Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene

Valla, Jon; Yaari, R.; Wolf, Andrew B.; Kusne, Yael; Beach, Thomas G.; Roher, Alex E.; Corneveaux, Jason J.; Huentelman, Matthew J.; Caselli, Richard J.; Reiman, Eric M.

doi:10.3233/jad-2010-100129

Cited by 138 publications

(121 citation statements)

References 34 publications

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“…Resting glucose metabolism reduction in brain regions affected by AD pathology, such as the parietal, temporal, and prefrontal cortices [14], decreased fractional anisotropy values and increase in mean duffusivity values [15], as well as alterations in activation patterns [16] and lower mitochondrial cytochrome oxidase activity [17] were reported in healthy adults possessing the 4 allele. The absence of differences in memory function between 4 and 2 carriers in our study and between 4 carriers and non-carriers in previous studies [5,16] implies that the brain preserves enough redundancy and efficiency at young age to avoid decline in clinical cognitive performance despite the presence of neural perturbations in healthy young individuals with the 4 allele.…”

Section: Discussionmentioning

confidence: 97%

Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Alexopoulos

Richter‐Schmidinger

Horn

et al. 2011

JAD

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Abstract.The apolipoprotein E (APOE) 4 allele is the major genetic risk factor for the development of late-onset Alzheimer's disease (AD), whereas the presence of the APOE 2 allele seems to confer protection. Here, we report that healthy young APOE 4 carriers have statistically significantly smaller hippocampal volumes than APOE 2 carriers, while no differences were detected between the two groups in memory performance. The difference in hippocampal morphology is cognitively/clinically silent in young adulthood, but could render APOE 4 carriers more prone to the later development of AD possibly due to lower reserve cognitive capacity.

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Section: Discussionmentioning

confidence: 97%

Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Alexopoulos

Richter‐Schmidinger

Horn

et al. 2011

JAD

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“…The DMN has also been shown to heavily rely on aerobic glycolysis (i.e., glucose use in excess of that used for oxidative phosphorylation), even more than other brain regions that also show high levels of energy consumption (e.g., visual cortex) (36,37). Neurons from PCC within the DMN show reduced mitochondrial activity in young adults carrying the apolipoprotein E4 gene, reflected by lower mitochondrial cytochrome oxidase activity (38) and lower expression of genes that encode subunits of the mitochondrial electron transport chain in AD compared with controls (35). The DMN may therefore represent a network in which amyloid deposition converges with metabolic vulnerability, rendering it susceptible to early neurodegeneration in AD.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Lehmann

Madison

Ghosh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

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Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular accumulation of amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss (1). Although most patients present with memory deficits, a significant minority of patients with AD present with nonamnestic syndromes (2, 3). Patients with nonfamilial early-onset AD (EOAD, defined as onset <65 y in most studies) often show heterogeneous cognitive deficits, including impairment in attention and executive functions (4, 5). Focal syndromes such as posterior cortical atrophy (PCA, characterized by predominant visuospatial and visuoperceptual deficits; ref. 6) and the logopenic variant of primary progressive aphasia [lvPPA, a progressive disorder of language (7,8)] are also most commonly caused by AD pathology. It has been suggested that up to 15% of patients with AD seen in dementia centers have nonamnestic presentations (2), and the importance of these syndromes is reflected in their inclusion in new diagnostic guidelines for AD (9, 10). The factors driving the clinicoanatomical heterogeneity in AD are not well understoo...

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“…For example, early decreases in brain metabolic activity can be detected in patients at risk of developing Alzheimer's disease, especially reductions in cytochrome oxidase activity. 100,101 Similarly, the phenotypic expression of mood disorders such as major depression and post-traumatic stress disorder have been shown to be associated with decreased metabolic capacity in prefrontal brain regions, 102 and electrical stimulation of prefrontal cortex has antidepressant effects. 103 LLLT is expected to enhance the metabolic capacity in those regions showing functional deficits, thus increasing the functional connectivity of the networks involved in the expression of a particular phenotype.…”

Section: Cognition and Emotional Statesmentioning

confidence: 99%

Low-level light therapy of the eye and brain

Rojas¹,

González-Lima²

2011

104

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Low-level light therapy (LLLT) using red to near-infrared light energy has gained attention in recent years as a new scientific approach with therapeutic applications in ophthalmology, neurology, and psychiatry. The ongoing therapeutic revolution spearheaded by LLLT is largely propelled by progress in the basic science fields of photobiology and bioenergetics. This paper describes the mechanisms of action of LLLT at the molecular, cellular, and nervous tissue levels. Photoneuromodulation of cytochrome oxidase activity is the most important primary mechanism of action of LLLT. Cytochrome oxidase is the primary photoacceptor of light in the red to near-infrared region of the electromagnetic spectrum. It is also a key mitochondrial enzyme for cellular bioenergetics, especially for nerve cells in the retina and the brain. Evidence shows that LLLT can secondarily enhance neural metabolism by regulating mitochondrial function, intraneuronal signaling systems, and redox states. Current knowledge about LLLT dosimetry relevant for its hormetic effects on nervous tissue, including noninvasive in vivo retinal and transcranial effects, is also presented. Recent research is reviewed that supports LLLT potential benefits in retinal disease, stroke, neurotrauma, neurodegeneration, and memory and mood disorders. Since mitochondrial dysfunction plays a key role in neurodegeneration, LLLT has potential significant applications against retinal and brain damage by counteracting the consequences of mitochondrial failure. Upon transcranial delivery in vivo, LLLT induces brain metabolic and antioxidant beneficial effects, as measured by increases in cytochrome oxidase and superoxide dismutase activities. Increases in cerebral blood flow and cognitive functions induced by LLLT have also been observed in humans. Importantly, LLLT given at energy densities that exert beneficial effects does not induce adverse effects. This highlights the value of LLLT as a novel paradigm to treat visual, neurological, and psychological conditions, and supports that neuronal energy metabolism could constitute a major target for neurotherapeutics of the eye and brain.

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Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene

Cited by 138 publications

References 34 publications

Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Low-level light therapy of the eye and brain

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