treatment with vitamin E, donepezil, or placebo

         Approximately 720 participants with MCI are currently being randomized to treatment with vitamin E, donepezil, or placebo for 3 years, with roughly an equal number of participants (240) in each treatment group.
      From previous data, it is known that individuals who meet criteria for MCI convert to AD at a rate of approximately 12% to 15% per year (Petersen, Smith, Ivnik, et al, 1995; Grundman, Petersen, Morris, et al., 1996b; Petersen et al., 1999). Additional data suggest that this conversion rate may be even higher (up to approximately 20% per year over the first 3 years) in MCI participants who are screened with a memory test assessing delayed recall. Based on these figures, it is expected that at the end of the 3 years, 45% to 60% of placebo-treated participants may develop AD.

     The trial is designed to evaluate whether the two treatment interventions are effective at reducing the rate of conversion to AD by approximately one third over the course of the 3 years. The MRI component of the protocol stipulates that MRI scans are obtained on participants at entrance into the trial, upon completion of the trial 3 years later, and at the time of diagnostic crossover to AD. In all participants the MRI study is performed according to a defined set of imaging sequences that are sufficiently generic so that they can be executed across a variety of MRI vendors. The cornerstone of the planned volumetric analyses includes a 3-dimensional (3D) volumetric imaging sequence that provides optimal spatial resolution in all three anatomic dimensions.

     Guidelines for the storage and archival procedures are provided to each of the individual participating sites. Magnetic resonance imaging data cassettes from participating sites are sent to the central data repository at the Mayo Clinic in Rochester, Minnesota, where imaging data are downloaded, checked for compliance with the prescribed imaging sequences, and then catalogued. Catalogued images are cross-checked with case report forms forwarded from participating clinical sites to the ADCS coordinating
center in San Diego, California. After the images are analyzed, the data are merged with other clinical data on each participant residing in the ADCS central database.

    The proposed analyses focus primarily on the medial temporal lobe, particularly the hippocampal formation. Nevertheless, with the imaging sequences outlined in the study protocol, the capability exists to measure serial whole brain, lobar, sublobar, and ventricular volumes, as well as gray and white matter volumes, and leukoaraiosis. Based on prior studies, we anticipate that the hippocampal volume or other baseline measurements on the baseline MRI scans will predict which participants are most likely to develop AD. Analyses of the serial images obtained over the course of the study will examine whether treatment with either vitamin E or donepezil alters the rate of atrophy in the whole brain, lobar and sublobar-medial temporal lobe, entorhinal cortex, as well as the gray and white matter. Similar analyses will examine whether there are treatmen differences in the rate of ventricular enlargement.

The earliest pathological changes in the brains of AD

    The earliest pathological changes in the brains of AD patients occur in the medial temporal lobe. The entorhinal cortex and its perforant pathway projections to the hippocampus are among the earliest brain regions to exhibit the neuropathological hallmarks of AD (Braak & Braak, 1996). The resulting loss of neurons and synapses in this region is manifested at a macroscopic level by medial temporal lobe atrophy, which can be observed by visual inspection of the brain at autopsy or by MRI in living patients.

    Paralleling the neuropathological changes, clinical symptoms of AD often involve cognitive impairments and fluctuations in body weight that are closely linked to medial temporal lobe atrophy (Grundman, Corey-Bloom, Jernigan, Archibald, & Thai, 1996a). In recent years, considerable effort has been devoted to imaging these structures to see if they serve as a useful adjunct in diagnosing and following patients with early AD.
    Previous work demonstrates that MRI-based quantitative measurements of the hippocampal formation are useful in differentiating patients with AD from normal control participants (Jack, Petersen, Xu, et al., 1997).
They found that the best discriminator between AD patients and normal controls was the hippocampal volume when different medial temporal lobe structures were compared. Participants with mild AD had mean hippocampal volumes that were approximately two standard deviations below the control mean.

   Volumetric measurements of the hippocampal formation may also be useful for predicting future conversion to AD in MCI participants. Jack, Petersen, Xu, et al. (1999) measured MRI-based hippocampal volume in
80 consecutive patients who met criteria for the diagnosis of MCI, and followed them longitudinally with approximately annual clinical and cognitive assessments. The primary endpoint was the crossover of individual MCI patients to a clinical diagnosis of AD during follow-up.

    During the period of observation, which averaged 33 months, 27 of 80 MCI patients developed dementia. Hippocampal atrophy at baseline was significantly associated with subsequent conversion from MCI to AD. The risk of AD was 50% within 3 years in MCI patients with moderate hippocampal atrophy; however, it was only 26% in patients with mild hippocampal atrophy (approximately 50% reduction in risk of conversion based solely on differences
in hippocampal volume). In MCI patients with normal hippocampal volume, the risk of developing AD dropped even further, with only 9% crossing over to AD within 3 years.

