Volume 31, Number 2, August 2012

Pages 243-251
Barbara Borroni, Marta Bianchi, Enrico Premi, Antonella Alberici, Silvana Archetti, Barbara Paghera, Carlo Cerini, Alice Papetti, Alessandro Padovani (Handling Associate Editor: Miryam Carecchio)
The Brain-Derived Neurotrophic Factor Val66Met Polymorphism is Associated with Reduced Hippocampus Perfusion in Frontotemporal Lobar Degeneration
Abstract: Brain-derived neurotrophic factor (BDNF) promotes several functions in neurons and modulates neurotransmissions, especially in hippocampal regions. Frontotemporal lobar degeneration (FTLD) has a strong genetic background, but genetic risk factors associated with sporadic disease are unknown. Hippocampal involvement is frequently observed in FTLD. The aims of this study were: i) to evaluate if BDNF genetic variations are associated with an increased risk of developing FTLD; and ii) to assess the neuroimaging profiles associated with BDNF polymorphisms. Ninety-one FTLD patients who underwent SPECT imaging and blood sampling entered the study, and clinical, cognitive, and behavioral examinations were performed. A larger group of FTLD patients (n=194) and controls (n=396; 162 healthy subjects and 234 Alzheimer’s disease (AD) patients) underwent genetic analyses, considering BDNF polymorphisms (Val66Met, rs2049045 C/G, G11757C). A significant different distribution of G11757C genotype in FTLD (GG 53.1%, GC 42.8%, CC 4.1%) compared to controls (G/G 55.6%, G/C 34.6%, C/C 9.8%, p=0.020) was found. No other significant differences in genotype and allele distributions were detected. The effect of BDNF polymorphisms on brain perfusion was analyzed. BDNF Val66Met A* carriers (A/A or G/A) showed a significant greater hypoperfusion parahippocampal regions as compared to G/G carriers (p<0.005). No effect of G11757C polymorphism on brain perfusion was found. rs2049045 C/G was not considered as in linkage disequilibrium with Val66Met polymorphism. BDNF Val66Met polymorphism may play a role as a modulator of the FTLD expression and may drive a selective damage in specific brain region affected by the disease.

Pages 253-258
Feng-Jiao Li, Liang Shen, Hong-Fang Ji
Dietary Intakes of Vitamin E, Vitamin C, and β-Carotene, and Risk of Alzheimer’s Disease: A Meta-Analysis
Abstract: In view of the vital role of oxidative stress in the pathogenesis of Alzheimer’s disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants vitamin E, vitamin C, and β-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. According to the pooled relative risk [(95% CI) 0.76 (0.67–0.84) for vitamin E, 0.83 (0.72–0.94) for vitamin C, and 0.88 (0.73–1.03) for β-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD.

Pages 259-263
Manon Brundel, Sophie M. Heringa, Jeroen de Bresser, Huiberdina L. Koek, Jaco J.M. Zwanenburg, L. Jaap Kappelle, Peter R. Luijten, Geert Jan Biessel
High Prevalence of Cerebral Microbleeds at 7Tesla MRI in Patients with Early Alzheimer’s Disease
Abstract: The prevalence of microbleeds on magnetic resonance imaging (MRI) in patients with Alzheimer’s disease (AD) is lower than that of its presumed pathological correlate, cerebral amyloid angiopathy. We examined 18 patients with early AD or mild cognitive impairment (MCI) and 18 non-demented controls with ultra-high field strength 7Tesla MRI, to assess if the actual prevalence of microbleeds could be higher than is currently reported. One or more microbleeds were visualized in 78% of the MCI/AD patients and in 44% of the controls (p=0.04). 7Tesla MRI shows that presence of microbleeds may be the rule, rather than exception in patients with MCI/AD.

