Aims

This work aims to characterize local and global impairments of cerebral metabolism in early stage of Alzheimer’s disease (AD) in terms of glucose uptake and ketone body utilization using a transgenic rat model of AD. Further, this study provides preclinical evidence for clinical use of MR-based imaging protocol for risk assessment of AD in human patients.

Methods

TgF344-AD (TgAD) rat model has been established as an animal model of AD that presents progressive amyloidosis, tauopathy, frank neuronal loss in addition to cognitive decline. Under 1 to 2% isoflurane, 9-month-old TgAD and age-matched homozygous non-transgenic (nTg) rats were studied using the imaging protocol that included multiple post-labeling delay pseudo-continuous arterial spin labeling for resting perfusion and chemical exchange saturation transfer with 2-Deoxy-D-glucose (2DG) injection and proton magnetic spectroscopy for quantification of tissue glucose and β-hydroxybutyrate (BHB) concentration, respectively.

Results

Glucose uptake of TgAD rats following 2DG injection was significantly reduced in cortex, hippocampus, and striatum compared to that of nTg rats. While tissue glucose concentration of TgAD rats following overnight fasting was significantly higher than that of the nTg rats, TgAD rats exhibited significantly lower tissue BHB concentration after 2DG injection compared to nTg rats despite having comparable blood BHB concentration.

Conclusions

There is a significant alteration in cerebral metabolism that precedes the onset of AD's clinical symptoms, corroborating the findings in human AD patients. Also, this study demonstrates the potential of MR imaging and spectrocopy as a viable alternative to FDG-PET imaging for longitudinal assessment of cerebral metabolism with improved spatial resolution.

Aims

To identify a characteristic metabolic pattern of Dementia with Lewy Bodies (DLB), to study its expression in Alzheimer’s disease dementia (AD) and to test its ability to differentiate between DLB and AD.

Methods

We applied scaled subprofile model/principal component analysis (SSM/PCA) on FDG-PET scans from 20 DLB1 and 20 normal controls (NC1) from which we removed previously identified Alzheimer's disease related pattern (ADRP) by an orthogonalization procedure. Expressions of newly identified DLB-related pattern (DLBRP) and ADRP were calculated on a validation group of 60 DLB2, 21 NC2 and 63 biomarker-confirmed AD patients.

Results

DLBRP was formed by a linear combination of first and third principal components, accounting for 19,1% and 7.1% variance, respectively. It was characterized by relative hypometabolism in occipital and relative hypermetabolism in temporal lobes and posterior cingulate cortex.

DLBRP expression was significantly higher in DLB1 than NC1, in DLB2 than NC2 and in DLB2 than AD groups (p < 0.001). No significant difference in DLBRP expression was found between AD and NC2 groups. ADRP expression was significantly higher in AD group in comparison to both NC groups (p < 0.001), but no significant difference was found between AD and DLB groups. ROC curves yielded high AUC values for DLBRP: DLB1 vs. AD (AUC = 0.979) and DLB2 vs. AD (0.898) and low AUC values for ADRP: DLB1 vs. AD (0.674) and DLB2 vs. AD (0.574).

Conclusions

DLBRP is a promising imaging biomarker of DLB with ability to distinguish not only between DLB from NC but also between DLB and AD.

Aims

Cerebral glucose hypometabolism is a hallmark feature of Alzheimer’s disease (AD), that is closely related to dementia symptoms (Benzinger, PNAS, 2013). Interconnected brain regions that form functional networks show correlated glucose metabolism (Savio, J Nucl Med, 2017), hence we tested whether FDG-PET-assessed glucose metabolic decline systematically propagates across interconnected brain regions in AD.

Methods

We included longitudinal FDG-PET (~3-yrs. follow-up) from 173 amyloid-positive (Aβ+) subjects (cognitively normal/CN, n=38 mild cognitive impairment/MCI, n=116; AD-dementia, n=19) and 78 Aβ- CN controls. Using resting-state fMRI from 1000 healthy human connectome project participants, we determined a group-atlas of connectivity-based distance between 200 neocortical regions of interest (ROIs; Schaefer, Cer Cor, 2018). Next, we assessed in Aβ+ longitudinal FDG-PET change-rates across the same 200 ROIs and tested, whether 1) connected brain regions showed correlated FDG-PET changes and 2) whether seed-based connectivity patterns of epicenters (i.e. 10% ROIs with fastest FDG-PET decline) predicted spatial patterns of FDG-PET change.

