Biomarkers and phenotypic expression in Alzheimer’s disease: exploring the contribution of frailty in the Alzheimer’s Disease Neuroimaging Initiative

AbstractThe present study aimed at investigating if the main biomarkers of Alzheimer’s disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual’s frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants’ frailty status: CSF Aβ1-42, 181P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the 18F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ1-42, hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the 18F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and 18F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as “complex diseases of aging,” determined by multiple, simultaneous, and interacting pathophysiological processes.

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PET-imaging of Cerebral Glucose Metabolism and of Cerebral Beta-amyloid-deposition and Its Value for the Understanding, Early Detection and Differential Diagnosis of Alzheimer's Disease

European Psychiatry ◽

10.1016/s0924-9338(15)31823-x ◽

2015 ◽

Vol 30 ◽

pp. 25

Author(s):

A. Gietl

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Glucose Metabolism ◽

Early Detection ◽

Pet Imaging ◽

Beta Amyloid ◽

Amyloid Deposition ◽

Cerebral Glucose Metabolism

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O3-06-05: Amyloid deposition and cerebral glucose metabolism in Alzheimer's disease: A longitudinal 11 C-PIB and 18 F-FDG PET study

Alzheimer s & Dementia ◽

10.1016/j.jalz.2006.05.236 ◽

2006 ◽

Vol 2 ◽

pp. S66-S66

Author(s):

Paul Edison ◽

Aren Okello ◽

Hilary Archer ◽

Rainer Hinz ◽

Nick Fox ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Fdg Pet ◽

Amyloid Deposition ◽

Cerebral Glucose Metabolism

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Crossed Cerebellar Diaschisis in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205015666180913102615 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1267-1275 ◽

Cited By ~ 1

Author(s):

F.E. Reesink ◽

D. Vállez García ◽

C.A. Sánchez-Catasús ◽

D.E. Peretti ◽

A.T. Willemsen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Left Hemisphere ◽

Pet Imaging ◽

Fdg Pet ◽

Pathophysiological Mechanism ◽

Crossed Cerebellar Diaschisis ◽

Amyloid Accumulation ◽

Cerebellar Diaschisis ◽

18F Fdg

Background: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer’s disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. Methods: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. Results: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. Conclusion: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

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Topographic patterns of white matter hyperintensities are associated with multimodal neuroimaging biomarkers of Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00759-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Malo Gaubert ◽

Catharina Lange ◽

Antoine Garnier-Crussard ◽

Theresa Köbe ◽

Salma Bougacha ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Glucose Metabolism ◽

Corpus Callosum ◽

Gray Matter ◽

Fdg Pet ◽

White Matter Hyperintensities ◽

Gray Matter Volume ◽

Matter Volume

Abstract Background White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

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The Transition of Mild Cognitive Impairment Over Time: An AV45- and FDG-PET Study of Reversion and Conversion Phenomena

Current Alzheimer Research ◽

10.2174/1567205018666211124110710 ◽

2021 ◽

Vol 18 ◽

Author(s):

Amir Ashraf-Ganjouei ◽

Kamyar Moradi ◽

Shahriar Faghani ◽

AmirHussein Abdolalizadeh ◽

Mohammadreza Khomeijani-Farahani ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Glucose Metabolism ◽

Pet Imaging ◽

Fdg Pet ◽

Amyloid Β ◽

Positron Emission ◽

One Year ◽

T Tau ◽

Over Time

Background: Mild cognitive impairment (MCI) is a state between normal cognition and dementia. However, MCI diagnosis does not necessarily guarantee the progression to dementia. Since no previous study investigated brain positron emission tomography (PET) imaging of MCI-- to-normal reversion, we provided PET imaging of MCI-to-normal reversion using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Methods: We applied comprehensive neuropsychological criteria (NP criteria), consisting of mem- ory, language, and attention/executive function domains, to include patients with a baseline diagno- sis of MCI (n=613). According to the criteria, the year 1 status of the patients was categorized into three groups (reversion: n=105, stable MCI: n=422, conversion: n=86). Demographic, neuropsycho- logical, genetic, CSF, and cognition biomarker variables were compared between the groups. Addi- tionally, after adjustment for confounding variables, the deposition pattern of amyloid-β and cere- bral glucose metabolism were compared between three groups via AV45- and FDG-PET modali- ties, respectively. Results: MCI reversion rate was 17.1% during one year of follow-up. The reversion group had the lowest frequency of APOE ε4+ subjects, the highest CSF level of amyloid-β, and the lowest CSF levels of t-tau and p-tau. Neuropsychological assessments were also suggestive of better cognitive performance in the reversion group. Patients with reversion to normal state had higher glucose metabolism in bilateral angular and left middle/inferior temporal gyri, when compared to those with stable MCI state. Meanwhile, lower amyloid-β deposition at baseline was observed in the fron- tal and parietal regions of the reverted subjects. On the other hand, the conversion group showed lower cerebral glucose metabolism in bilateral angular and bilateral middle/inferior temporal gyri compared to the stable MCI group, whereas the amyloid-β accumulation was similar between the groups. Conclusions: This longitudinal study provides novel insight regarding the application of PET imag- ing in predicting MCI transition over time.

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