Pages 265-275
Kyle Steenland, Conny Karnes, Ryan Seals, Claudine Carnevale, Adrian Hermida, Allan Levey
Late-Life Depression as a Risk Factor for Mild Cognitive Impairment or Alzheimer’s Disease in 30 US Alzheimer’s Disease Centers
Abstract: Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer’s Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer’s disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score ≥5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR=2.35; 95% CI 1.93-3.08) versus never depressed normal subjects, identified as depressed at first visit but subsequently improved, who were found to have lower risk of progression (RR 1.40 (1.01-1.95)). The ‘always depressed’ had only a modest increased risk of progression from MCI to AD (RR=1.21 (1.00-1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI.

Pages 277-283
Panagiotis Zis, Mark Dickinson, Sima Shende, Zuzana Walker, Andre Strydom
Oxidative Stress and Memory Decline in Adults with Down Syndrome: Longitudinal Study
Abstract: By the age of 40, virtually all patients with Down syndrome (DS) have neuropathological changes characteristic of Alzheimer’s disease (AD). The aim of our study was to investigate whether the levels of superoxide dismutase enzymes (SOD), glutathione peroxidase (GPx), or their ratio could predict cognitive decline in people with DS over a 4-year period. Thirty-two adults with DS participated in a longitudinal study with SOD and GPx assays at baseline. Informants rated their functional ability and memory function at baseline and at 4 years follow-up. The more able adults with DS also completed assessments of language skills and memory, at two different time points 4 years apart. Twenty-six individuals with DS completed assessments of memory (Modified Memory Object Task, MOMT), adaptive behavior (ABAS), and receptive vocabulary (British Picture vocabulary, BPVS) at both time-points. SOD positively correlated with change on the MOMT score (r = 0.578, p =0.015). There were no significant correlations between GPx level or SOD/GPx ratio and temporal changes in ABAS, BPVS, or MOMT scores. Our results suggest that SOD predicts memory decline over time and that these antioxidant enzymes could be a potential target for prevention of memory deterioration in adults with DS. Further research is required to test whether supplements which improve SOD function can also prevent cognitive decline. These findings may also have implications for prevention of cognitive decline in other groups which are at high risk of developing dementia, such as adults with familial AD or mild cognitive impairment.

Pages 285-300
Selene Lomoio, Irene López-González, Ester Aso, Margarita Carmona, Benjamín Torrejón-Escribano, Elda Scherini, Isidro Ferrer (Handling Associate Editor: Irina Alafuzoff)
Cerebellar Amyloid-β Plaques: Disturbed Cortical Circuitry in AβPP/PS1 Transgenic Mice as a Model of Familial Alzheimer’s Disease
Abstract: Cerebellar amyloid-β (Aβ) deposition in the form of neuritic plaques and Purkinje cell loss are common in certain pedigrees of familial Alzheimer’s disease (FAD) mainly linked to PS1 mutations. AβPP/PS1 transgenic mice, here used as a model of FAD, show a few Aβ plaques in the molecular layer of the cerebellum at 6 months, and which increase in number with age. Motor impairment is apparent in transgenic mice aged 12 months. Combined methods have shown degenerated parallel fibers as the main component of dystrophic neurites of Aβ plaques, loss of synaptic contacts between parallel fibers and dendritic spines of Purkinje cells, and degeneration of granule cells starting at 12 months and increasing in mice 18/20 months old. In addition, abnormal mitochondria and focal loss of Purkinje and basket cells, together with occasional axonal torpedoes and increased collaterals of Purkinje cells in mice aged 18/20 months, is suggested to be a concomitant defect presumably related to soluble extracellular or intracellular Aβ. These observations demonstrate serious deterioration of the neuronal circuitry in the cerebellum of AβPP/PS1 transgenic mice, and they provide support for the interpretation of similar alterations occurring in certain pedigrees with FAD.

Pages 301-313
Lap Ho*, Wei Zhao*, Kristen Dams-O’Connor, Cheuk Y. Tang, Wayne Gordon, Elaine R. Peskind, Shrishailam Yemul, Vahram Haroutunian, Giulio Maria Pasinetti *These authors contributed equally to this work.
Elevated Plasma MCP-1 Concentration Following Traumatic Brain Injury as a Potential “Predisposition” Factor Associated with an Increased Risk for Subsequent Development of Alzheimer’s Disease
Abstract: We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer’s disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer’s disease.

