2008 ICAD

The International Conference on Alzheimer’s Disease &
Related Disorders Meeting
In Chicago, July 26 – 31, 2008

Additional Material

Brain Atrophy Patterns May Aid Early Identification of Alzheimer’s
A pattern of Alzheimer’s disease-type brain atrophy in asymptomatic patients may help diagnose incipient disease at its very earliest stages.

 In 109 patients ages 60 and older with no cognitive impairment, the presence of Alzheimer’s-like patterns of structural abnormality, as seen by serial MRIs, increased slowly with age, Christos Davatzikos, Ph.D., or the University of Pennsylvania, reported.

The rate at which the Alzheimer’s-like pattern was found accelerated at about age 75, he said.

“Although the clinical significance of these Alzheimer’s-like patterns of brain atrophy must be further evaluated,” he said, “we are very hopeful that these pattern analysis tools will provide early indicators of brain changes that resemble those seen in people with Alzheimer’s, years before memory problems are recognized clinically.”

Dr. Davatzikos & colleagues used MRI scans from the Alzheimer’s Disease Neuroimaging Initiative for high-dimensional pattern analysis and classification to find the Alzheimer’s-like patterns of structural changes.

Each patient was given a score (called the SPARE-AD index) on the basis of how closely their brain patterns matched negative Alzheimer’s-like pattern scores, which indicated a more normal brain and positive scores which indicated a more normal brain, and positive scores, which indicated an Alzheimer’s-like pattern. The SPARE-AD index can be used in conjunction with other imaging markers to recognize the early signs of Alzheimer’s disease before they present clinically

1. One such biomarker – increased expression of the protein CD-69 in peripheral blood lymphocytes – was identified by researchers at the University of Leipzig in Germany.
   The LymPro test, which measures the expression of CD-69, differentiated patients who were diagnosed with Alzheimer’s from patients with normal cognitive function with 88% & 82% accuracy respectively. It also differentiated those who were diagnosed with Alzheimer’s from demented Parkinson’s patients with 91% accuracy when the diagnosis was Alzheimer’s and 92% accuracy when the diagnosis was Parkinson’s.
   A larger trial is underway to verify the results and the test could be on the market in October.
   Two other studies explored biomarkers in cerebrospinal fluid:

2. Beta-amyloid 42 – The level of beta-amyloid 42 in cerebrospinal fluid is inversely associated with plaque in the brain, as measured with PET scans using Pittsburgh Compound B as a tracer. This suggests that decline in beta-amyloid 42 in cerebrospinal fluid may effectively identify non-demented individuals who are in the preclinical stage of Alzheimer’s.

3. Beta-secretase – Beta-secretase is involved in the processing of amyloid precursor protein and the production of toxic beta-amyloid and it is over-expressed in the brains of Alzheimer’s patients.Researchers at Trinity College Dublin showed that BACE1 levels and APOE e4 genotype were the strongest predictors for progression to Alzheimer’s.

4. A new tracer for PET scans of amyloid plaques – The tracer, called 18F-AV-45, was retained in the brains of patients.
   diagnosed with Alzheimer’s but not in older individuals with normal cognitive function and
   showed rapid uptake and steady levels in the brain from 50 to 90 minutes after administration. The compound “has the potential to aid in the diagnosis and early detection of Alzheimer’s in a community setting and may be a useful biomarker for the development and monitoring of novel amyloid reducing therapies.
   Phase II trials with the compound have been initiated.

New Advances in the Treatment Against Alzheimer’s Disease
New advances in different approaches to treating Alzheimer’s disease were reported at the 2008 ICAD.
These hopefully will one day lead to better therapies for the mind-robbing condition.

1. Monoclonal antibody* Therapy
   With a goal of enabling the body to more easily clear beta-amyloid 42, from which plaques are predominantly made, an investigational monoclonal antibody LY2062430 was given intravenously to 52 patients with mild-to-moderate Alzheimer’s in a phase II trial reported researchers at Eli Lilly & Co.
   Results suggested that not only did the antibody bind to free beta-amyloid but was also dissolving plaques in the brain. The researchers said that the resulting increase in the clearance of beta-amyloid could potentially slow the progression of the disease by preventing the build-up of plagues. The antibody was well tolerated.
   A phase III trial will be conducted starting 2009.     
   
