Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play

Abstract

Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with the absence of any approved disease-modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-β 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials.

Figure 1:

Plaques and tangles. Photomicrograph shows a neuritic plaque (upper arrow) and a neurofibrillary tangle (lower arrow) in an 85-year-old individual with autopsy-verified AD. (Beilchowsky silver stain.)

Figure 2:

Amyloid imaging spectrum. Illustration of the spectrum found on PET amyloid images with Pittsburgh compound B. Top row: Negative amyloid imaging scans with “low” Pittsburgh compound B retention in an elderly cognitively normal control subject and in a subject with MCI. Bottom: Positive amyloid imaging scans with “high” Pittsburgh compound B retention in an elderly cognitively normal control subject, a subject with MCI, and a subject with AD. Around 70% of cognitively normal elderly people have negative amyloid imaging scans, while 30% have clearly abnormal scans. Around 60% of MCI subjects have positive scans, while 40% have negative scans. Most AD dementia subjects have positive scans.

Figure 3:

Typical FDG PET uptake pattern in AD. Decreased FDG uptake in lateral temporoparietal cortex (arrows) and posterior cingulate–precuneus area is seen in the AD subject and more mildly in the MCI subject.

Figure 4:

Atrophy and clinical stage of AD. Coronal three-dimensional T1-weighted volume MR images (repetition time msec/echo time msec/inversion time msec, 7/900/2.8/900) in three individuals in their 70s are shown. The cognitively normal control subject shows little atrophy; the AD subject, considerable atrophy; and the MCI subject, an intermediate level of atrophy.

Figure 5:

Graph shows amyloid and neurodegeneration model, relating imaging, pathologic, and clinical manifestation over an individual’s adult lifetime. The lifetime clinical course of the disease (horizontal axis) is divided into presymptomatic, prodromal (MCI), and dementia phases. The vertical axis illustrates increasing amyoid deposition, decreasing brain volume, and decreasing cognitive ability as the disease progresses from left to right. Dashed line = neurodegeneration detected on MR images, dotted-and-dashed line = cognitive function, solid line = amyloid deposition detected on Pittsburgh compound B (Pi B) PET. The time course of amyloid deposition in late middle age is represented as two possible theoretic trajectories (dotted lines), reflecting uncertainty about the time course of early amyloid deposition. (Reprinted, with permission, from reference .)

Figure 6:

Hypothetical model of the dynamic biomarkers of the AD cascade. Horizontal axis indicates clinical stages of AD: cognitively normal, MCI, and dementia. Vertical axis indicates changing values of each biomarker—from maximally normal (bottom) to maximally abnormal (top). Aβ in the brain is identified by presence of CSF Aβ₄₂ or PET amyloid imaging findings (red line). Tau-mediated neuronal injury and dysfunction are identified by means of CSF tau level or FDG PET findings (blue line). Brain atrophy is measured with structural MR imaging (light green line). Onset and worsening of cognitive function are indicated by a purple line. Onset and worsening impairment in functional activities of daily living are indicated by dark green line. (Reprinted, with permission, from reference .)

Figure 7:

Fractional anisotropy in AD. Diffusion-tensor MR imaging (repetition time msec/echo time msec, 68/12 200; 41 diffusion-encoding directions). Voxel-wise analysis with tract-based spatial statistics in patients with AD (n = 17) and control subjects (n = 34) (Mayo Clinic, unpublished pilot data, January 2011). Fractional anisotropy is reduced in the parahippocampal gyrus (cingulum tract) (white arrows) and fornix (yellow arrow) in patients with AD as compared with control subjects, as shown in colored regions.

Figure 8:

Perfusion MR imaging in AD patients (n = 33) and control subjects (n = 62). Pulsed arterial spin labeling MR imaging (1.5/5.2) shows significant hypoperfusion (red areas) in AD patients, as compared with control subjects. (Reprinted, with permission, from reference .)

Figure 9:

Resting-state functional connectivity in AD. Echo-planar MR imaging (2900/30) seed-based voxel-wise connectivity analysis in 56 APOEε4 noncarrier control subjects versus 28 AD subjects. Seed was placed in posterior cingulate gyrus for connectivity analysis. Purple indicates areas where AD patients have greater connectivity than control subjects; green, areas where AD patients have less connectivity than control subjects. Control subjects show greater connectivity with the seed within the posterior cingulate gyrus, precuneus, and left anterior temporal lobe (green) than AD subjects. AD subjects show greater connectivity than control to bilateral medial and lateral frontal regions (purple) (225).