Pages 315-323
Chi Hun Kim, Sang Won Seo, Geon Ha Kim, Ji Soo Shin, Hanna Cho, Young Noh, Suk-Hui Kim, Min Ji Kim, Seun Jeon, Uicheul Yoon, Jong-Min Lee, Seung Jun Oh, Jae Seung Kim, Sung Tae Kim, Jae-Hong Lee, Duk L. Na
Cortical Thinning in Subcortical Vascular Dementia with Negative 11C-PiB PET
Abstract: To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11C-Pittsburgh compound B (PiB) positron emission tomography scan and to compare the topography of cortical thinning between PiB-negative SVaD and Alzheimer’s disease (AD), we enrolled 24 patients with PiB(-) SVaD, 81 clinically probable AD individuals, and 72 normal cognitive controls. Compared with controls, cortical thinning in PiB(-) SVaD was most profound in the perisylvian area, medial prefrontal area, and posterior cingulate gyri, while the precuneus and medial temporal lobes were relatively spared. When the cortical thickness of AD and PiB(-) SVaD were directly compared, PiB(-) SVaD demonstrated significant cortical thinning in the bilateral inferior frontal, superior temporal gyri, and right medial frontal and orbitofrontal lobes, while AD showed significant cortical thinning in the right medial temporal region. SVaD without amyloid burden may lead to substantial cortical atrophy. Moreover, characteristic topography of cortical thinning in PiB(-) SVaD suggests different mechanisms of cortical thinning in PiB(-) SVaD and AD.

Pages 325-334
Michel Benoit, Gilles Berrut, Johanna Doussaint, Serge Bakchine, Sylvie Bonin-Guillaume, Patrick Frémont, Thierry Gallarda, Pierre Krolak-Salmon, Thierry Marquet, Claude Mékiès, François Sellal, Stéphane Schuck, Renaud David, Philippe Robert
Apathy and Depression in Mild Alzheimer’s Disease: A Cross-Sectional Study using Diagnostic Criteria
Abstract: Apathy and depression are the most frequent neuropsychiatric symptoms in Alzheimer’s disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders. According to the specific diagnostic criteria, depression had a 47.9% prevalence, while apathy prevalence was 41.6%. Apathy and depression were associated in 32.4% of patients (n = 225). 9.4% (n=65) had only apathy, 15.4% (n=107) had only depression, and 42.9% had no apathy and no depression (n=298). The three most frequent depressive symptoms were fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%), and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition was the most frequently altered (63.6%), followed by loss of goal-directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently required a resource allowance for dependency. Neurological comorbidities were more frequent in the “apathy and depression” and “depression alone” groups (p<0.001). Apathy and depression overlap considerably, and this might be explained by the presence of some non-specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria.

Pages 335-341
Erik Portelius, Henrik Zetterberg, Robert A. Dean, Alexandre Marcil, Philippe Bourgeois, Magdalena Nutu, Ulf Andreasson, Eric Siemers, Kwasi G. Mawuenyega, Wendy C. Sigurdson, Patrick C. May, Steven M. Paul, David M. Holtzman, Kaj Blennow, Randall J. Bateman
Amyloid-β1-15/16 as a Marker for γ-Secretase Inhibition in Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer’s disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ1-15 is produced by concerted β- and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ1-15/16 represent a biomarker for this effect. Twenty healthy men were treated with placebo (n=5) or the γ-secretase inhibitor semagacestat (100 mg [n=5], 140 mg [n=5], or 280 mg [n=5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ1-15/16, Aβx-38, Aβx-40, Aβx-42, sAβPPα, and sAβPPβ. The CSF concentration of Aβ1-15/16 showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβx-38, Aβx-40, and Aβx-42 decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ1-15/16 increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.

