WASHINGTON, DC—Advances in diagnostic evaluations for Alzheimer’s disease and mild cognitive impairment (MCI)—including CT, MRI, 18fluorodeoxyglucose (FDG)-PET, and lumbar puncture—were reviewed by three leading researchers at the 2008 Alzheimer’s Disease Summit.

Diagnostic MRI
The majority of patients with MCI harbor neurodegenerative pathology, most frequently of the Alzheimer’s type, according to Liana Apostolova, MD, Assistant Professor of Neurology at the Mary S. Eaton Center for Alzheimer’s Disease Research, David Geffen School of Medicine, University of California, Los Angeles. Current guidelines from the American Academy of Neurology (AAN) for the evaluation of patients with dementia recommend structural brain imaging (either MRI or CT) for all patients presenting with cognitive decline. Up to 5% of these patients have been reported to harbor an underlying causative structural lesion, such as a slow-growing frontal brain neoplasm, normal pressure hydrocephalus, or subdural hematoma, which could be readily detected with surveillance imaging. Dr. Apostolova recommended that all patients presenting with MCI or Alzheimer’s disease be imaged with noncontrast CT or MRI, in accordance with AAN guidelines.

In addition, close examination of the medial temporal lobe—especially the hippocampus and entorhinal cortex—with high-resolution MRI may help predict which patients will progress from MCI to Alzheimer’s disease. These structures are affected early in Alzheimer’s disease, with neurofibrillary tangles beginning in the entorhinal cortex. Patients with MCI who progress to Alzheimer’s disease demonstrate a predictable progression of atrophy in the hippocampus; the CA1 region and subiculum are affected first, followed by CA2, CA3, and CA4.

“New state-of-the-art imaging techniques show great promise as future diagnostic/prognostic biomarkers and surrogate markers for Alzheimer’s disease clinical trials,” said Dr. Apostolova.

FDG-PET Imaging
Unlike conventional MRI, which shows brain anatomy, PET provides images of brain metabolism. Mark Mintun, MD, Professor of Radiology, Psychiatry, and Biomedical Engineering and Director of the Center for Clinical Imaging Research, Washington University School of Medicine, St. Louis, discussed the role of FDG-PET imaging in Alzheimer’s disease.

“FDG-PET is diagnostic of Alzheimer’s disease,” said Dr. Mintun. “Hypometabolism/hypoperfusion is first seen in the high biparietal and posterior cingulate regions, then in the bitemporal and frontal regions. This decreased activity may be seen independent of atrophy and is likely due to local damage and deafferentation.” Dr. Mintun added that PET scans are Medicare approved for differentiating Alzheimer’s disease from frontotemporal dementia.

All identified genetic causes of Alzheimer’s disease in humans involve amyloid production or processing, noted Dr. Mintun. In vivo imaging of β-amyloid plaques can now be performed with carbon 11–labeled Pittsburgh Compound B ([11C]PIB). Because amyloid plaques may be present in healthy people, amyloid PET imaging is not likely to be used for diagnosis. However, an absence of amyloid plaques reduces one’s risk for Alzheimer’s disease. Another application of [11C]PIB may be to monitor antiamyloid Alzheimer’s disease therapy. Amyloid PET scans may also identify those at high risk for Alzheimer’s disease. Dr. Mintun pointed out that amyloid imaging is currently limited to research purposes, in part because carbon 11 has a half-life of only 20 minutes and must be produced on-site with a cyclotron.

“Longitudinal and postmortem studies will be needed to define utility of β-amyloid imaging,” Dr. Mintun commented.

Lumbar Puncture
A lumbar puncture may be clinically indicated in the differential diagnosis of dementia and delirium, according to Elaine Peskind, MD, Associate Director of the Alzheimer’s Disease Research Center, University of Washington School of Medicine, Seattle. For example, patients who present with acute or subacute onset of altered mental status, rapid cognitive decline, and young age (

Dr. Peskind said that a lumbar puncture could be performed safely with minimal patient discomfort and morbidity by using a 24-gauge Sprotte atraumatic spinal needle with a 20-gauge introducer and local anesthesia. In an observational study of 428 lumbar punctures in patients ages 21 to 88, 6.8% of patients had a headache and 0.9% required an epidural blood patch. Back pain or soreness was mild in 2.6% of participants and moderate in 0.5%. A vasovagal response, nausea, or other complication occurred in less than 1% of patients.

For patients with MCI or Alzheimer’s disease, CSF biomarkers such as total tau, phosphorylated tau, and β-amyloid 42 may be useful in improving diagnostic accuracy and monitoring treatment, according to Dr. Peskind. For example, CSF β-amyloid 42 levels are decreased by about 50% in patients with Alzheimer’s disease versus healthy controls. Conversely, CSF tau is increased twofold to threefold in patients with Alzheimer’s disease, compared with controls. In addition, a high CSF tau/β-amyloid 42 ratio may suggest that patients will convert from no cognitive impairment to MCI. Levels of CSF β-amyloid 42, total tau, and phosphorylated tau may also be useful in monitoring response to antiamyloid or other treatments.

—Andrew N. Wilner, MD

Diagnostic Evaluations for Alzheimer's Disease and MCI