Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on¹⁸F-FDG PET Patterns in Clinical Alzheimer Disease

Abstract

Purpose: Comorbid Lewy body (LB) pathology is common in AD. The effect of LB co-pathology on FDG-PET patterns in AD is yet to be studied. We analysed associations of neuropathologically-assessed tau pathology, LB pathology, and substantia nigra neuron loss (SNnl) with ante-mortem FDG-PET hypometabolism in patients with a clinical AD presentation.Methods: Twenty-one patients with autopsy-confirmed AD ('pure-AD'), 24 with AD and LB co-pathology ('AD-LB'), and 7 with LB but no or low evidence of AD pathology ('pure-LB') were studied. Pathologic groups were compared on regional and voxel-wise FDG-PET patterns, the cingulate island sign ratio (CISr), and neuropathological ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with FDG-PET patterns.Results: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporo-parietal hypometabolism and did not differ in CISr, regional FDG SUVR, or SNnl. By contrast, pure-LB showed the expected DLB-like pattern, accompanied by pronounced occipital hypometabolism and elevated CISr and SNnl compared to the AD groups. In continuous analyses, Braak tangle stage was significantly correlated with more AD-like, and SNnl with more DLB-like, FDG-PET patterns. Conclusions:In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG-PET pattern. A more DLB-like FDG-PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology

“…According to our classification, 12.2% of the whole aMCI cohort and 12.5% of the ADD cohort showed a posterior-occipital FDG-PET pattern suggestive of Lewy body pathology. While these percentages are in good agreement with the proportion of clinical Alzheimer’s disease cases in the ADNI autopsy cohort who were found to have a primary pathological diagnosis of Lewy body pathology, 20 , 40 they are higher than those reported by previous neuropathological studies focusing on similar clinical Alzheimer’s disease cohorts (3–11%). 41 , 42 According to our previous imaging-pathological study, 20 several of the LB-like cases in our study may actually reflect pathologically mixed AD-LB cases for which Lewy body pathology represents an important contribution to the neurodegeneration phenotype, which may explain the relatively large size of our LB-like group.…”

“…While these percentages are in good agreement with the proportion of clinical Alzheimer’s disease cases in the ADNI autopsy cohort who were found to have a primary pathological diagnosis of Lewy body pathology, 20 , 40 they are higher than those reported by previous neuropathological studies focusing on similar clinical Alzheimer’s disease cohorts (3–11%). 41 , 42 According to our previous imaging-pathological study, 20 several of the LB-like cases in our study may actually reflect pathologically mixed AD-LB cases for which Lewy body pathology represents an important contribution to the neurodegeneration phenotype, which may explain the relatively large size of our LB-like group. Although the actual underlying pathology in the FDG-PET-defined LB-like patients in our current study remains unknown, these patients did indeed show significantly lower PET biomarker levels of Alzheimer’s disease pathology compared to patients with an AD-like FDG-PET pattern, indicating that co-pathologies may have a greater contribution to the clinical phenotype.…”

“…However, in light of the characteristic posterior-occipital FDG-PET pattern and the mixed clinical phenotype that characterizes the LB-like cases in our study, it appears likely that these patients may have a greater contribution of (comorbid) LB pathology to their neurodegeneration phenotype and associated clinical features. 20 Of note, a very similar posterior-occipital FDG-PET hypometabolism pattern has also been reported in patients with posterior cortical atrophy, and thus some of the classified LB-like patients may also reflect such a rare, atypical subtype of Alzheimer’s disease. 46 Posterior cortical atrophy typically presents as a form of early onset Alzheimer’s disease (EOAD, < 65 years), so our results may not directly translate to younger populations where the proportion of patients with posterior cortical atrophy and other forms of EOAD is expected to be higher.…”

“… 15–19 In a recent imaging-pathological association study, we observed that a significant subset (12%) of clinical Alzheimer’s disease patients actually had a primary pathological diagnosis of Lewy body pathology at autopsy, and these also showed the corresponding posterior-occipital hypometabolism pattern characteristic of dementia with Lewy bodies in ante-mortem FDG-PET. 20 Furthermore, this pattern was also observed in a subset of pathologically mixed AD-LB patients, and was strongly associated with substantia nigra degeneration, 21 which suggests that this posterior-occipital FDG-PET pattern links with Lewy body-related neurodegeneration even in clinical Alzheimer’s disease cases.…”

Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers

“…DLB is also neuropathologically heterogeneous and up to seven pathologies can coexist creating a diverse mix of combinations with variable clinical consequences [9 ▪▪ ]. The few “pure” LB pathology cases usually show a more typical DLB profile with higher frequency of core features such as RBD, VH and parkinsonism [10,11]. However, the vast majority of DLB cases are “mixed”, most commonly with concomitant Alzheimer's disease neuropathological changes (ADNC), followed by other co-pathologies such as TDP-43 and cerebrovascular disease (CVD), which increase in frequency with age [9 ▪▪ ,11–19].…”