Pages 343-358
Lotta Agholme, Martin Hallbeck , Eirikur Benedikz, Jan Marcusson, Katarina Kågedal
Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy
Abstract: The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer’s disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

Supplementary Data for Agholme et al. article (PDF)

Pages 359-369
Feng Xu, Michael P. Vitek, Carol A. Colton, Mary Lou Previti, Judianne Davis, William E. Van Nostrand (Handling Associate Editor: Marcel Verbeek)
Human Apolipoprotein E2 Promotes Parenchymal Amyloid Deposition and Neuronal Loss in Vasculotropic Mutant Amyloid-β Protein Tg-SwDI Mice
Abstract: Human apolipoprotein (ApoE) genotype influences the development of Alzheimer’s disease and cerebral amyloid angiopathy (CAA), where the ε4 allele increases and the ε2 allele decreases the risk for developing disease. Specific mutations within the amyloid-β (Aβ) peptide have been identified that cause familial forms of CAA. However, the influence of APOE genotype on accumulation of CAA mutant Aβ in brain is not well understood. Earlier, we showed that human ApoE4 redistributes fibrillar amyloid deposition from the cerebral microvasculature to parenchymal plaques in Tg-SwDI mice, a model that accumulates human Dutch/Iowa (E22Q/D23N) CAA mutant Aβ in brain (Xu et al., J Neurosci 28, 5312-5320, 2008). Human ApoE2 can reduce Aβ pathology in transgenic models of parenchymal plaques. Here we determined if human ApoE2 can influence the location and severity of amyloid pathology in Tg-SwDI mice. Comparing Tg-SwDI mice bred onto a human APOE2/2 or human APOE4/4 background, we found there was no change in the brain levels of total Aβ40 and Aβ42 compared to mice on the endogenous mouse APOE background. In Tg-SwDI mice on either human APOE background, there was a similarly strong reduction in the levels of microvascular CAA and emergence of extensive parenchymal plaque amyloid. In both Tg-SwDI-hAPOE2/2 and Tg-SwDI-hAPOE4/4 mice, the distribution of ApoE proteins and neuronal loss were associated with parenchymal amyloid plaques. These findings suggest that compared with human ApoE4, human ApoE2 does not beneficially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice.

Pages 371-386
Tiffany Rideaux, Sherry A. Beaudreau, Senaida Fernandez, Ruth O'Hara
Utility of the Abbreviated Fuld Object Memory Evaluation and MMSE for Detection of Dementia and Cognitive Impairment Not Dementia in Diverse Ethnic Groups
Abstract: To address the growing need for ethnically unbiased cognitive screening, we examined whether the Mini Mental State Exam (MMSE), the abbreviated Fuld Object Memory Evaluation (FOME), or a combination of the two provided optimal detection of dementia in an ethnically diverse group of older adults with no cognitive impairment (normal); cognitive impairment not dementia (CIND); and dementia. Participants included 509 Caucasians, 124 African Americans, and 68 Latinos (>70 years old) from the Aging, Demographics, and Memory Study who completed the MMSE and FOME. Empirically derived decision trees were computed using signal detection software for receiver operator characteristics (ROC). Among the three ethnic groups, ROC analyses revealed that lower scores on both the MMSE and FOME provided better detection of CIND or dementia. Sensitivity and specificity of the MMSE was augmented by the addition of the FOME among Caucasian and African American older adults. The MMSE alone was the best screen in Latino older adults to distinguish any cognitive impairment from normal. However, when comparing CIND versus dementia, the FOME alone was best for detecting dementia among Latinos. The abbreviated FOME is recommended to increase clinical validity and thus minimize ethnic biases when administering the MMSE to Caucasian and African American older adults. The MMSE alone is preferred for older Latinos unless comparing CIND and dementia, in which case the FOME alone would then be recommended. Findings suggest that ethnicity is important in the selection of an appropriate cognitive screen and cut-score to use with older adults.

Pages 387-399
Alessandra Marcone*, Valentina Garibotto*, Rosa Maria Moresco, Ioana Florea, Andrea Panzacchi, Assunta Carpinelli, Jere R. Virta, Marco Tettamanti, Barbara Borroni, Alessandro Padovani, Alessandra Bertoldo, Karl Herholz, Juha O. Rinne, Stefano Francesco Cappa, Daniela Perani (Handling Associate Editor: Agneta Nordberg) *These authors contributed equally to this work.
[11C]-MP4A PET Cholinergic Measurements in Amnestic Mild Cognitive Impairment, Probable Alzheimer’s Disease, and Dementia with Lewy Bodies: A Bayesian Method and Voxel-Based Analysis
Abstract: Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer’s disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.

