Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

Ramanan, Vijay K.; Przybelski, Scott A.; Graff‐Radford, Jonathan; Castillo, Anna; Lowe, Val J.; Mielke, Michelle M.; Roberts, Rosebud O.; Reid, Robert I.; Knopman, David S.; Jack, Clifford R.; Petersen, Ronald C.; Vemuri, Prashanthi

doi:10.3233/jad-180446

Cited by 27 publications

(36 citation statements)

References 56 publications

(54 reference statements)

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“…Diffusion tensor imaging (DTI) sequences were processed and analyzed for fractional anisotropy (FA) of the corpus callosum. 23 Loss of white matter microstructural integrity measured using DTI is a good indicator of axonal injury. We used FA in the corpus callosum as an imaging marker of axonal damage, which has previously been shown to be a sensitive measure of axonal injury.…”

Section: Methodsmentioning

confidence: 99%

Plasma and CSF neurofilament light

et al. 2019

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ObjectiveWe aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes.MethodsSeventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression.ResultsThere were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET.ConclusionElevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change.

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Section: Methodsmentioning

confidence: 99%

Plasma and CSF neurofilament light

et al. 2019

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“…While associations have been found between vascular dementia and blood lipid levels, the same has not been demonstrated for AD [400,401]. Additionally, treatment with lipid-lowering drugs has been found not to influence AD risk [401,402]. Cross-sectional studies have found that high cholesterol is associated with some features of AD such as neuritic plaques, but not NFT pathology [403].…”

Section: Systemic Vascular Health and Dementia Riskmentioning

confidence: 99%

Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

Govindpani

McNamara

Smith

et al. 2019

JCM

162

142

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Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

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“…Our findings also reveal the importance of elucidating the role of cholesterol biosynthesis in adult myelin maintenance as this may have implications for long-term use of cholesterol-lowering drugs in humans. Indeed, there is evidence that patients taking statins, which can cross the blood-brain barrier, have lower fractional anisotropy, indicating deficits in white matter integrity, than statin-untreated individuals 44 . Further studies will be necessary to determine neurological effects of long-term use statin treatment.…”

Section: Discussionmentioning

confidence: 99%

Single-cell Sequencing Reveals Brain/Spinal Cord Oligodendrocyte Precursor Heterogeneity and Requirement for mTOR in Cholesterol Biosynthesis and Myelin Maintenance

Khandker

Jeffries

Chang

et al. 2020

Preprint

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Brain and spinal cord oligodendroglia have distinct functional characteristics, and cell autonomous loss of individual genes can result in different regional phenotypes. However, sequencing studies to date have not revealed distinctions between brain and spinal cord oligodendroglia. Using single-cell analysis of oligodendroglia during myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis. We further identify mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglial-specific loss of mTOR compromises cholesterol biosynthesis in both the brain and spinal cord. Importantly, mTOR loss has a greater impact on cholesterol biosynthesis in spinal cord oligodendroglia that corresponds with more pronounced developmental deficits. However, loss of mTOR in brain oligodendroglia ultimately results in oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain.

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Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

Cited by 27 publications

References 56 publications

Plasma and CSF neurofilament light

Plasma and CSF neurofilament light

Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

Single-cell Sequencing Reveals Brain/Spinal Cord Oligodendrocyte Precursor Heterogeneity and Requirement for mTOR in Cholesterol Biosynthesis and Myelin Maintenance

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