Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer's and Lewy body disease

Abstract

Polypathology is a major driver of heterogeneity in the clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer's disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy body disease (LBD). Patients with multiple aetiology dementia such as AD + LBD have faster progression and potentially differential responses to targeted treatments, although the diagnosis of AD + LBD can be challenging given the overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD + LBD pathologies. We hypothesized that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with PET, MRI and CSF seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ versus A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Strikingly, A+S+ patients had parieto-occipital 18F-fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ status on SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer's pathologies in mixed dementia, although our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. Overall, A+S+ patients had posterior mismatch with excessive 18F-fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuronal integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD + LBD aetiologies harbour a unique metabolic PET mismatch signature.

Keywords: Alzheimer’s disease; Lewy body; biomarkers; metabolism; multiple aetiology dementia; α-synuclein.

Figure 1

Imaging examples highlight mismatch residuals between tau and neuronal ¹⁸F-FDG PET hypometabolism, and MRI/¹⁸F-FDG PET mismatch relationships. (A) Mismatch between tau pathology (T) and neuronal ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) hypometabolism (N_M) occurs in mixed Alzheimer’s and Lewy body disease (AD + LBD) since N_M may reflect a balance of both T and α-synuclein (S) pathologies. (B) Associations between worse ¹⁸F-FDG hypometabolism and greater T burden show outliers with worse N_M than expected based on T. (C) Mismatch between atrophy on MRI (N_S) and N_M occurs in mixed AD + LBD since S appears to impact N_M on PET moreso than N_S on MRI. (D) Associations between worse ¹⁸F-FDG hypometabolism and lower cortical thickness (mm) in the inferior temporal gyrus highlight outliers with worse N_M than expected based on N_S. Amyloid (A), T, S status, ¹⁸F-FDG PET and MRI are shown for two cognitively impaired older adults, whose residuals are highlighted in B and C. (D) A 70-year-old male with A+T+S+ markers has AD Assessment Scale-Cognitive (ADAS-Cog) score of 29 (higher is worse) and cingulate island sign, while a (F) 75-year-old female with A+T+S– markers has an ADAS-Cog score of 24 and higher metabolism, despite both having similar A and T burdens. Regression lines of best fit and standard deviation based-lines are shown.

Figure 2

Imaging reveals a metabolic mismatch signature in patients with concomitant amyloid+synuclein pathology. Mean regional residual z-score maps show posterior mismatch (arrows) in amyloid+ α-synuclein+ (A+S+) patients compared with A+S– patients in [A(i)] mismatch residuals between tau and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET (TN_M) and [B(i)] mismatch residuals between MRI and ¹⁸F-FDG PET (N_SN_M). Here, the white colour represents a mismatch residual value close to about 0.6 standard deviations from the regression line, and the blue colour denotes a negative mismatch residual with an N_M worse than expected. Mismatch maps of average residual z-scores in regions that significantly differ between A+S+ and A+S– groups are seen for [A(ii)] TN_M and [B(ii)] N_SN_M mismatch, after adjusting for age, sex and tau load. Here, white colour represents no significant difference between A+S+ and A+S– groups, and blue colours depict a negative mismatch residual that significantly differs between groups, where residual values (and hence the colour) in A(i) and B(i) are similar to those shown in A(ii) and B(ii), respectively.

Figure 3

CSF metabolite and proteome analysis reveal altered dopamine neurotransmission and neuron integrity in patients with concomitant amyloid+synuclein pathology. (A) Dopamine is metabolized by enzymes, including catechol-O-methyltransferase (COMT), monoamine oxidase (MAO), aldehyde dehydrogenase (ALDH) and sulfotransferase (SULT). The CSF metabolite study demonstrated decreased dopamine metabolites (B) homovanillic acid and (C) 3-methoxytyramine sulfate (normalized concentration) with amyloid+ α-synuclein+ (A+S+) status. (D) The synaptic protein neuronal pentraxin-2 (NPTX2) is significantly decreased in A+S+. RFU = relative fluorescence unit. Box plots: filled circles = data points; × = mean; mid-line = median; lower and upper edges of each filled box = first (Q1) and third (Q3) quartiles (interquartile range, IQR); whiskers = minimum/maximum points and outliers based on thresholds <Q1 – 1.5(IQR) or >Q3 + 1.5(IQR). (E) Ontology of CSF proteomics comparing A+S+ versus A+S– indicates that S+ status is associated with neuron signalling, synapse organization and vesicles. (F) Comparing A+S+ versus A–S+ highlights that A+ status is associated with immune responses, protein degradation and lipoparticles. False discovery rate correction, Benjamini–Hochberg adjustment and weighted set cover were performed. Comparisons were made using likelihood ratio tests with covariates of age and sex, where *P < 0.05 and **P < 0.005.