   * Explanation of terms:
   Antibodies are proteins that attach to foreign material in the body (such as bacteria and viruses and are released by certain cells of the immune system. They “mark” these foreign material for removal or destruction by other components of the immune system.
   Any foreign substances that can make the immune system release antibodies is called an antigen.
   Antibodies are unique because they are made in response to specific antigens. In fact, antigens and antibodies fit like puzzle pieces.
   A monoclonal antibody is an antibody produced by a single clone of cells (specifically, a single clone of hybridoma cells) and therefore a single pure homogenous type of antibody. Monoclonal antibodies can be made in large amounts in the laboratory and are a cornerstone of immunology. When used s medications, the generic name ends in –mab.
   
   Bapineuzumab 
   Bapineuzimab,a fully humanized monoclonal antibody was found to have no evidence of efficacy in patients who are carriers of the ApoE4 gene, representing some 65% of Alzheimer’s patients. However, the agent may be effective in those with no genetic risk for dementia.
   The findings reaffirmed the decision to move forward with a phase III trial of the drug.

2. Intravenous Immunoglobulin (IVIG) Therapy
Mild-to-moderate Alzheimer’s can be safely and effectively treated with intravenous immunoglobulin therapy, according to preliminary results from a phase II trial reported by Weill Cornell Medical College researchers.
Over 9 months, patients randomized to IVIG demonstrated significant improvement on a number of cognitive measures compared with placebo, with no evidence of toxicity.
IVIG is an appealing therapy option because “it is obtained from the plasma of healthy humans and, as such, it has the advantage of having an established safety record. Moreover, it is literally loaded with antibodies, including antibodies against beat amyloid.
An 18-month phase III trial is scheduled to begin this fall, recruiting at 35 clinical sites.

3. Tau-Targeted Therapy – The accumulation of neurofibrillary tangles (hyperphosphorylated tau) have long been recognized as a hallmark of Alzheimer’s disease, but it is only now that therapeutics targeting tau have reached clinical trials. Neurofibrillary tangles contribute to microtubule destabilization. (See illustration)
   
   a.   Tau Aggregation Inhibitor (TAI) Therapy
           Tau-targeted therapy with rember an old drug for urinary-tract infections,         methylene blue arrests disease progression in mild and moderate         Alzheimer’s disease over 50 week.
           The drug rember is a formulation of methylene blue made by TauRx         Therapeutics which attacks tau, which promotes tangles, as opposed to         amyloid plaques.
           A phase III trial with 1,000 to 1,200 patients is being planned, but details         await talks with the FDA.
    b.    Agent AL-108
           Donald E. Schmechel, M.D. of Duke University, said that a 16-week treatment         with AL-108 (a small, naturally occurring neuroprotective 8-amino acid         peptide) inhaled therapeutic dementia agent demonstrated not only safety but         “exciting efficacy” in several secondary endpoints that he said were good         measures of “working memory”.  In animal studies, AL-108 appeared tp         stabilize microtubules. (See illustration)

4. Investigational Drug Dimebon
   Dimebon is an antihistamine. Earlier (The Lancet, July 19, 2008) researchers of Baylor College of Medicine, reported that patients with mild to moderate Alzheimer’s who received dimebon had significantly improved cognitive function, memory, activities of daily living, and behavior compared with those on placebo, who progressively worsened. In a 6-month, open-label extension trial, dimebon continued to show benefits and safety. Although the patients continued to decline to below baseline values, the declines were delayed compared with the estimated drop in function with placebo. The researchers commented, “We did not arrest the disease permanently. Eventually the mechanisms of the disease overwhelm the benefits of dimebon. This emphasizes the benefit of earlier treatment.” Patients are currently being enrolled in multiple countries for a phase III clinical trial.

5. Investigational Metal-Protein Attenuation Compound
   Researchers of  Uppsala University Hospital, report patients treated with 250 mg of clioquinol PBT2 (a second generation metal-protein attenuation compound) had a dose-dependent reduction in the 42 amino acid form of amyloid beta in cerebrospinal fluid compared with placebo, but did no reduce beta amyloid in the blood. Moreover, the patients also showed significant improvement on 2 components of a new neuropsychological test battery.
   This PBT2 study suggests a novel approach to treating Alzheimer. Rather than targeting the accumulation of amyloid plaque in the brain, or tau tangles, it targets the zinc and copper-mediated toxic oligomerisation of amyloid beta, but does so without affecting the availability of zinc and copper ions, which are essential to brain function