Paraphrenia is a condition, affecting primarily women, in which the cellular skeleton of brain cells involved in social perspective and emotion is weakened. This happens when a key structural protein called tau falls out of solution, said Dr. Manuel F. Casanova, neurologist and neuropathologist at the Medical College of Georgia and lead author on the research published in the March issue of the journal Acta Neuropathologica. Dr. Casanova also will present the research at the April 13-20 annual meeting of the American Academy of Neurology.
Prior to the findings, little was known about the pathology of paraphrenia or schizophrenia, Dr. Casanova said. And, despite some common symptoms, scientists and clinicians alike have speculated that the two had glaring differences as well, such as the fact that schizophrenia typically gets worse and paraphrenia typically does not. Research seeking clarification of the relationship, Disentangling the Pathology of Schizophrenia and Paraphrenia, recently won Dr. Casanova the Senior Scientist Award from the World Congress on Schizophrenia.
The work examined the brains of 64 schizophrenics and 18 control patients from the Corsellis Collection housed at West London Hospital, comparing schizophrenics diagnosed before age 40 to those diagnosed after age 40 as well as the control patients. The average age of onset for schizophrenia is 16 to 25; late-onset, or paraphrenia, has been described as diagnosis after age 40, Dr. Casanova said.
Microscopic analysis of tissue revealed no distinctive pathology among the schizophrenics, but among the paraphrenics Dr. Casanova and his collaborators found a surprising deterioration of the skeletal structure of some brain cells. The key is the hippocampus, a sort of gateway for the brain that gives emotional and social context to information, Dr. Casanova said. After staining the cells and examining them microscopically, the researchers found in the paraphrenics changes in a varying number of brain cells going into and coming out of the hippocampus. "Connections coming in and out of the hippocampus have been severed, which renders the hippocampus ineffective and you a paraphrenic," he said.
The ineffectiveness is caused by tau, a protein that links microtubules, a core component of the cellular skeleton that provides shape and communication. "It provides for transportation from one area of the cell to another. It provides the ability to transport neurotransmitters such as dopamine and serotonin," Dr. Casanova said. But, for some still unknown reason, in some brain cells of some people the tau falls out of solution. "It becomes what's called hyper-phosphorylated. There are some groups of phosphate molecules that attach to it and make it insoluble. When that happens, there is nothing to keep the microtubules going straight and carrying out their function."
The researchers found this tauopathy not only in the majority of patients who had been diagnosed with late-onset schizophrenia but also in a third of patients who had been diagnosed with schizophrenia before age 40.
Dr. Casanova theorizes that tau may begin falling out of solution relatively early in life, but some patients can compensate and so the symptoms may not appear until later in life when more cells are affected. Conversely, in some patients, just a few cells experiencing tauopathy may make cells misfire and patients symptomatic. He noted, however, that paraphrenia is not a progressive condition as schizophrenia often is because the logical progression of tauopathy is cell death, accumulation of another protein called amyloid and the development of Alzheimer's disease.
Another key difference already noted between paraphrenics and schizophrenics is that paraphrenics don't have prominent hallucinations, although they do have delusions and may lack motivation, he said. "But, because there was no defined pathology for either, according to the fourth edition of the "Diagnostic and Statistical Manual," or DSM IV, they are classified together and age of onset is not a defining criteria. You can be 8 years of age and have schizophrenia, you can be 25 or 60 at age of onset," he said. "What we are saying is now we have a well-defined pathology for those whose symptoms start later in life."
One of his next steps will be to find why tau falls out of solution; tau already can be measured in the cerebral spinal fluid and sophisticated imaging equipment can enable it to be seen as well, which could lead to early diagnosis of paraphrenia, Dr. Casanova said.
Another important follow up is to look at the role of hormones in keeping tau functional; most patients became symptomatic after menopause, he said.
The research was funded by the Maryland-based Theodore and Vada Stanley Foundation and the Veterans Affairs Merit Review Board.
Co-authors include Dr. Janice R. Stevens, professor of psychiatry, Oregon Health Sciences University; Rosemary Brown (now retired) and the late Dr. Clive Burton, Department of Neuropathology, Rumwell Psychiatric Hospital in England; and Dr. Claire Royston, director of research and development, Hinchingbrooke Health Care Trust in England.
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