Laura D. Baker, PhD; Donna J. Cross, PhD; Satoshi Minoshima, MD, PhD; et al.
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Arch Neurol. 2011;68(1):51-57. doi:10.1001/archneurol.2010.225
BackgroundInsulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fludeoxyglucose F 18–positron emission tomography (FDG-PET) in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.ObjectivesTo examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task.DesignRandomized crossover design of resting and activation FDG-PET.SettingUniversity imaging center and Veterans Affairs clinical research unit.ParticipantsTwenty-three older adults (mean [SEM] age, 74.4 [1.4] years) with no prior diagnosis of diabetes but who met American Diabetes Association glycemic criteria for PD (n = 11) or diabetes (n = 12) based on fasting or 2-hour oral glucose tolerance test (OGTT) glucose values and 6 adults (mean [SEM] age, 74.3 [2.8] years) with normal fasting glucose values and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment.InterventionsFasting participants underwent resting and cognitive activation FDG-PET imaging on separate days. Following a 30-minute transmission scan, subjects received an intravenous injection of 5 mCi of FDG, and the emission scan commenced 40 minutes after injection. In the activation condition, a 35-minute memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words randomly presented in series through earphones. Delayed free recall was assessed once the emission scan was complete.Main Outcome MeasuresThe HOMA-IR value was calculated using fasting glucose and insulin values obtained during OGTT screening and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding activation scan to examine task-related patterns of CMRglu.ResultsGreater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-hour OGTT glucose concentration, or apolipoprotein E ε4 allele carriage. During the memory encoding task, healthy adults showed activation in right anterior and inferior prefrontal cortices, right inferior temporal cortex, and medial and posterior cingulate regions. Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.ConclusionsInsulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment.
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Editorial
Should We Target Insulin Resistance to Prevent Dementia Due to Alzheimer Disease?
José A. Luchsinger, MD; Scott Small, MD; Geert-Jan Biessels, MD
Arch Neurol
Lon S. Schneider, MD, MS; Philip S. Insel, MS; Michael W. Weiner, MD; et al.
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Arch Neurol. 2011;68(1):58-66. doi:10.1001/archneurol.2010.343
Raffaele Lodi, MD; Caterina Tonon, MD; Maria Lucia Valentino, MD; et al.
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Arch Neurol. 2011;68(1):67-73. doi:10.1001/archneurol.2010.228
ObjectiveTo assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene.DesignWe used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis.SettingUniversity neuromuscular and neurogenetics and magnetic resonance imaging units.PatientsEighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haploinsufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy.Main Outcome MeasuresPresence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis.ResultsPhosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (−24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (−36%; P < .001; ranging from −28% to −49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies.ConclusionsDefective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1 -related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies.
Carlos D. Marquez de la Plata, PhD; Juanita Garces, BS; Ehsan Shokri Kojori, MSc; et al.
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Arch Neurol. 2011;68(1):74-84. doi:10.1001/archneurol.2010.342
Shyam Prabhakaran, MD, MS; Sohal K. Patel, MD; Jordan Samuels, MD; et al.
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Arch Neurol. 2011;68(1):85-89. doi:10.1001/archneurol.2010.320
Angela Nervi, MD; Christiane Reitz, MD, PhD; Ming-Xin Tang, PhD; et al.
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Arch Neurol. 2011;68(1):90-93. doi:10.1001/archneurol.2010.319
Julie Azoulay-Zyss, MD; Emmanuel Roze, MD, PhD; Marie-Laure Welter, MD, PhD; et al.
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Arch Neurol. 2011;68(1):94-98. doi:10.1001/archneurol.2010.338
Christiane Reitz, MD, PhD; Rong Cheng, PhD; Ekaterina Rogaeva, PhD; et al.
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Arch Neurol. 2011;68(1):99-106. doi:10.1001/archneurol.2010.346
Nathalie Jetté, MD, MSc; Lisa M. Lix, PhD; Colleen J. Metge, PhD; et al.
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Arch Neurol. 2011;68(1):107-112. doi:10.1001/archneurol.2010.341
Ozioma C. Okonkwo, PhD; Michelle M. Mielke, PhD; H. Randall Griffith, PhD; et al.
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Arch Neurol. 2011;68(1):113-119. doi:10.1001/archneurol.2010.334