Orientation-Memory-Concentration test

    Approximately 830 individuals over age 75 years were on the computer roster of a large outpatient clinic affiliated with a managed care organization in Minneapolis, Minnesota. We selected those individuals from this roster without diagnoses of dementia, Alzheimer's disease (AD), and their synonymous diagnostic codes in any patient encounter in the prior 2 years. Of the 611 individuals who met these criteria, we sent an introductory letter to 447 potential participants, informing them that they would be receiving a phone call as part of this study.
    Upon reaching a participant on the telephone, the examiner (an RN experienced in geriatrics and formally trained to administer the mental status examinations) informed the individual of who she was and the
nature of the study. For those who agreed to participate, they were given either the Orientation-Memory-Concentration (OMC) test (Katzman, Brown, Fuld, et al., 1983) or the Minnesota Cognitive Acuity Screen (MCAS) (Knopman, Knudson, Yoes, & Weiss, 2000). Administration of the two generally alternated, except in a few circumstances in which a participant would agree only to the shorter of the two tests.

     After completion of the mental status examination, the participants were questioned on four issues. The first question asked how they thought they performed on the mental status examination ("How do you
think that you did on the tests we just finished?"), and the responses were good, fair, poor, or very poor. The second question was, "Apart from this interview, in the past few months, have you felt that you have had memory problems?", with the rating scheme as follows: "my memory is excellent," "my memory is as good as anyone else my age," "my memory isn't as good as it used to be, but it doesn't cause me any problems," "my memory has definitely deteriorated in the past few years and interferes with my daily activities," or "my memory is severely impaired." The third question was whether they would follow-up with their physician if the  were told that they had done poorly ("Suppose that the present interview showed that you had memory problems, would you be willing to have a medical assessment for memory problems at your clinic?", with yes, no, or possibly as the responses.
      The final question was open-ended, asking what they thought of the process of telephonic examinations. The study was approved by the HealthPartners Institutional Review Board. Oral consent was obtained to conduct the phone interview.

Disscusion

       Under conditions that might be present in many clinical practices, the acceptance/completion rate for telephonic mental status assessment among participants 75 years and older was only 55%. Of those who underwent cognitive assessment, the yield of cognitively impaired participants was low. Only 3% scored in the range that was indicative of cognitive impairment.

      Among the interviewees, willingness to consult with a physician regarding memory problems detected during a telephonic screen was quite high (87%).

       The low number of individuals who scored in the impaired range suggests that the telephonic strategy did not serve to uncover undiagnosed cognitive impairment in this elderly cohort. We believe we should have
encountered 20 screen failures (roughly a 10% prevalence in this 75+ year only age group), in contrast to the seven we found.
       We suspect that the lower-than-expected number of cases occurred as a result of selective refusal by participants with cognitive difficulties to participate in the telephonic screening. Unfortunately, we have no way of determining the cognitive status of those individuals who refused to be interviewed. From other studies in which cognitive status was available from an earlier visit prior to a refusal to continue to participate, those who refused to participate in follow-up had lower performance at baseline. In the Canadian experience, of 147 participants whose cognitive screening was abnormal, but who refused to undergo a clinical examination, their mental status score was more than seven points lower on the Modified Mini-Mental State examination, compared with those who continued to participate in the study (81.3 vs. 88.8).
     The low overall rate of completion of interviews could be attributed to a basic flaw in the telephonic strategy. In current American culture, telephone marketing is widespread, and many people, upon receiving phone
calls from strangers, may resent the intrusion. An alternative strategy would have been for us to have engaged the primary physicians in this clinic and encouraged them to promote participation. Because patients might see their physicians only every 6 months or less, such an approach would work only if our project had had a longer time scale.
      The findings of the present study suggest to us that telephonic screening is a useful and efficient strategy to identify those who do not need face-to-face cognitive assessments. Assuming that telephonic screening
were to be identified to the health plan membership as "required" or "strongly recommended," as opposed to an optional activity tied to research as was necessarily the case with the present project, the completion rate
could be higher. The number of elders who would then need face-to-face examinations would be perhaps only a half or a third of all individuals over age 75 years.

Magnetic resonance imaging (MRI)

       Magnetic resonance imaging (MRI) volumetric analysis is a relatively new assessment tool in clinical trials for Alzheimer's disease (AD). It is a technique that is particularly well suited for clinical trials designed to prevent AD or slow its progression. The Alzheimer's Disease Cooperative Study, a multicenter consortium that performs AD-related clinical trials, is presently conducting a clinical trial with vitamin E and donepezil (Aricept®) in participants with mild cognitive impairment (MCI). The objective of the trial is to determine if either agent is capable of delaying a diagnosis of AD.

