Isak Prohovnik - US grants

In this study of regional Cerebral Blood Flow (rCBF) in normal aging and Alzheimer's disease (AD), results to date indicate that: 1) AD is associated with substantial reductions of mean cortical perfusion, compared to normal aging, 2) these flow reductions are greatest in a parietotemporal focus, and minimal in periRolandic and occipital regions, 3) the distinct regional flow pattern of AD can achieve highly effective discrimination of such patients from normal aging and other diseases, and thus may be diagnostically useful, and 4) these rCBF abnormalities, although related to age- at-onset (AAO) and severity, are largely present in all patients, and do not lose sensitivity even at very early stages of the disease. Consequently, the current proposal is intended to complete documentation of rCBF as a diagnostic marker, test the validity if its discrimination in a new patient sample, continue longitudinal follow-up of current cohorts, and begin to develop a cohort of high-risk individuals to assess the possibility of predictive discrimination. The current samples of 60 AD patients and 60 normal controls will be recruited and entered, and longitudinally followed. A new sample of 32 patients will be recruited at another hospital, independently diagnosed by another group. Finally, 200 first- degree relatives of AD probands will be recruited and followed as a high-risk sample. All subjects will undergo diagnostic procedures, a short neuropsychological battery, and rCBF measurements at rest and during cognitive challenge. All AD patients will be rigorously stratified by AAO, crossed with severity of disease. For assignment to severity groups, it is required that each patient show-concordant scores on three dimensions: duration of disease, cognitive deficits, and activities of daily living. This design will provide a test of rCBF discrimination between AD patients and elderly controls, as well as discrimination among the four subsamples stratified by AAO and severity. Additionally, family members will provide data on the temporal relations between rCBF changes and eventual symptomatic manifestations and AD diagnosis. Finally, the assessment of rCBF response to cognitive challenge may provide insights into the mechanisms of disease, and may have implications for selection of patients in therapeutic trials.

Schizophrenia, a devastating and common disease, traditionally has been studied in early adulthood. Its course and outcome during senescence are largely unknown and subject to controversy. We have reviewed the neuropathological records of 1,046 patients who were chronically hospitalized in mental institutions. For cases who died after age 50, clinical lifetime diagnosis, as noted in the autopsy notes, was schizophrenia in 544 patients and dementia in 258 patients. The ii prevalence of neuropathological diagnoses consistent with Alzheimer's disease (AD) was 51% in the demented patients and 28% in the schizophrenics. When evaluated against age of death, AD findings in demented patients was constant, whereas the rate of such findings in schizophrenic patients rose monotonously from <5% below age 60 to 50% at age greater than or equal to 90. The age-relative rate of AD diagnosis in schizophrenic patients was markedly higher than that expected in the general population, and similar to the rate postulated in first-degree relatives of AD patients. These findings strongly suggest a hitherto-unsuspected link between aging, schizophrenia (or chronic neuroleptic treatment), and AD-like neuropathological changes. The current findings, however, are limited by the known limitations of chart diagnosis, as noted in autopsy reports. Prior to investing in a very demanding prospective study and/or a complex examination of archival historical brain tissue from neuroleptic-naive patients, we propose to confirm and extend these findings in a retrospective study, providing extensive psychiatric and normal control samples. We will identify and evaluate tissue specimens and medical charts of 600 recent schizophrenic patients. These will be compared to samples of major mood disorders (n=200) and Primary Degenerative Dementia (n=200), as well as other chronically institutionalized psychiatric patients and normal controls (n=250). We will apply blind, rigorous methods of diagnostic assessment and determine rater reliability for both neuropathological interpretation and psychiatric chart review. The results are expected to definitively detect whether chronic schizophrenia and aging are associated with increased rate of AD-like neuropathological findings in this population. This cost-effective study will then serve as the basis for a prospective determination, which will include detailed assessment of family history, and/or a similar retrospective study of tissue and records of medication-free patients.

[unreadable] DESCRIPTION (provided by applicant): Creutzfeldt-Jakob Disease (CJD), the most notable of the human prion diseases, is invariably fatal. The rarity of CJD, difficulty of early diagnosis, virulent course, and variable modes of transmission, have made clinical studies exceedingly difficult. We here propose a unique method of addressing the difficulties of clinical research in this area. We will use advanced MRI methodology to elucidate early, and even premorbid, cerebral abnormalities of structure and function in such patients. We plan to capitalize on a singular cluster of high incidence occurring among Libyan Jews living in Israel, caused by familial transmission of a mutated prion protein (PrP) gene. Healthy carriers of the relevant mutation (E200K) will be identified (n=50), and will be studied before, as well as after, symptomatic expression. Family members lacking the mutation will serve as controls (n=50). In addition, we will recruit into the study all incident CJD cases in Israel that carry this mutation. We believe we will be able to examine these incident cases within 2 months of onset, and follow them for the duration of the disease. All subjects will have extensive neurological and neuropsychological examinations, as well as MRI, using both traditional structural imaging and newer neuroimaging methods: Diffusion- Weighted Imaging (DWI) and Chemical Shift Imaging (CSI). This project will be the largest neuroimaging study ever conducted in this disease, and the first to observe a genetically homogenous sample. Further, it will provide data on the earliest stages of the disease, including healthy mutation carriers before frank onset of symptomatology. The large sample sizes, availability of healthy mutation carriers, the noncarriers of similar environmental and cultural background, and rapid access to symptomatic patients, are all unprecedented features that should yield definitive data on the early stages of this devastating disease. [unreadable] [unreadable] [unreadable]

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