Results

Aβ+ subjects showed reduced temporo-parietal FDG-PET hypometabolism (Fig.1A) and faster FDG-PET decline (Fig.1B) than CN-Aβ-. As hypothesized, functionally connected regions showed strongly correlated FDG-PET change-rates in Aβ+ (R²=0.442,p<0.001;Fig.2A,C-E) but also in Aβ- (R2=0.400,p<0.001;Fig.2B). In Aβ+, seed-based connectivity of epicenters (i.e. ROIs with fastest FDG-PET decline) predicted spatial patterns of FDG-PET changes on the group- (Fig.3A-C) and subject-level (Fig.3D-F).

Conclusions

In AD, connected brain regions show correlated FDG-PET decline, where connectivity patterns of fast declining epicenters predict brain-wide FDG-PET change patterns. These results suggest that metabolic brain changes propagate across functional brain networks in AD.

Aims

To uncover underlying patterns of FDG-PET hypometabolism in early-onset (EO) and late-onset (LO) cognitively impaired A-/T- ADNI subjects without significant hippocampal atrophy (N_HIP-).

Methods

Data for 159 cognitively normal (CN), 74 EO, and 40 LO ADNI subjects classified as A-/T-/N_HIP- were selected based on their first FDG-PET visit. FDG-PET images were processed in SPM12 and normalized to mean pons uptake, generating SUVR images. Statistical maps of FDG-PET SUVR were created using voxel-wise regression in SPM12, where EO and LO A-T-N_HIP- were compared to young-CN and old-CN, correcting for age, sex, and education. Results were displayed at a cluster-level FWE correction of p<0.05. Subject demographics, global cognitive, Crane cognitive composite, and biomarker measures were compared between A-T-N_HIP- groups in SPSS.

Results

Main demographic comparisons showed the expected differences in age and CDR-SB across groups. Relative to CN, both EO and LO A-T-N_HIP- showed significantly worse performance on CDR-SB (both p<0.001), memory function (EO, p=0.006; LO, p<0.001), and executive functioning (EO, p=0.02; LO, p=0.001). LO A-T-N_HIP- also showed worse performance in the language domain compared to CN (p<0.001). LO A-T-N_HIP- had significantly less total white matter volume (p<0.001) and significantly more total gray matter volume (p=0.035) when compared to CN. In the voxel-wise regression, LO A-T-N_HIP- showed a frontotemporal pattern of FDG hypometabolism, while EO A-T-N_HIP- subjects did not show significant hypometabolism relative to CN.

Conclusions

The observed frontotemporal hypometabolism in LO A-T-N_HIP- might be indicative of non-AD dementias such as late-onset frontotemporal dementia or limbic-predominant age-related TDP-43 encephalopathy (LATE).

Aims

27-hydroxycholesterol (27-OH) is the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer’s disease (AD). The current project aims at elucidating 1) Whether the 2-year multidomain lifestyle/vascular intervention FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) had an impact on 27-hydroxycholesterol (27-OH) levels; and 2) Whether change in 27-OH during the intervention was related to change in cognition and dementia-related neuroimaging markers.

Methods

The 2-year FINGER study included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in 1:1 ratio. This FINGER exploratory sub-study included 47 participants with measures of 27-OH, cognition, brain MRI, brain FDG- and PiB-PET. Linear regression models were used to assess cross-sectional and longitudinal associations between 27-OH, cognition and neuroimaging markers, considering several potential confounders/intervention effect modifiers.

Results

27-OH reduction during the intervention was associated with improvement in cognition. The intervention reduced 27-OH particularly in individuals with the highest 27-OH levels, and younger age. At baseline higher 27-OH was associated with lower total gray matter and hippocampal volume, and lower cognitive scores. These associations were unaffected by total cholesterol levels. While sex seemed to influence associations at baseline, it did not affect longitudinal associations.

Conclusions

27-OH appears to be a marker not only for dementia/AD risk, but also for monitoring the effects of preventive interventions on cholesterol metabolism.

Aims

We have developed a unique 8-amino acid Abeta42-oligomer Interacting Peptide (AIP) as a novel anti-amyloid strategy against Alzheimer disease (AD). Our lead candidate has successfully advanced from test tubes (in vitro characterization of AIP) to flies (in vivo rescue of human Abeta42-mediated toxicity via AIP-supplemented food) (Barucker 2015, Zhong 2019). Further, we validated the drug candidate AIP, i.e. testing the stability in multiple biological matrices (i.e. mouse whole blood, plasma, and liver S9 fractions) and if AIP could penetrate the blood brain barrier (BBB) of C57BL/6 (wildtype) mice.

