Molecular imaging of Alzheimer disease pathology

Abstract

Development of molecular imaging agents for fibrillar β-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that β-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of β-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However β-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping β-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents.

Figure 1. Associations between cortical PiB retention and standardized memory and global cognitive domain scores according to APOE ε4 status

Higher Aβ load is associated with greater global cognitive impairment (partial r_s = −0.18; p<0.01) and memory impairment (partial r_s = −0.14; p<0.01). However global cognitive function in APOE ε4 carriers is influenced more by the Aβ load compared to APOE ε4 non-carriers matched on age, gender, education and Aβ load (sequential ANOVA interaction; p=0.01), suggesting that APOE isoforms modulate the harmful effects of Aβ on cognitive function (A). A similar trend is seen with memory function (sequential ANOVA interaction; p=0.08). With permission from Neurology

Figure 2. Preclinical staging of Alzheimer’s disease and short-term progression rates

Using the preclinical staging criteria, at fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of cognitive scores of cognitively normal individuals, Stage 0 corresponds to low Aβ load on PET and absence of imaging markers of neuronal injury (i.e. normal hippocampal volumes on MRI and/or absence of AD-like pattern of hypometabolism on PET); Stage 1 corresponds to high Aβ load on PET and absence of imaging markers of neuronal injury; Stage 2 corresponds to high Aβ load on PET and presence of imaging markers of neuronal injury; Stage 3 corresponds to low Aβ load on PET, presence of imaging markers of neuronal injury, and subtle cognitive impairment. The proportion (%) of patients who progressed to mild cognitive impairment during a median follow-up of 15 months is demonstrated. Diagnosis of MCI was made according to Petersen criteria, blinded to the imaging biomarker data used for staging.

Figure 3. Correlations of cortical PiB retention and Aβ (A) and Lewy body (B) densities in individual brain regions of a case with dementia with Lewy bodies

There was a strong correlation between PiB retention and Aβ density in the 17 ROIs that were analyzed on pathological examination using Spearman rank order correlation (r=0.899; p<0.0001). There was no correlation between Lewy body density and PiB retention (r=0.13; p=0.66). MH: middle hippocampus; PH: posterior hippocampus; Th: thalamus; Cd: caudate; Ad: amygdala; CC: calcarine cortex; Pt: putamen; STG: superior temporal gyrus; MTG: middle temporal gyrus; IP: inferior parietal; PG: precentral gyrus; PCG: posterior cingulate gyrus; MFG: middle frontal gyrus; Mf: midfrontal; ACG: anterior cingulate gyrus; Pc: Precuneus; SPL: superior parietal lobule. With permission from Neurobiology of Aging

Figure 4. Multi-modality imaging markers in distinguishing Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB)

Regional FDG hypometabolism and PiB uptake on PET patients with probable DLB (n=21), are compared to control subjects (n=42) and gray matter atrophy in and patients with AD (n=21), compared to DLB patients are displayed on surface rendered brain images using SPM (p<0.05; family wise error corrected for multiple comparisons). Although occipital lobe hypometabolism, global cortical PiB retention and hippocampal volumes (% of total intracranial volume ) was overlapping among probable DLB and AD patients, multi-modality imaging approach almost completely separated DLB and AD patients. Logistic regression modeling demonstrated that each imaging modality independently contributed to distinguishing the AD and DLB patients with area under the receiver operating characteristic of 0.98. With permission from Neurobiology of Aging