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Feature Alzheimer’s DiseAse

neurodegenerative disorder. Worldwide, 36 million people are estimated to suffer from dementia. With the ageing population, that number is expected to double every 20 years, reaching 115 million by 2050. There is no cure for AD; existing treatments provide short-term symptomatic relief only. Nevertheless, early identification of AD is critical to advance progress towards a cure and to optimize patient care. The definitive diagnosis of AD occurs after death, and relies upon autopsy findings of amyloid beta plaques and neurofibrillary tangles in the brain. During life, clinical diagnosis of possible or probable AD is made when a patient’s progressive cognitive deterioration has become severe enough to interfere with daily life, and other possible causes of cognitive impairment have been ruled out. Thus clinical diagnosis of AD requires the presence of dementia and is made through a process of exclusion rather than on the basis of supportive findings. Advances in understanding the progressive nature of AD and the development of biomarkers sensitive to AD in the pre-dementia phase have set the stage for changes in how and when AD is clinically diagnosed.


MILD COGNITIVE IMPAIRMENT Growing evidence suggests that AD neuropathology accumulates silently in the brain over many years before cognitive impairment develops. The earliest clinical sign of AD is mild cognitive impairment (MCI), characterized by impairment in one or more cognitive domains, severe enough to be noticeable by the patient and detectable with neuropsychological testing, but not severe enough to interfere with daily living. Memory is the domain most often affected in early AD. Individuals with amnestic MCI progress to dementia at a rate of 15-20% per year, compared to only 1-2% year for older individuals without cognitive impairment. Despite this increased risk, MCI is a heterogeneous disorder, and not all patients with MCI develop dementia. Recent recommendations from the National Institutes of Health and the Alzheimer’s Association in North America, and the International Working Group for New Research Criteria for the Diagnosis

lzheimer’s disease (AD) is the most common cause of dementia. It is a progressive, ultimately fatal,

of AD have proposed incorporation of biomarkers evidence to increase certainty that individuals diagnosed with MCI or AD in research studies actually have underlying AD pathophysiology. Incorporation of these biomarkers not only improves etiological specificity, but also improves predictive prognosis in MCI.

BIOMARKERS FOR EARLY DIAGNOSIS Biomarkers for early detection of AD include direct and indirect indicators of amyloid pathology in the brain, and indicators of secondary neuronal injury associated with AD pathology. Biomarkers of amyloid pathology include reduced levels of Ab42

in cerebrospinal fluid (CSF)

obtained from lumbar puncture, or increased levels of amyloid deposition in the brain obtained from positron-emission tomography (PET) of amyloid-sensitive ligands, such as the Pittsburgh Compound


 Growing evidence suggests that AD neuropathology accumulates silently in the brain over many years before cognitive impairment develops

B (11 C-PiB), or 18 F-labeled tracers. CSF and

imaging biomarkers of amyloid pathology correlate well with each other, and with levels of amyloid pathology observed in the brain on autopsy. Biomarker and post- mortem studies of amyloid pathology have shown that the brains of older individuals can harbor substantial amounts of amyloid pathology in the absence of cognitive impairment or dementia. Current research suggests that amyloid pathology may precede clinical symptoms by a decade 

 Figure 1: A) Difference in cortical thickness, relative to healthy older adults, for patients with Alzheimer’s disease (top), patients with mild cognitive impairment (MCI) who show similar atrophy to AD patients (middle), and MCI patients who do not show the AD atrophy pattern (bottom). Brighter blue indicates greater thinning. B) The regions used to quantify atrophy. Atrophy quantified in the brain regions indicated, along with volumes of the whole brain volume inferior lateral ventricle, was used to predict risk of developing AD. C) Risk of developing AD within the next year as a function of degree of regional atrophy quantified from a baseline MRI scan (top), and as a function of degree of baseline atrophy plus annual rate of change from a one year follow-up MRI. An individual patient’s risk of developing AD can be read from the graph after computing the atrophy percentile. Figures are modified from those presented in McEvoy, Fennema-Notestine, Roddey, Hagler, Holland, Karow, Pung, Brewer, Dale and the Alzheimer’s Disease Neuroimaging Initiative (2009). Alzheimer Disease: Quantitative structural neuroimaging for detection and prediction of clinical and structural changes in Mild Cognitive Impairment. Radiology, 251(1):195-205 and in McEvoy, Holland, Hagler, Fennema-Notestine, Brewer, Dale, and the Alzheimer’s Disease Neuroimaging Initiative (2011). Mild Cognitive Impairment: Baseline and longitudinal structural MRI measures improve predictive prognosis. Radiology, 259: 834-843.

Imaging & Diagnostics Issue 4 2011 37

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