Methods

The stability and possible degradation of the AIP was qualitatively assessed by MALDI mass spectrometry. MALDI imaging data confirmed that orally-administered AIP penetrated the BBB of both male and female wildtype mice.

Results

AIP was relatively stable over 3 hours in whole blood and in S9 liver fractions. AIP could cross the BBB of male and female wildtype mice using both intraperitoneal and oral delivery strategies. Thus, our AIP is significantly more stable compared to protease-sensitive peptides which implies its potential use as an orally administrable drug candidate against AD.

Conclusions

Based upon the unique ability of AIP to “trap” and neutralize toxic Abeta42 oligomers and the stability of AIP, AIP efficacy is currently being tested in mouse models of AD towards behavioral impairments, age-associated cognitive deficits and amyloid and/or tau pathologies.

Aims

To interrogate the metabolomic and lipidomic signatures in Alzheimer disease (AD) brain donors including sporadic AD cases, Mendelian mutation (ADAD), and TREM2 risk variant carriers.

Methods

Metabolomic and lipidomic data from parietal brain tissue from donors to the Knight ADRC and DIAN cohorts (ADAD, n=25; TREM2, n= 21; sporadic AD, n=305) and neurologically healthy controls (CO, n=27) were generated using the Metabolon global metabolomics platform. 627 metabolites passed our QC process. Associations between AD subtypes and controls were tested using linear regression models correcting for sex, age, and post-mortem interval. Age was excluded from ADAD models. Benjamini-Hochberg multiple test correction was applied. Pathway analysis was performed with MetaboAnalyst and IMPaLA.

Results

Our analyses identified 138 metabolites associated with disease status (FDR q-value<0.05). For AD brains these include tryptophan betaine (b=-0.55) and N-acetylputrescine (b=-0.14). Metabolites associated both with AD and ADAD brains include ergothioneine (b=-0.22 and -0.26 respectively) and serotonin (b=-0.34 and -0.57 respectively). TREM2 and ADAD brains show association with alpha-tocopherol (b=-0.12 and -0.12). Abundance of beta-citrylglutamate, a component of glutamate metabolism which can be increased by the SSRI fluoxetine, is associated with AD, ADAD, and TREM2 when compared to controls (b=-0.14; -0.22; and -0.29 respectively). Pathway analysis revealed associations with glutamate and serotonin metabolism.

Conclusions

Our findings suggest that AD shows distinct perturbations in various components of metabolism. Investigation of these differentially abundant metabolites may lead to greater insight into the metabolic etiology of AD and/or development of novel biomarkers for disease detection or differentiation between disease types.

Aims

Transgenic animal models have contributed immensely to the discovery of the pathological mechanisms of human neurodegenerative diseases. However, it is challenging to investigate brain functional connectivity in awake animals using the classical method of fMRI, because this requires head fixation and therefore sedation of the animal. Metabolic connectivity analysis with [¹⁸F]FDG-PET offers a way to separate the activity-dependent [¹⁸F]FDG accumulation from subsequent scanning under anesthesia, allowing to visualize neuronal networks of the awake brain. In the tauopathy mouse model rTg4510, we studied the fronto-thalamo-hippocampal network which is impaired in Alzheimer's disease (AD) patients.

Methods

Eight rTg4510 mice at ages 7–9 months and 8 non-transgenic littermates were injected intraperitoneally with 11.1±0.8 MBq [¹⁸F]FDG. The mice spent the 40-min uptake period in single cages. Subsequently, they were anesthetized and measured in a small animal PET scanner (Focus 220, Siemens) for 30min. Images were intensity-normalized to whole brain activity, and three seed-based connectivity analyses were performed per group. A seed was placed either in the frontal cortex, dorsal hippocampus or dorsal thalamus, and correlated with all other voxels of the brain across animals.

Results

In the control group, the emerging correlative pattern was the same for all three seed locations, indicating a uniform fronto-thalamo-hippocampal network. In contrast, rTg4510 mice showed a fragmentation into three distinct networks with minimal overlap.

Conclusions

We conclude that metabolic connectivity is strongly reduced in the brain of rTg4510 mice, indicating that this animal model reproduces the symptom of functional network impairment found in AD patients.