Longitudinal Cortical Tau Uptake in Alzheimer Disease Anshul K.
1 Kulkarni , 1Donald
Jesús J.
1,2 Gomar ,
and Marc L.
1,2 Gordon
and Barbara Zucker School of Medicine at Hofstra/Northwell 2The Litwin-Zucker Research Center, The Feinstein Institutes for Medical Research
Background Alzheimer disease (AD) is a chronic neurodegenerative disease and the leading cause of dementia in the United States. It is characterized by progressive cognitive decline and memory deterioration. This study focuses on tau, which is a normally present axonal protein that promotes microtubule assembly and stability. However, when hyperphosphorylated, tau self-associates into insoluble neurofibrillary tangles (Querfurth 2010). Tau neurofibrillary tangles are one of the pathological hallmarks of Alzheimer disease, along with neuritic plaques of amyloid-beta (Aβ) (Mayeux 2012). Widespread tau accumulation occurs with normal aging, while faster rates of accumulation have been observed in cognitively impaired rather than cognitively healthy individuals. The appearance of tau deposition is typically found first in the middle and inferolateral temporal cortical regions and is closely associated with cognitive impairment (Jagust 2018). In this study, we aimed to compare tau pathology at baseline and longitudinally in patients in the prodromal stage of AD (namely Mild Cognitive Impairment) with cognitively healthy individuals.
Hypothesis We hypothesize that Mild Cognitive Impairment (MCI) patients will show greater tau accumulation compared to healthy subjects (HS) at baseline and after 2 years of follow-up.
Conclusions
Results Table 1 : Demographic and Cognitive Status Characteristics of the Samples Variable Gender (Male / Female) Patient Age at PET Education (yrs.) Years from Baseline to Follow-Up CDR-SB at Baseline CDR-SB at Follow-Up MMSE at Baseline MMSE at Follow-Up
HS Patients (n=12) 5 Male 7 Female 77.0 (±7.2) 16.5 (±1.7) 2.38 (±0.65) 0.125 (±0.226) 0.167 (±0.326) 29.1 (±1.0) 29.0 (±0.9)
MCI Patients (n=12) 5 Male 7 Female 77.3 (±7.0) 17.1 (±2.5) 2.35 (±1.13) 1.17 (±0.72) 1.42 (±1.18) 28.1 (±1.9) 27.6 (±1.7)
Significance N/A p=0.929 p=0.409 p=0.934 p=0.001 p=0.002 p=0.08 p=0.004
Figure 1. Baseline comparison of cortical [18F]-AV1451 binding between MCI (N=12) and HS (N=12). Color scale represents logarithmic base 10 scale of significance with a threshold of p < 0.01 (0.001 - 0.01).
(a)
Methods We examined the ADNI (http://adni.loni.usc.edu/) database to study longitudinal cortical tau deposition in Alzheimer Disease using PET imaging with the radiotracer [18F]-AV1451. We selected gender-, age-, and education-matched groups of 12 healthy subjects (HS) and 12 subjects with Mild Cognitive Impairment (MCI). Each patient underwent longitudinal assessments using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Mini-Mental State Exam (MMSE). The CDRSB is a semi-structured interview used to assess global functioning (Morris 1993). The MMSE is a cognitive screening tool to evaluate cognitive impairment over time (Folstein et al., 1975). Structural MRI and tau PET images from baseline and follow-up were obtained for each patient from the ADNI database and then processed using FreeSurfer software (https://surfer.nmr.mgh.harvard.edu/). Each tau PET image was co-registered with the corresponding longitudinal structural MRI. A group analysis was run to compare the cortical [18F]-AV1451 uptake data between MCI and HS groups at baseline. Within-group paired analyses were then run to measure the difference in cortical [18F]-AV1451 uptake data between baseline and endpoint data from the HS group and from the MCI group.
(b)
Figure 2. Longitudinal paired analysis of cortical [18F]-AV1451 binding for (a) HS group (N=12) and (b) MCI group (N=12) between baseline and endpoint. Color scale represents logarithmic base 10 scale of significance with a threshold of p < 0.01 (0.001 - 0.01).
Table 2 : Magnitude of Longitudinal Tau Increase in Standardized Uptake Value Ratio (SUVR) Units HS Patients (n=12) MCI Patients (n=12)
Frontal Lobe < 0.05 0.12
Parietal Lobe < 0.05 0.12
Temporal Lobe < 0.05 0.08
Limbic Lobe < 0.05 0.09
At baseline, MCI patients displayed widespread increases in tau uptake, including marked regional increases in the supramarginal, inferior parietal, and superior temporal regions of both right and left hemispheres (Figure 1). Tau pathology in the parietal and temporal lobes is consistent with the cognitive impairment observed clinically in the MCI population. The longitudinal paired analysis revealed that HS group (Figure 2a) displayed only minimal focal increases in tau uptake (Table 2; all differences were <0.05 SUVR units over 2 years). These findings are likely attributed to signal noise, but minor increases in tau accumulation is expected for HS due to normal accumulation of tau that occurs with age, irrespective of diagnosis. On the other hand, MCI patients displayed widespread increases in tau uptake (Figure 2b) throughout the frontal, parietal, temporal, and limbic lobes (Table 2; specifically, the differences in SUVR units were greatest for the frontal and parietal lobes over 2 years). The greater increase in tau uptake seen in MCI patients is commensurate with the greater decline seen in MMSE scores from baseline to follow up (Table 1).
Future Directions This study involved a whole-brain comparison of tau uptake between MCI and HS groups, but tau in the context of aging and memory disorders has been shown to accumulate first in the medial temporal and inferolateral temporal regions. Therefore, an ROI analysis focused on those regions may better illustrate the difference between groups as well as between timepoints. A larger sample size would also improve the statistical significance of the study. We employed an ROI-based analysis of tau uptake, which measures significant voxels within each ROI pre-defined by the FreeSurfer atlas. Thus, another future study would be to perform a voxel-wise study, in which each voxel of the image is measured and compared independently, regardless of the ROI in which they are located. An additional future study would be to measure longitudinal changes in brain atrophy associated with tau pathology in Alzheimer Disease. Lastly, the [18F]-AV1451 tracer used in this study is a first-generation tracer that has a lower binding specificity than newer tracers (Leuzy et al., 2019), which may be more sensitive to detect differences.
References 1. 2. 3. 4. 5. 6.
Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010 Jan 28;362(4):329-44. doi: 10.1056/NEJMra0909142. Erratum in: N Engl J Med. 2011 Feb 10;364(6):588. PMID: 20107219. Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Aug 1;2(8):a006239. doi: 10.1101/cshperspect.a006239. PMID: 22908189; PMCID: PMC3405821. Jagust W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat Rev Neurosci. 2018 Nov;19(11):687-700. doi: 10.1038/s41583-018-0067-3. PMID: 30266970; PMCID: PMC7032048. Morris, J.C., The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology, 1993. 43(11): p. 2412-4. Folstein, M.F., S.E. Folstein, and P.R. McHugh, "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 1975. 12(3): p. 189-98. Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, Nordberg A. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry. 2019 Aug;24(8):1112-1134. doi: 10.1038/s41380-018-03428. Epub 2019 Jan 11. PMID: 30635637; PMCID: PMC6756230.