory tasks. A one-way MANOVA analysis did not show a positive interaction between the two groups ( p > 0.05) at the baseline and at the follow-up. Nevertheless, the analyses of the single-task effect showed lower performances for non-T carriers only in Rey's recognition task. Recent data reported poorer memory performances in healthy subjects carrying the T variant, in age-dependent manner (no differences between T vs. nT carriers were observed for age >50 years). In our AD sample, we did not find significant differences in verbal memory scores in T vs. nT carriers while a significant difference was found only in attentional task. At variance with that in healthy subjects, no correlation has been found between memory profiles of AD patients and His452Tyr polymorphism.

BuChE K variant is decreased in Alzheimer's disease not in fronto-temporal dementia.

Alzheimer's disease (AD) is characterized by a significant reduction in AcetylCholinesterase and an increase in ButyrylCholinesterase (BuChE) activity. The existence of polymorphic regions on the BuChE gene has been previously described; the most frequently found polymorphism is the so-called K variant, which leads to a 30% decreased enzymatic activity. Different studies reported a positive association between K variant and AD, strongest among late-onset AD and Apolipoprotein E (APOE) e4 carriers. We analyzed APOE and BuChE polymorphisms in 167 AD and 59 fronto-temporal dementia (FTD) patients compared with 129 healthy controls (HC). We reported a significantly lower frequency of the BuChE K variant in AD compared with HC and FTD and a significant increased frequency of the K variant in FTD. These results are in agreement with the known increase of the BuChE activity in AD and support the evidence of different molecular pathways involved in the pathogenesis of AD and FTD.

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation.

BACKGROUND: A recently devised test of motor cortex excitability (short latency afferent inhibition) was shown to be sensitive to the blockade of muscarinic acetylcholine receptors in healthy subjects. The authors used this test to assess cholinergic transmission in the motor cortex of patients with AD. METHODS: The authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. RESULTS: Afferent inhibition was reduced in the patients (mean responses +/- SD reduced to 85.7% +/- 15.8% of the test size) compared with controls (mean responses +/- SD reduced to 45.3% +/- 16.2% of the test size; p < 0.001, unpaired t-test). Administration of a single oral dose of rivastigmine improved afferent inhibition in a subgroup of six patients. CONCLUSIONS: The findings suggest that this method can be used as a noninvasive test of cholinergic pathways in AD. Future studies are required to evaluate whether short latency afferent inhibition measurements have any consistent clinical correlates.

Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine.

We tested DNA from 15 centrally infected cases of iatrogenic Creutzfeldt-Jakob disease (CJD) (dura mater or corneal homografts and stereotactic EEG electrodes), 11 peripherally infected cases (native human growth hormone or gonadotrophin), and 110 control individuals for the presence of mutations in the chromosome 20 amyloid gene. No patient or control had any of the known pathogenic point or insert mutations found in familial disease, but allelic homozygosity at polymorphic codon 129 was present in all but two (92%) of the 26 patients, compared with 54 (50%) of the 110 controls (p < 0.001). Pooled data from all identified and tested cases of iatrogenic disease yielded a worldwide total of 56 patients, of whom all but four were homozygous at codon 129 (p < 0.001). These findings support the thesis that homozygosity at codon 129 enhances susceptibility to iatrogenic infections of both central and peripheral origin, with evident implications for the population of dura mater homograft and pituitary hormone recipients whose lives have been complicated by the possibility of exposure to the infectious agent of CJD.

European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors.

Medical risk factors for Creutzfeldt-Jakob disease (CJD) were analyzed in a prospective ongoing case-control study based on European CJD surveillance. Detailed data on past and recent medical history were analyzed in 405 cases and controls matched by sex, age, and hospital. Data were correlated with polymorphism at codon 129 of the prion protein gene. Our analysis did not support a number of previously reported associations and failed to identify any common medical risk factor for CJD. Although not statistically significant, brain surgery was associated with an increased risk of CJD. A detailed medical history should be obtained in every suspected CJD case in order to identify iatrogenic sources of CJD.

