Dataset Information

Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer's disease.

ABSTRACT: The interplay among neuropathological mechanisms underlying Alzheimer's disease (AD), as neuroinflammation and amyloid-beta (Aβ), as well their impact on neuronal function remains elusive. A major gap in knowledge is the functional impact of neuroinflammation. The posterior cingulate cortex (PCC), as the most prominent site of amyloid pathology in AD, is a pivotal region to investigate the concomitant presence of pathophysiological mechanisms such as microglia activation, indexing neuroinflammation, and changes in task related activity. Here we used a dual PET approach to simultaneously study Aβ load and neuroinflammation (TSPO uptake marker), using ¹¹C-PiB and ¹¹C-PK11195 radiotracers, respectively and fMRI to study task related neural activation in an AD sample (n = 19) and matched controls (n = 19). Here we show significantly increased Aβ deposition, neuroinflammation and brain activity related to a visual object working memory task in this key region. Microglia activation was associated with increased brain activity specifically in patients, independently of amyloid binding, raising the possibility that abnormal brain activity might be restored in clinical trials aimed at reducing microglia activation.

SUBMITTER: Canario N

PROVIDER: S-EPMC9365841 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer's disease.

Canário Nádia N Jorge Lília L Martins Ricardo R Santana Isabel I Castelo-Branco Miguel M

Communications biology 20220810 1

The interplay among neuropathological mechanisms underlying Alzheimer's disease (AD), as neuroinflammation and amyloid-beta (Aβ), as well their impact on neuronal function remains elusive. A major gap in knowledge is the functional impact of neuroinflammation. The posterior cingulate cortex (PCC), as the most prominent site of amyloid pathology in AD, is a pivotal region to investigate the concomitant presence of pathophysiological mechanisms such as microglia activation, indexing neuroinflammat ...[more]

PMID: 35948611

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Project description:BACKGROUND:The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated ?-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease. METHODS:Forty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine ?-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years. RESULTS:Those MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their ?-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising ?-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation. CONCLUSIONS:Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising ?-amyloid load show correlated levels of microglial activation which then later decline when the ?-amyloid load approaches AD levels. Later, as tau tangles form in ?-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.

Project description:Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

Dataset Information

Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer's disease.

Publications

Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer's disease.

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