Presymptomatic Signs in Healthy CJD Mutation Carriers

Abstract

Creutzfeldt-Jacob disease (CJD) is a rapidly progressing dementia with neurological, psychiatric and cognitive symptoms. We focused our study on the familial CJD form among Libyan Jews (the E200K mutation), trying to identify preclinical neuropsychological signs in mutation carriers to facilitate early diagnosis of the disease. A wide range of neuropsychological tests was administered to 27 healthy volunteers, all first-degree relatives of genetic CJD patients. Thirteen of our participants were gene mutation carriers (E200K) and 14 controls. The healthy mutation carriers reported significantly lower Trait and higher State anxiety scores. Repeated Measure analysis showed statistical significance. The Anxiety Index (State-Trait Anxiety Score) progressed with age in the carriers’ group but not in the controls. Since this was more pronounced in the older subjects, we suggest that abnormal stress mechanisms precede the clinical onset of CJD. Cognitive differences have also been found between carriers and controls, especially in visual recognition of pictured objects. Both kinds of differences (anxiety levels and cognitive deficits) were most pronounced in elderly subjects. This study is the first to show any dysfunction in healthy CJD mutation carriers.

The role of stress and anxiety in the onset of familial Creutzfeldt-Jakob Disease (CJD): Review

“…Moreover, it is documented that genetically vulnerable individuals are more likely to develop psychiatric illness (e.g., major depression) in response to stress than individuals without genetic loading (Kendler et al 1995). The results of our recent double-blind study on fCJD mutation carriers (Gigi et al 2005) are in line with this literature summary. Although all of the healthy participants (carriers as well as non-carriers), were exposed to similar environmental stressors including the death of a first-degree relative as a result of a CJD illness, significant anxiety differences between the two groups was documented.…”

“…Surgery and anesthesia are known to result in a stress response with increase in the release of stress hormones (Dalin et al 1993). In line with our recent observations with presymptomatic CJD participants (Gigi et al 2001(Gigi et al , 2003(Gigi et al , 2005, it is suggested that CJD mutation carriers are predisposed to stress. Results indicate that healthy people who carry the fCJD mutation experience stressful events more severely than non-carriers and this may lead to the clinical disease onset.…”

“…Biochemical studies have shown a correlation between the cellular amounts of normal PrP and the resistance of brain cells to chemical stressors (Brown and Besinger 1998). Our results showed that anxiety rates reported by the healthy carriers are enhanced with age ( Figure 1; Gigi et al 2005). This may support the idea of accumulation of a stress-related damaging agent during the lifetime.…”

“…However, our results (Gigi et al 2005) show high anxiety scores in healthy CJD mutation carriers, which raises the question of whether an inadequate stress response (e.g., anxiety) is a preclinical sign resulting from the accumulation of a critical amount of the abnormal PrP SC isoform, or whether it is more directly to the mutated PRNP gene.…”

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

“…Atypical cases such as the one that we report can facilitate the investigation of factors that influence clinical phenotypes of prion diseases, thereby providing opportunities to develop methods for earlier and more accurate diagnoses and understanding of the natural history of these diseases. Furthermore, this report adds to the evidence that prion diseases may display an identifiable prodrome that can be clinically detected [26,27] . This may present opportunities for prophylactic therapies for individuals at risk for developing genetic prion disease [28,29] .…”