Isonicotinic hydrazide causes seizures in scrapie-infected hamsters with shorter latency than in control animals: a possible GABAergic defect.

Isonicotinic hydrazide, a drug that decreases the level of GABA, when injected subcutaneously in control and scrapie-infected hamsters induced tonic-clonic seizures in scrapie hamsters significantly earlier (P less than 0.0001) than in control animals. This suggests depression of the GABAergic system in scrapie-infected hamsters. To determine whether this lesion is pre or postsynaptic we measured the level of GABA, glutamate, cGMP and cAMP and the GABA-benzodiazepine receptor complex.

Choline acetyltransferase activity and [3H]quinuclidinylbenzilate binding in brains of scrapie-infected hamsters.

Choline acetyltransferase (ChAT) activity and [3H]quinuclidinylbenzilate binding were studied in the brain of scrapie-infected hamsters and sham inoculated controls. Although scrapie-infected hamsters showed no reduction of ChAT activity compared to the controls, they showed a decrease in the affinity and maximum number of post-synaptic muscarinic receptors. Scrapie virus thus alters the cholinergic system at the post-synaptic rather than at the pre-synaptic level.

Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer's disease.

Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Alzheimer's disease (AD) we examined the activity of the enzyme copper-zinc superoxide dismutase (CuZnSOD) in red blood cells, the levels of the mitochondrial inducible enzyme manganese superoxide dismutase (MnSOD) mRNA in lymphocytes, and the total radical-trapping antioxidant capacity (TRAP) in plasma of AD patients and in a group of age-matched non-demented controls. We found that CuZnSOD activity (P < 0.01 vs. controls) was significantly increased as well as the MnSOD mRNA levels while the total antioxidant status (P < 0.001 vs. controls) was decreased in AD patients. These findings support the role of oxidative alterations in the pathogenetic mechanism underlying AD neurodegeneration.

The Apolipoprotein E genotype in patients affected by syndromes with focal cortical atrophy.

The role of the Apolipoprotein E (APOE) alleles in syndromes associated with focal cerebral atrophy (fronto-temporal dementia, primary progressive aphasia, corticobasal degeneration) is still controversial. We studied the APOE allele distribution in 39 patients with clinically diagnosed syndromes associated with focal cerebral atrophy (FCA), in 50 patients with early-onset probable Alzheimer's disease (EOAD), and in 60 patients with late-onset probable AD (LOAD). The APOE genotype was determined from a blood sample, using polymerase chain reaction and restriction enzyme digestion. The APOE epsilon4 allele frequency was significantly higher in the EOAD (21.0%) and LOAD (33.3%) groups, but not in the FCA group (5.1%), as compared with controls. In our population, the epsilon2 allele frequency was significantly higher in patients with FCA (12.8%) than in controls (4.8%). These results show that the APOE epsilon4 allele is not a risk factor for syndromes associated with FCA. The potential role of the epsilon2 allele in these syndromes needs further investigation.

Cognitive impairment and chronic alcohol abuse: a neuropsychological study.

Twenty-eight chronic alcoholic subjects were submitted to our Mental Deterioration Battery. The scores obtained by this group, corrected for age and educational level, were compared with those achieved by a control group. Our data do not confirm a selective impairment of the functions related to the right hemisphere; they show a diffuse cerebral damage and suggest, perhaps, a major impairment of the verbal functions subserved by the left hemisphere. Therefore, according to our data the question of selective hemispheric impairment as opposed to more diffuse cerebral damage in chronic alcoholism still remains open.

The relationship between type of naming error and semantic-lexical discrimination in aphasic patients.