Pages 401-410
Brenna Cholerton, Laura D. Baker, Emily H. Trittschuh, Paul K. Crane, Eric. B. Larson, Matthew Arbuckle, Hector Hernandez, Susan M. McCurry, James D. Bowen, Wayne C. McCormick, Suzanne Craft
Insulin and Sex Interactions in Older Adults with Mild Cognitive Impairment
Abstract: Alzheimer’s disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ε4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype.

Pages 411-420
Henry Brodaty, Megan Heffernan, Brian Draper, Simone Reppermund, Nicole Kochan, Melissa J. Slavin, Julian N. Trollor, Perminder S. Sachdev (Handling Associate Editor: Katie Palmer)
Neuropsychiatric Symptoms in Older People with and without Cognitive Impairment
Abstract: Neuropsychiatric symptoms (NPS) are non-cognitive disturbances such as depression. Rates of NPS have been shown to increase as cognitive ability declines and may be useful in predicting transition from mild cognitive impairment (MCI) to dementia. This community-based study reports the association between NPS and cognitive decline over two years. Participants included 873 community dwelling adults aged 70-90 years enrolled in the Sydney Memory and Ageing Study. NPS were assessed by the Neuropsychiatric Inventory (NPI). Cognitive impairment was defined by diagnosis (MCI or incident dementia) or neuropsychological test performance across five cognitive domains. Cognitive decline was defined by progression to dementia or worse neuropsychological performance. Total NPS at baseline did not differ between those without cognitive impairment (26.2%) and those with MCI (28.8%), but agitation and apathy were associated with MCI. Only baseline depression was associated with dementia at follow-up. Total NPS at baseline was cross-sectionally associated with cognitive impairment in executive function, attention, and global cognition, but did not predict cognitive decline. Depression, anxiety, agitation, anxiety, and apathy were all associated with impairment in at least one cognitive domain, but only anxiety and agitation were significantly associated with cognitive decline. Sensitivity analyses applied more stringent criteria for NPS and cognitive impairment in MCI but did not alter interpretation of results from the main analysis. Overall rates of NPS at baseline were not associated with MCI, dementia, or cognitive decline over two years. Additional follow-up is needed to further examine this association over a longer time course.

Supplementary Data for Brodaty et al. article (PDF)

Pages 421-428
Kenji Kamogawa, Katsuhiko Kohara, Yasuharu Tabara, Rie Takita, Tetsuro Miki, Tomoko Konno, Saori Hata, Toshiharu Suzuki
Potential Utility of Soluble p3-Alcadeinα Plasma Levels as a Biomarker for Sporadic Alzheimer’s Disease
Abstract: Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer’s disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18-1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD.

Supplementary Data for Kamogawa et al. article (PDF)

Pages 429-437
James R. Hall, Leigh A. Johnson, Robert C. Barber, Hoa T. Vo, A. Scott Winter, Sid E. O’Bryant for the Texas Alzheimer’s Research and Care Consortium (Handling Associate Editor: Sindre Rolstad)
Biomarkers of Basic Activities of Daily Living in Alzheimer’s Disease
Abstract: Functional impairment is common in Alzheimer’s disease (AD) and related to increased caregiver burden and institutionalization. There is a dearth of research investigating the relationship between specific biomarkers and basic activities of daily living (BADLs) such as toileting, feeding, dressing, grooming, bathing, and ambulating. The present study examined the relationship between serum based biomarkers and specific ADLs in a sample of AD patients. Data were collected from 196 participants enrolled in the Texas Alzheimer’s Research and Care Consortium Project and diagnosed with AD. BADLs were measured using the Lawton-Brody Physical Self-Maintenance Scale. A panel of 22 biomarkers previously found to be related to AD pathology was used for the analysis. Stepwise regression modeling was used to assess the link between the biomarkers and BADLs. Results were also examined by gender. Nine of the 22 biomarkers were significantly related to BADLs. When stratified by gender, the biomarkers accounted for 32% of the variance in the males and 27% in females. The pattern of significant biomarkers differed by gender with IL 7 and Tenascin C significantly related to BADLs for females and IL 15 significantly related to BADLs for males. The results of this study indicated that a small number of serum based biomarkers are related to BADLs, and these biomarkers differed by gender.

