This 2-year follow-up study of [18F]FDDNP PET in people without dementia and relatively minimal cognitive impairment (overall median Mini-Mental State Examination score of 29) indicates that increases in [18F]FDDNP brain cortical binding values correlate with increases in clinical symptoms of neurodegeneration and regional baseline [18F]FDDNP binding values are significant predictors of future cognitive decline.
In the present study, [18
F]FDDNP cortical binding values followed the expected neuropathologic patterns.12,13
The MCI patients who already had high medial temporal binding did not show significant binding increases in this region; thus, medial temporal binding in MCI seems to plateau and remain stable for 2 years, consistent with earlier observations.9
By contrast, a high proportion of the MCI patients with frontal and parietal binding above the ROC established threshold showed cognitive decline after 2 years, whereas none of the MCI patients below this threshold showed cognitive change. Moreover, the results of the ROC analysis indicated that high baseline [18
F]FDDNP binding in frontal and parietal regions (corresponding to spread of disease to these regions) is associated with more rapid cognitive decline. Thus, the pattern of [18
F]FDDNP binding in MCI, consistent with known disease progression observed at autopsy, may provide useful information for physicians when individual patients are evaluated.32
Our previous work using cluster analysis of [18
F]FDDNP binding values in individuals with normal aging and MCI identified a subgroup of individuals with high frontal and parietal binding who may be at high risk for future cognitive decline.33
Moreover, those with this high frontal and parietal pattern in MCI also show fluorodeoxyglucose F18 PET patterns consistent with an increased risk for AD.34
Of the 21 individuals with a diagnosis of MCI at baseline, 12 demonstrated memory impairment consistent with amnestic MCI, whereas the other 9 had amnestic MCI plus deficits in other cognitive areas. These MCI subtypes have a high rate of conversion to dementia,35,36
which provides a useful model for evaluating the predictive ability of molecular imaging probes to determine disease progression. In our study, 6 of the 21 MCI patients (29%) converted to AD at the 2-year follow-up visit, a proportion consistent with the 10% to 15% expected annual risk of conversion of amnestic MCI subtypes.37
The finding that MCI patients with high frontal and parietal binding are more likely to convert to AD after 2 years than those with low binding in these regions further supports the potential utility of [18
F]FDDNP PET as a biomarker predictor of cognitive decline in MCI.
We expect that many of the normal aging individuals in this study will eventually progress to MCI, and those with higher baseline [18
F]FDDNP binding, particularly in the medial temporal region, might be at the greatest risk for decline within the next few years. In fact, 2 of the 3 normal-aging individuals who converted to MCI at follow-up had the highest baseline regional [18
F]FDDNP values in the medial temporal, parietal, and frontal regions. Our results suggest that longer duration of follow-up and larger samples of normal aging individuals would further improve specificity of [18
F]FDDNP in predicting future cognitive decline and risk for conversion to a diagnosis of MCI. In less impaired individuals, medial temporal [18
F]FDDNP binding might be a more informative predictor of future decline because tau and amyloid deposit accumulation in this area precedes measurable cognitive decline.32,38
Our previous autopsy follow-up study9
of a patient with high medial temporal [18
F]FDDNP binding showed both amyloid and tau, with a preponderance of tau tangle deposits in the medial temporal regional.
In the entire study group and the MCI subgroup, baseline medial temporal [18
F]FDDNP binding values predicted future executive function decline, an observation that could be explained by disruptions in neural circuitry between medial temporal and frontal regions. Other studies of normal aging indicate neural circuitry disconnections between these 2 cortical areas, including lower entorhinal cortical thickness associated with decreased anterior cingulate and medial frontal activation during a memory retrieval task.39,40
Thus, our observation that high baseline medial temporal [18
F]FDDNP binding predicts executive function decline is consistent with tau-mediated disruption of neuronal circuits projecting to pre-frontal regions that control executive functioning.
A useful neuroimaging biomarker for neurodegeneration would not only provide visualizations of relevant disease pathophysiologic characteristics and predict the course of disease but would also demonstrate correlations with disease progression over time.10,41
Our findings indicate that [18
F]FDDNP PET demonstrates such utility. For example, for the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline. These results are consistent with those of Shin and coworkers42
and Tolboom and colleagues,43
who have reported that higher [18
F]FDDNP binding levels are associated with episodic memory impairments.
Finding practical in vivo measures of neurodegeneration for early disease detection and predicting and tracking disease progression are major challenges to the field. Such noninvasive measures of disease progression might assist in testing and monitoring new preventive treatments for protecting neuronal integrity before significant neural damage emerges.10,44–46
The encouraging longitudinal findings with [18
F]FDDNP presented in this work will be useful in future clinical trials for successful monitoring of treatments designed to eliminate or prevent the deposition of amyloid or tau or both.
Recent clinical trials of novel treatments have targeted fibrillar amyloid, but efficacy results have been negative,47
pointing to limitations in treatment strategies based solely on the amyloid hypothesis. Amyloid and tau aggregates are clearly important in vivo diagnostic targets, but tau aggregates are associated with both neuronal and cognitive losses and are better indicators of disease progression.48,49
Using an in vivo tau marker for detection and tracking of neurodegenerative diseases is critically important given findings that severity of tau neurofibrillary tangle load, rather than amyloid plaque burden, correlates with rates of tissue loss and neuronal decline.50,51
Even if current antitau treatments prove negative, an in vivo marker for tau aggregates constitutes a useful method to track disease progression at its earlier stages.51
Thus far, [18
F]FDDNP is the only available imaging probe that provides in vivo measures of tau in humans.9,10
As in all imaging studies, methodologic limitations should be considered for appropriate interpretation of results. Important considerations include partial volume effects,14
errors introduced from head motion during scanning (particularly with patients with dementia),52
and study population selection (eg, educated samples that may not represent the general population). Our MCI sample was relatively younger than other samples reported in the literature, which might reflect our recruitment focus on normal aging rather than populations with dementia. We have found that head motion error is more likely in more severe forms of cognitive impairment observed in patients with dementia, and this can be corrected effectively.52
Also, the accuracy of cutoffs in the ROC analyses were maximized for this data set, so results from other populations might differ. It is important to cross-validate these results in a larger sample. In addition, we have used combined left and right regions in our analyses. Future studies will examine the contribution of the left and right regions separately.
Our findings indicate that in vivo regional [18F]FDDNP binding patterns are consistent with known patterns of disease deposition and associated with future disease course. Using [18F]FDDNP PET may not only assist in predicting future cognitive decline and identifying individuals more likely to benefit from prevention treatments, but it may also track the effectiveness of such treatments to accelerate drug discovery efforts.