When submitted to confrontation naming tasks, aphasic patients show different types of naming errors: phonetic, phonemic and verbal-semantic paraphasias, neologisms and anomia, but it is generally difficult to decide whether these errors are mainly due to a breakdown of the semantic systems or to post-lexical phonological disorders. In order to clarify this issue, 118 aphasic patients were given 3 tests of confrontation naming and 3 tests of semantic-lexical discrimination. Naming errors on confrontation were used to classify aphasic patients in various subgroups (according to the prevalence of a given type of naming error), whereas performances obtained on tests of semantic-lexical discrimination were taken as an index of disorganization of the semantic systems. The performances on semantic discrimination tests of patients showing a prevalence of phonetic, phonemic and verbal-semantic paraphasias, neologisms and anomia on confrontation naming tasks were compared. A very small number of semantic discrimination errors was obtained by patients showing a prevalence of phonetic and phonemic transformations on confrontation, whereas a much larger number of semantic discrimination errors was obtained by patients showing a prevalence of verbal-semantic paraphasias, neologisms and anomia.

Molecular forms of cholinesterases in CSF of Alzheimer's disease/senile dementia of Alzheimer type patients and matched neurological controls.

Acetylcholinesterase, pseudocholinesterase and their molecular forms were measured in the CSF of patients affected by Alzheimer's disease and of matched neurological controls. Three different molecular forms of ChE were found in the CSF of both groups of patients, but only two of them belonged to 'true' AChE. No differences were found between Alzheimer's disease patients and neurological controls in all the examined parameters.

Resistance of the hippocampus in Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) belongs to the group of subacute spongiform encephalopathies of animals and man. Their pathogenesis is certainly related to the formation and deposition in the brain of an amyloid-type specific protein, named PrPres (prion protein-resistant). The neuropathological topography of CJD does generally admit that archicortex is relatively spared, but only a few papers have been devoted to this issue. A neuropathological study of CJD cases divided in sporadic, familial, and iatrogenic forms of the disease has been carried out, taking into consideration the archipallial lesions in relation to different clinical and neuropathological parameters. The pyramidal cell layer of CA1 of all CJD cases did not show any major loss of neurons in comparison to that observed in other cortical fields of the limbic cortex (mainly in the presubicular and entorhinal cortex) and of the neocortex. Spongiogliotic reaction was observed only in the stratum radiatum and molecularis lacunosum in a iatrogenic case of the disease. The findings observed in the pyramidal cell layer of CA1 were neither related to the clinical duration of the disease nor to the severity of the lesions found in other limbic and neocortical areas. The results of this study support the view of no close relationships between the demential syndrome typically related to the clinical onset and progression of CJD, and the structural damage of the hippocampus classically involved in the pathogenetic mechanism of the amnestic syndrome related to the clinical presentation and course of more common forms of dementias, such as Alzheimer's disease.

Does PRNP gene control the clinical and pathological phenotype of human spongiform transmissible encephalopathies?

BACKGROUND: Human spongiform transmissible encephalopathies (TSE) are a group of neurodegenerative diseases caused by a transmissible not yet recognized agent; their distinctive neuropathological features are astrocytosis, spongiform lesions of the neuropil, neuronal loss and occasionally amyloid plaques in the cortical and subcortical gray matter. TSE are biochemically characterized by the deposition in the nervous system of an amyloid-type protein, PrPres derived from the post-translational modification of a normal protein, PrPsen. The expression of this protein is controlled by the PRNP gene mapped on chromosome 20 in man. A number of point mutations of the PRNP gene have been described in the familial forms of these TSE. Some of these mutations have been associated with differences in the phenotypic expression of the disease. MATERIAL AND METHODS: This study was designed to verify whether it was possible to identify a selective phenotype depending upon a given PRNP modified genotye; for this purpose, a group of familial TSE cases (CJD 210ILE, CJD 201LYS, FFI 178ASN) were selected and their neuropathological profiles have been compared with those of a large series of sporadic CJD cases. RESULTS: No significant differences were found between the topography and severity of lesions in the cerebral cortex, cerebellum, hippocampus, basal ganglia and thalamus between the two groups. Two differences were found: the clinical duration of the disease which appeared significantly (p = 0.02) shorter in the 210ILE-mutated cases compared to that of non-mutated sporadic cases. The highly selective vulnerability of thalamus in FFI showing a severe pathology especially in its dorso-medial part in comparison with that of the sporadic CJD cases. CONCLUSION: The results of this study confirm that the different polymorphism at codon 129 of the PRNP gene, which could be involved in the structural "domains" of human PrP, might modulate the pathological phenotype of TSE.