Pages 439-445
Li-San Wang, Yuk Yee Leung, Shu-Kai Chang, Susan Leight, Malgorzata Knapik-Czajka, Young Baek, Leslie M. Shaw, Virginia M.-Y. Lee, John Q. Trojanowski, Christopher M. Clark
Comparison of xMAP and ELISA Assays for Detecting Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease
Abstract: The best-studied biomarkers of Alzheimer’s disease (AD) are the pathologically-linked cerebrospinal fluid (CSF) proteins amyloid-β 42 (Aβ1-42), total tau (t-tau), and tau phosphorylated on amino acid 181 (p-tau181). Many laboratories measure these proteins using enzyme-linked immunosorbent assay (ELISA). Multiplex xMAP Luminex is a semi-automated assay platform with reduced intra-sample variance, which could facilitate its use in CLIA-approved clinical laboratories. CSF concentrations of these three biomarkers reported using xMAP technology differ from those measured by the most commonly used ELISA, confounding attempts to compare results. To develop a model for converting between xMAP and ELISA levels of the three biomarkers, we analyzed CSF samples from 140 subjects (59 AD, 30 controls, 34 with mild cognitive impairment, and 17 with Parkinson’s disease, including 1 with dementia). Log-transformation of ELISA and xMAP levels made the variance constant in all three biomarkers and improved the linear regression: t-tau concentrations were highly correlated (r=0.94); p-tau181 concentrations by ELISA can be better predicted using both the t-tau and p-tau181 xMAP values (r=0.96) as compared to p-tau181 concentrations alone (r=0.82); correlation of Aβ1-42 concentrations was relatively weaker but still high (r=0.77). Among all six protein/assay combinations, xMAP Aβ1-42 had the best accuracy for diagnostic classification (88%) between AD and control subjects. In conclusion, our study demonstrates that multiplex xMAP is an appropriate assay platform providing results that can be correlated with research-based ELISA values, facilitating the incorporation of this diagnostic biomarker into routine clinical practice.

Supplementary Data for Wang et al. article (PDF)

Pages 447-452
Andrea Arighi*, Giorgio G. Fumagalli*, Francesca Jacini, Chiara Fenoglio, Laura Ghezzi, Anna M. Pietroboni, Milena De Riz, Maria Serpente, Elisa Ridolfi, Rossana Bonsi, Nereo Bresolin, Elio Scarpini*, Daniela Galimberti* (Handling Associate Editor: Andreas Reif) *These authors contributed equally to this work.
Early Onset Behavioral Variant Frontotemporal Dementia due to the C9ORF72 Hexanucleotide Repeat Expansion: Psychiatric Clinical Presentations
Abstract: A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration with or without concomitant motor neuron disease phenotype and TDP-43 based pathology. Here, we report on three cases carrying the hexanucleotide repeat expansion with an atypical presentation consisting in the development of psychiatric symptoms. Patient #1, a 53 year old man with positive family history for dementia, presented with mood deflection, characterized by apathy, social withdraw, and irritability in the last two years. He was diagnosed with "mild cognitive impairment due to depressive syndrome” six months later and subsequently with Alzheimer’s disease. Patient #2, a woman with positive family history for dementia, developed behavioral disturbances, aggressiveness, and swearing at 57 years of age. Patient #3 presented, in the absence of brain atrophy, with mystical delirium with auditory hallucinations at 44 years of age, and did not present neurological symptoms over a 7-year follow up. The description of these cases underlines that the hexanucleotide repeat expansion in chromosome 9 could be associated with early onset psychiatric presentations.

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