Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease

By Clifford R. Jack Jr., V. Lowe, S. Weigand, H. Wiste, Matthew L. Senjem, D. Knopman, M. Shiung, Jeffrey L. Gunter, Brad Boeve, B. Kemp and 2 more. Brain : a journal of neurology, 2009

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The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources—ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) < amnestic mild cognitive impairment (2.5 cm3/year) < Alzheimer's disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = −0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =−0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =−0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

Subfields: Physiology, Psychiatry and Mental health, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/1b7acdea007ddfffa7ebf602a96f173a7de2b1b8

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Citations in the corpus

Alzheimer's disease: strategies for disease modification (2010, background): “Imaging studies with amyloid ligands suggest that significant plaque deposition occurs already before clinical declin”
A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease (2010, background): “The sensitivity of amyloid imaging for diagnosis, prognosis, and longitudinal AD progression are improved considerably, however, when amyloid imaging is combined with measures of neuronal dysfunction, such as cerebral glucose metabolism or brain volume.(10,14,15) Although details of the mechanism re”
2016 Alzheimer's disease facts and figures (2016, positive): “This proposed preclinical or presymptomatic stage reflects current thinking that Alzheimer’s-related brain changes may begin 20 years or more before symptoms occur [18-20].”