          Mild cognitive impairment participants are randomized to treatment with vitamin E, donepezil, or placebo, and followed longitudinally for 3 years. A subset of randomized participants is undergoing MRI of the brain prior to beginning treatment and during the course of the trial. The objectives of the MRI component of this trial are to determine (a) whether MRI volumes predict cognitive and functional performance in a well-defined cohort of participants with MCI; (b) whether hippocampal volume or other baseline volumetric measurements predict subsequent crossover to clinical AD; and (c) whether treatment with either vitamin E or donepezil alters the rate of brain atrophy over the course of treatment.

         Although the trial is still recruiting participants, analysis of the MRI scans collected thus far indicate that hippocampal volumes measured at the time of study entry predict baseline cognitive and functional performance. These results support the hypothesis that brain volumetric analysis may also be useful to predict future prognosis and for monitoring the effects of treatment on disease progression.

Autosomal recessive genes

    Consanguinity increases the prevalence in a population of autosomal recessive genes that may have undesirable characteristics. For example, an additional 1/16 of the variation of DNA is made homozygous by the inbreeding of a marriage of first-cousins. Conversely, the probability of identifying recessive or quasirecessive susceptibility factors is enhanced by inbreeding. Childhood mortality is increased in offspring of first-cousin marriages by a factor of 1.4 to 1.7, and children born to consanguineous unions have poorer health than the offspring of nonconsanguineous unions (including malignancies, congenital abnormalities, mental retardation, and physical handicap). Curiously, there are few studies of the effects of inbreeding on the health of adults. We have hypothesized that consanguinity in the Wadi Ara community has increased the prevalence of autosomal recessive genes that are responsible, in part, for the increased prevalence of the disease.
    It has been reported that 44% of all Arab marriages in Israel are consanguineous, with a mean inbreeding coefficient of .0192 (Jaber, Shohat, Rotter, & Shohat, 1997). The inbreeding rates for Israeli Arabs may be particularly high (as compared with Egyptians or Syrians) because mobility was reduced for centuries by the Turks. At times in Arab communities, it has been required for children to marry into their own family in part to avoid sharing resources with competing family groups.

All of the known Alzheimer-related genes (on chromosomes 21, 14, 1, and 19) are dominant (chromosomes 21,14,1) or codominant (chromosome 19). There are no known genes affecting the development of AD that are recessive, perhaps because there have been few studies of AD in populations with high levels of inbreeding. De Braekeleer et al. (1989) reported an association between inbreeding and the development of AD (inbreeding coefficient 9 times higher in AD cases than in controls) in a rural population in Quebec. Studies in the Old Order Amish have found a low prevalence of disease in this inbred community, also having a low frequency of the apo E-e4 allele (.037). Inbreeding could be linked to AD through a confounding effect of education, but the association of inbreeding and education is controversial (found for a Saudi population but not for Israeli Arabs). We expect that there are recessive factors for AD because of indirect evidence: genetic modeling studies of AD in apo E-e4 negative families are unable to reject a recessive model (Rao et al., 1996).
    However, it is difficult to evaluate recessive models in outbred populations. The high prevalence we have seen in our highly inbred Arab population in Israel might be due to the inculcation of recessive AD susceptibility alleles or to a dominant gene that became frequent by founder effect.

Alzheimer's disease from which the disease occurs

Brain - soft nerve tissue, it should be protected by destroyers and poisons: stress, alcohol, narcotics, psychotropic drugs. In Alzheimer's disease brain cells atrophy and die "bundles". I had to deal with the disease up close.

First, the disease goes unnoticed: chudit people sometimes forget what happened yesterday, but remembers well what happened in childhood. However, there comes a critical moment, as a rule on the background of a stressful situation when the problem becomes obvious: the person loses touch with the outside world ceases to recognize the closest, he was haunted by delusions. There are periods of exacerbation when patients become unbearable. It is terrible, irreparable, but will have to adapt.

What does it happen?

In Alzheimer's disease in the brain is the deposition of protein in the form of "senile plaques" and the formation of neurofibrillary tangles of so-called, consisting of damaged neurons - both of these processes lead to the destruction of nerve pathways of the brain.

While still not clear what exactly causes these changes, but in recent years, scientists were able to identify specific genes responsible for human predisposition to Alzheimer's disease.

And what is interesting: the disease is more common in poorly educated people with unskilled occupations. A person with high intelligence are less likely to face the manifestations of this disease for the reason that it has a greater number of connections between nerve cells. So when the death of some cells lost the functions can be transferred to others who have not previously been involved.