Tissue transglutaminase (tTG) is a marker for apoptosis, and its protein level is known to be increased in post-mortem Alzheimer's and Huntington's disease brains. tTG is increased in the cerebrospinal fluid of patients with Alzheimer's disease. However, the influence of psychotropic medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic. The protein level of tTG was examined in the cerebrospinal fluid obtained from 29 patients under neuroleptic medication in the last 24 h before lumbar puncture (eight patients diagnosed with Alzheimer's disease and 21 patients with other neurological diseases), and compared with those from 55 patients without antipsychotic medication (25 Alzheimer's patients and 30 others). In addition, the influence of several other psychotropic drugs on apoptosis was analysed. A significant influence (P<0.01) of antipsychotic drugs for both the Alzheimer's and the non-Alzheimer's group was found with respect to tTG protein levels in cerebrospinal fluid. By contrast to the male subgroups, the female groups showed a strong influence of neuroleptics on cerebral cell death. Surprisingly, atypical antipsychotics did not differ from typical neuroleptics in neurotoxicity. By contrast, no influence of antidepressants, cholinesterase-inhibitors, nootropics, tranquilizers and tramadol on cerebral cell death was found. The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death, especially in female patients. Subjects with Alzheimer's disease might be even more vulnerable to any antipsychotic. Therefore, subsequent research should aim to identify atypical neuroleptics without neurotoxicity. A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed. Finally, the possible connection between the observed increased cerebral cell death and tardive dyskinesia, the most threatening side-effect in antipsychotic therapy, is discussed.

Despite advances in understanding the pathogenesis of Huntington’s disease (HD), there is no effective treatment. In the HD transgenic mouse, expression of a dominant-negative caspase-1 mutant extended survival and delayed the onset of symptoms, suggesting that caspase-1 is crucial in HD pathogenesis.1 In fact, the caspase inhibitor minocycline delayed disease progression and extended survival by 14% in the HD mouse model.2 Minocycline is a second-generation tetracycline commonly used for a prolonged period to treat acne. Minocycline crosses the blood–brain barrier and inhibits caspase-1 in acute stroke and decreases infarct size in a mouse stroke model.2 Minocycline protects neurons in mixed spinal cord cultures …

Tissue transglutaminase (tTG) is an indicator of acute cell death in vitro. An increase in tTG protein level is found in postmortem Alzheimer's disease (AD) brains as well as in Huntington's disease. No study revealed tTG in vivo so far. We investigated the concentrations of tTG in the cerebrospinal fluid (CSF) obtained from 84 patients using ELISA assays. We compared 33 patients with probable AD to 18 patients with probable vascular dementia (VaD) and 33 control patients without neuropsychological deficit. Diagnosis was supported by CSF parameter and neuroimaging. We found a highly significant difference (P = 0.001) between the concentration of tTG in the AD groups (7.58 pg/ml) and controls (2.99 pg/ml). There was no statistical difference between controls and VaD (2.93 pg/ml). Interestingly, tTG did not show an association with tau protein, Abeta42, apoE4, neuropsychological items, or age. Males showed lower tTG values than females; however, this difference did not reach statistical significance. To our knowledge, this is the first demonstration that tTG is increased in AD in vivo. Our results suggest that tTG may be a powerful biochemical marker of the acute degenerating process in vivo. It may serve as completion of CSF analysis in the diagnosis of dementing disorders and may be a simple way of assessing the efficacy of possible new antiapoptotic drugs.