Tau Imaging Correlates of Psychiatric Symptoms in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease Gary
1 Tan ,
Jesús J.
1,2 Gomar ,
and Marc L.
1,2 Gordon
1Donald
and Barbara Zucker School of Medicine at Hofstra/Northwell 2The Litwin-Zucker Research Center, The Feinstein Institutes for Medical Research
Background Psychosis emerging in the context of Alzheimer’s disease (AD+P) has grave clinical implications. AD+P is associated with a greater burden of cognitive impairment (1, 2), functional impairment (3) and a steeper decline (6). The excess cognitive impairment that manifests in AD+P precedes the onset of psychosis, (5) indicating that psychosis is the expression of a distinctly aggressive pathophysiology. Efficacious treatments are lacking, while current medications used to treat AD+P carry significant risks (6). Evidence collected by our lab support a frontal deficit model of AD+P driven by an acceleration of tau pathology (7). tau is an axonal protein that binds to microtubules, promoting microtubule assembly and stability. Hyperphosphorylated tau sequesters normal tau into neurofibrillary tangles causing disassembly of microtubules, and ultimately disrupting axonal transport. Together with neuritic plaques of amyloid-beta (Aβ) protein, neurofibrillary tangles constitute one of the pathological hallmarks of AD. In AD+P, early post-mortem studies consistently pointed to a heavier burden of tangle rather than Aβ pathology, especially in the frontal cortex (8-9). Recent post-mortem and CSF studies, including our own, support a specific association between tau pathology and psychosis risk in AD (10-11). Additionally, evidence supporting an association between tau pathology and psychosis comes from recent work on chronic traumatic encephalopathy (CTE). Although a very recent study in CTE found that severity of psychosis correlated with binding capacity of the PET tau ligand 11CPBB3 (12), to date, no published studies have employed tau PET to evaluate the correlation of tau with psychosis in the context of AD. ➢ Our aim is to test the hypothesis that AD+P patient will show evidence of greater tau deposition compared to AD patients without psychosis (AD-P), not only in the medial temporal lobe, but also extended to the frontal and parietal lobes.
Conclusions
Results Table 1 : Demographic and Cognitive Status Characteristics of the samples Variable Gender (Male / Female) Patient Age at PET Education (yrs.) Clinical Dementia Rating – Sum of Boxes (CDR-SB) Mini-Mental State Exam (MMSE)
AD- Psychosis (n=18) 11 Male 7 Female 79.3 (±1.37) 15.4 (±0.59)
AD+ Psychosis (n=18) 11 Male 7 Female 79.3 (±1.53) 15.6 (±.59)
Significance n.a. p= 0.978 p= 0.792
2.6 (± 0.57)
6.1 (± 0.69)
p= 0.00039
26.2 (± 3.63)
21.2 (± 5.00)
p= 0.0018
(a)
(b)
Structural MRI images were manually pre-screened and then processed using FreeSurfer software (https://surfer.nmr.mgh.harvard.edu/). PET images were concatenated using the last 6 images, representing the final 30 minutes post-injection of the tracer. The tau PET image was co-registered onto the FreeSurfer output that was generated from the structural MRI images. The co-registration was checked and adjusted using the FreeSurfer segmentation as a guide. The intensities of the PET images were then normalized by the cerebellum cortex uptake, to compute Standardize Uptake Value Ratio (SUVR) images. In a final step, these PET images were also analyzed using partial volume correction (PVC) to account for grey matter atrophy. Group Analysis (AD-P vs AD+P). The normalized, co-registered PET images were concatenated into a single file. The volumes were then mapped onto a shared surface. The surface was smoothened and a group analysis comparing the mean tau uptake was performed. We first determined [18F]-AV1451 uptake in AD-P and AD+P groups in SUVR units. We then compared both groups in their [18F]-AV1451 uptake using a voxel-wise approach. This latter analysis was repeated using PVC to account for grey matter atrophy. Finally, we compared both groups SUVRs using regions of interest (ROI). analysis.
