Carlo Masullo

Neuropathological Diagnostic-criteria for Creutzfeldt-jakob-disease (cjd) and Other Human Spongiform Encephalopathies (prion Diseases)

Neuropathological diagnostic criteria for Creutzfeldt‐Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD ‐ sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno‐reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann‐Sträussler‐Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population).

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

BackgroundA 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. MethodsThe authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. ResultsAfferent 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. ConclusionsThe 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.

Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95

BACKGROUND Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy. Genetic and iatrogenic forms have been recognised but most are sporadic and of unknown cause. We have studied risk factors for CJD as part of the 1993-95 European Union collaborative studies of CJD in Europe. METHODS The 405 patients with definite or probable CJD who took part in our study had taken part in population-based studies done between 1993 and 1995 in Belgium, France, Germany, Italy, the Netherlands, and the UK. Data on putative risk factors from these patients were compared with data from 405 controls. FINDINGS We found evidence for familial aggregation of CJD with dementia due to causes other than CJD (relative risk [RR] 2.26, 95% CI 1.31-3.90). No significant increased risk of CJD in relation to a history of surgery and blood transfusion was shown. There was no evidence for an association between the risk of CJD and the consumption of beef, veal, lamb, cheese, or milk. No association was found with occupational exposure to animals or leather. The few positive findings of the study include increased risk in relation to consumption of raw meat (RR 1.63 [95% CI 1.18-2.23]) and brain (1.68 [1.18-2.39]), frequent exposure to leather products (1.94 [1.13-3.33]), and exposure to fertiliser consisting of hoofs and horns (2.32 [1.38-2.91]). Additional analyses, for example stratification by country and of exposures pre-1985 and post-1985, suggest that these results should be interpreted with great caution. INTERPRETATION Within the limits of the retrospective design of the study, our findings suggest that genetic factors other than the known CJD mutations may play an important part in CJD. Iatrogenic transmission of disease seems rare in this large population-based sample of patients with CJD. There is little evidence for an association between the risk of CJD and either animal exposure, or consumption of processed bovine meat or milk products for the period studied.

Neuropsychological correlates of localized cerebral lesions in non-aphasic brain-damaged patients

A neuropsychological test battery made up of verbal, visual-spatial, and intelligence tests was administered to 82 right and 67 on-aphasic left brain-damaged patients with localized cerebral lesions, in order to draw impairment profiles of the various subgroups. Separate analyses were undertaken on patients with unilobar and multilobar lesions. As for hemisphere effects, LH patients performed worse than RH subjects on verbal tests, while the reverse was true for visual-spatial tasks. As for lobe effects, patients with frontal lobe damage fared worse than other subgroups on word fluency, independent of the side of the lesion. RH patients with multilobar posterior lesions were significantly more impaired than other RH subgroups on the test of Copying Drawings with Landmarks, probably owing to the detrimental effect of unilateral spatial neglect on tasks requiring an accurate visual-spatial analysis.

Sulphate polyanions prolong the incubation period of scrapie-infected hamsters

The effect of the organic sulphated polyanions, pentosan sulphate (SP54), dextran sulphate 500 (DS500) and suramin, have been tested on golden Syrian hamsters infected with the 263K strain of scrapie by the intraperitoneal (i.p.) or the intracerebral route. SP54 had the greatest effect in prolonging the incubation period of the disease when administered within 2 h of the i.p. inoculum. The same amount of SP54 given 24 h after scrapie inoculation had a potent effect in some animals and no effect in others. This result suggests that SP54 inhibits the uptake of the scrapie agent into the nerve endings and/or carrier cells at the site of the inoculum, i.e. the peritoneum, and that this event occurs in about 24 h. DS500 had a similar although less potent effect (22.4 days delay during the incubation period) than SP54 (54.4 days) when administered within 2 h of scrapie injection by the i.p. route, and suramin had only a minimal effect (10 days). This study suggests that treatment of scrapie and related spongiform encephalopathies of animals and man is possible only before the agent has reached the clinical target areas of the brain.

Amphotericin B Delays the Incubation Period of Scrapie in Intracerebrally Inoculated Hamsters

The scrapie-infected hamster has been considered an excellent model for the study of slow virus diseases of man (Creutzfeldt-Jakob disease) and animals. At the moment no therapy is available for the cure of these fatal central nervous system diseases, although several drugs have been tested. We found that amphotericin B (AmB), a polyene antibiotic, increased the incubation time of scrapie disease in animals infected by either the intraperitoneal or intracerebral route. Hamsters inoculated with a 10% brain suspension of the 263K strain of scrapie showed clinical signs of disease in 54.6 +/- 4.7 days. Under AmB treatment (1 mg/kg for 6 days a week) the incubation time increased with the length of treatment, up to a maximum delay of 45 days. AmB may interact with the scrapie agent on cell plasma membranes and may thereby decrease the rate of scrapie replication. However, AmB did not have any effect when administered after the clinical onset of scrapie disease.

Some aspects of phonological impairment in aphasia

Abstract The relationships between expressive and receptive phonemic disorders and between disturbances of phoneme processing and general disorders of auditory comprehension were studied in 69 aphasic patients, by means of a phoneme discrimination test and of a standard aphasia battery. A significant but incomplete correlation between disorders of phonemic output and of phoneme analysis was found. The view is put forth that in some patients only phoneme encoding or decoding is disturbed, whereas in others a central level of phoneme processing is impaired. A significant but partial correlation was also found between disorders of phonological analysis and general disorders of auditory comprehension. This supports the view that, besides sequential phonological analysis, other processes operate in auditory comprehension.

Polymorphisms of the Prion Protein gene in italian patients with Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of the amyloid protein PrP in the CNS. Two coding polymorphisms of the PrP gene (PRNP) are a methionine (Met) to valine (Val) change at codon 129, and a deletion in the octapeptide coding region. In the United Kingdom, homozygosity at codon 129 appears to be associated with a predisposition to develop CJD. However, in Japan, where allelic frequencies and genotype distribution are significantly different, such an association has not been demonstrated. To determine whether such deletion(s) or codon 129 polymorphisms of PRNP predispose to the development of CJD in Italian patients, 31 sporadic CJD patients with no known PRNP mutations, and 186 unrelated control subjects were studied. Genotypic frequencies at codon 129 in these Italian CJD patients revealed a significant excess of methionine alleles, and a different genotype distribution in comparison with the normal Italian population. Deletions of a 24-bp segment located in the PrP octapeptide coding region were found in two control subjects, but in none of the sporadic CJD patients. These data suggest that Met homozygosity at codon 129 may contribute, with other enviromental or endogenous factors, to CJD development.

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.

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 Alzheimers 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.