Early marker for Alzheimer's disease: Hippocampus T1rho (T1ρ) estimation

Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder in elderly and results in progressive memory loss and cognitive decline. The appearance of senile plaques and neurofibrillary tangles are the neuropathological hallmarks of AD (1). Autopsy studies have shown the hippocampus to be affected by AD pathology early in the disease process, with ≈20%–50% loss of neurons by the time individuals are moderately affected (2,3). As a result, imaging studies have focused on this region in order to detect the early changes during the disease progression. Currently the diagnosis of clinically probable AD can be confirmed only once the stage of dementia has been reached. Neuropsychological tests are necessary to recognize and monitor the subjects at risk. However, to date there is no accurate cognitive marker to identify AD in the early disease process. Moreover, cognitive performances depend not only on age and education but also on mood and attention at the time of testing, and thus lack wide generalizability. Quantitative analysis of tau protein and amyloid-Aβ in the cerebrospinal fluid (CSF) has shown some diagnostic value in probable AD (4,5), but the procedure is totally invasive and has thus received only little attention so far in diagnosing AD. An accurate diagnosis of AD in the early symptomatic stage is extremely challenging despite the development of useful clinical constructs like mild cognitive impairment (MCI), which enables the identification of individuals who may be in an early clinical phase of AD. MCI was previously defined as a transitional state that can precede dementia, but the condition and the rates of conversion remain controversial. Despite many consensus conferences, experts cannot agree on critical aspects of MCI, particularly with respect to its clinical utility. Based on neuropsychological studies, a hippocampal memory profile has been proposed for MCI as prodromal AD (6). In light of current drug development aimed at slowing AD progression, diagnosing AD at its prodromal stage is particularly important. Recently, research has begun to focus on developing new tools, such as neuroimaging and CSF biomarkers, that could increase the specificity of the prodromal AD diagnosis. The goal of research in this area is therefore to develop highly specific and sensitive methods capable of identifying the subjects in the early stage who progress to AD. Neuroimaging markers provide an alternative and objective assessment of progression of AD. Out of various imaging techniques MRI is the most widely accepted technique to diagnose the various pathological conditions, and to monitor the treatment response, based on the changes in T2 and T1 contrast relaxation properties. It has been shown that the T2 value was not significantly different between normal subjects and AD patients (7). In one recent study, Yuan et al (8) have shown that fluorodeoxyglucose positron emission tomography (FDG-PET) performs slightly better than single photon emission tomography (SPECT) and structural imaging in prediction of conversion to AD in patients with MCI. However, the wide clinical utility of the PET technique is hampered by its poor resolution and necessity of a cyclotron at the imaging center that can produce the radioactive tracers. Other MR techniques like diffusion tensor imaging (DTI) and proton spectroscopy (1HMRS) have also been used in detection of normal white matter changes in patients with AD (9, 10). Ukmar et al (9) have shown a significant difference in fractional anisotropy (FA) between control and AD, while the FA was not significantly different in AD compare to MCI. Similarly, in a 1HMRS study it has been shown that the hippocampal metabolite profile in MCI is similar to AD (10). An alternative contrast mechanism is T1rho (T1ρ), the spin lattice relaxation time constant in the rotating frame, which determines the decay of the transverse magnetization in the presence of a “spin-lock” radiofrequency field (11). In biological tissue, exchange between protons in different environments is expected to contribute T1ρ relaxation. The molecular process that occurs in the milliseconds range influences the T1ρ relaxation time constant. T1ρ MRI has been previously used to measure T1ρ relaxation time in normal human brain and showed the higher range of values compared to T2 (11). Earlier, T1ρ has been used to delineate brain tumors, characterize breast cancer tissue, and monitor the level of cartilage degeneration (12–14). The current study was performed with an aim to measure the baseline T1ρ in hippocampus in the brain of AD (n = 49), MCI (n = 48), and control (n = 31) cohorts and to determine whether the T1ρ value shows any significant difference between these cohorts.