The major regions with a significant difference in SUVR lie within both the medial and lateral surfaces of the posterior brain. On the lateral surface of the brain, the SUVR map showed the greatest difference in the supramarginal and inferior parietal regions. Although ROI based differences were not detected in the temporal lobes of the brain (Figs 3a-3b), the voxel-wise maps showed localized areas within the middle temporal, inferior temporal ,and the bank of the superior temporal sulcus regions. This suggests psychotic symptoms may be associated with only specific regions of the temporal lobe.
Figure 1: (a) AD–P group Cortical distribution of [18F]-AV1451 Binding ( N=18) (b) AD+P group Cortical Distribution of [18F]-AV1451 Binding (N=18). Color wheel represents SUVR values relative to cerebellar cortex and projected onto a shared surface. (a)
(b)
Except for the caudal middle frontal, differences in the frontal cortex were sparser. Only by using the PVC method were minor differences noted in the superior frontal and middle orbital frontal regions. These may represent smaller difference or later-stage disease, although additional studies would be required to elucidate its significance. Although there are minor differences in tau detected in the pre/post-central areas tau, previous studies have demonstrated that there are very low levels of tau accumulation in these areas in both aging and AD.
Future Directions
Methods We examined the ADNI database to explore the association of tau burden in AD+P compared to AD-P using PET imaging with the radiotracer [18F]-AV1451. The presence/absence of psychotic symptoms was assessed with the Neuropsychiatric Inventory (NPI) considering the first 2 items, i.e. delusions and hallucinations. Subjects were classified as AD+P if they had a score greater than 0 in any of those two items; ADP participants had a score of 0 in each of the items. Following this criterion, we identified 18 AD+P subjects with a valid [18F]-AV1451 PET scan. We also selected a gender and age matched subgroup of AD-P patients. All patients showed evidence of Aβ deposition (Aβ positive) as measured with PET. In brief, both subgroups had a 61% of men, a mean age of 79 years old, and a mean of years of education of 15 (Table 1).
The SUVR signal for both groups showed increases in uptake in the medial temporal lobes, specifically the entorhinal cortex, that extends to the medial and inferior temporal lobes. The increase is greater in the AD+P group. This distribution is consistent with the pathologic staging of Alzheimer's disease in autopsy and imaging studies (13-14). When compared to the AD–P group, the tau distribution of the AD+P group was diffusely elevated, with a regional increase in the parietal and temporal lobes.
Figure 2: Cortical distribution of [18F]-AV1451 Binding, Voxel-wise analysis of contrast between AD–P group (N=18) and AD+P group (N=18). Color scale represents logarithmic base 10 scale of significance with a threshold of p < .05 (.00275 - .05). a) Results from two-tailed unpaired t-test, uncorrected for partial volume effects; (b) Results form two-tailed unpaired t-test analysis corrected for partial volume effects (threshold p < .05). (a)
(b)
Although the findings of this study were significant, the main limitation is that the AD+P group were significantly more cognitively impaired. This brings to question whether the differences in tau detected is a function of disease stage rather than psychosis. Since psychosis and cognitive impairment are linked, it is difficult to isolate the outcomes despite matching for age and gender. Future studies can attempt to circumvent this issue by analyzing the effect of cognition within the AD+P and AD-P groups. The regional differences identified in this study between psychotic AD patients and non-psychotic AD patients can facilitate the use of tau imaging not only in the diagnosis of this form of AD but also guiding the potential treatment election in these patients. Longitudinal studies will be more informative to establish the use of tau PET localization as a predictor of clinical outcomes in the context of psychosis in AD.
References
Figure 3: ROI [18F]-AV1451 by group uptake in SUVR units. (a) Results uncorrected for partial volume effects; (b) Results corrected for partial volume effects. *p < .05.
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