Creutzfeldt-Jakob disease in an Iranian: the first clinico-pathologically described case.

This is the first report of a definite case of Creutzfeldt-Jakob disease in an Iranian and it has been confirmed by a neuropathological study and by the immunoelectrophoretic demonstration of PrP, the pathological amyloid protein specific to the spongiform encephalopathies. The clinical course and the topography and severity of brain pathology classify this case as of panencephalopathic type and support the view of different phenotypic expressions of CJD in relation to the existence of multiple strains of the causative agent.

[The pattern of neuropsychologic compromise in patients with Parkinson disease]. / Profilo di compromissione neuropsicologica in pazienti affetti da morbo di Parkinson.

We carried out a neuropsychological study on cognitive impairment in 57 subjects affected by idiopathic Parkinson's Disease (P.D.) and 32 subjects affected by Alzheimer's Disease (A.D.). First, we found two different subgroups of parkinsonian patients, the first one with dementia and the second one without dementia. We clearly identified these two distinct subclinical entities regardless of mean age, age of onset, duration of treatment; on the contrary, the type of treatment seems to play a specific role on the appearance of dementia in P.D., anticholinergics being assumed almost exclusively by demented parkinsonian patients (chi square c. Yates = 422; p less than 0.05). Second, we showed two distinct patterns of cognitive impairment between P.D. with dementia and A.D. In fact, cognitive impairment is consistently more evident in Alzheimer patients than in parkinsonian ones with dementia; in addition, demented parkinsonians show a pattern of impairment similar to that exhibited by patients affected by frontal lobe lesions. This result supports neuroanatomical and neurochemical data on the involvement of the whole dopaminergic system in P.D. and the role played by the ventro-medial tegmental area projecting to the frontal cortex. In conclusion, our study, identifying a specific pattern of cognitive impairment in P.D., well-differenciated from demented patients of different aetiology, suggests beneficial effects with dopaminergic agonists in these patients; in fact, these agents, acting on the second neuron, may stimulate the prefrontal region that is probably involved in the cognitive impairment of parkinsonian patients.

The APOE-491 A/T promoter polymorphism effect on cognitive profile of Alzheimer's patients.

Alzheimer's Disease (AD) is a neurodegenerative disorder with a complex aetiology displayed by multiple pathogenic factors. The APOE varepsilon4 allele represents the only established genetic risk factor for sporadic AD; in addition, previous findings on three single nucleotide polymorphisms (SNPs) located on the APOE promoter region, have led to a growing interest in their potential role in AD pathogenesis. The -491 A/T promoter polymorphism has been the one most frequently shown to be associated with AD, as it influences the APOE coding region transcription. The aim of this study was to evaluate the possible effect of the -491 A/T polymorphism on the cognitive profile of sporadic AD patients with a disease severity ranging from mild to moderate. Our results showed that patients carrying the -491 AA genotype had poorer cognitive performances than the -491 AT ones, statistically significant in demanding tests of visual attention, especially for the late-onset AD (LOAD). No further differences on cognitive profile were observed when stratifying AA and AT patients according to their APOE genotype. These results suggest a possible functional effect of the -491 A/T promoter on the neuropsychological performances of AD. This role seems to be independent of APOE genotype. In fact the effect of -491 A/T occurs predominantly on attention while the APOE varepsilon4 allele mainly affects memory performances. According to the biological effect exerted on APOE transcription, the -491 A/T polymorphism could be considered a disease modifier more than a risk factor for sporadic AD.