Journal of Alzheimer's Disease - Volume 31, issue 2

Authors: Agholme, Lotta | Hallbeck, Martin | Benedikz, Eirikur | Marcusson, Jan | Kågedal, Katarina

Article Type: Research Article

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. Show more

Keywords: AβPP processing, Alzheimer's disease, amyloid-β peptide, autophagy, cell death, LC-3, lysosome, p70S6K, proteasome

DOI: 10.3233/JAD-2012-120001

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 343-358, 2012

Authors: Xu, Feng | Vitek, Michael P. | Colton, Carol A. | Previti, Mary Lou | Davis, Judianne | Van Nostrand, William E.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid β protein, apolipoprotein E, cerebral amyloid angiopathy, transgenic mice

DOI: 10.3233/JAD-2012-120421

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 359-369, 2012

Authors: Rideaux, Tiffany | Beaudreau, Sherry A. | Fernandez, Senaida | O'Hara, Ruth

Article Type: Research Article

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. When comparing CIND versus dementia, however, 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. Show more

Keywords: Cultural diversity, diagnosis, memory disorders, mild cognitive impairment, psychometrics

DOI: 10.3233/JAD-2012-112180

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 371-386, 2012

Authors: Marcone, Alessandra | Garibotto, Valentina | Moresco, Rosa Maria | Florea, Ioana | Panzacchi, Andrea | Carpinelli, Assunta | Virta, Jere R. | Tettamanti, Marco | Borroni, Barbara | Padovani, Alessandro | Bertoldo, Alessandra | Herholz, Karl | Rinne, Juha O. | Cappa, Stefano Francesco | Perani, Daniela

Article Type: Research Article

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 [11 C]-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. Show more

Keywords: 11C MP4 PET, acetylcholinesterase activity, Alzheimer's disease, amnestic mild cognitive impairment, dementia with Lewy bodies

DOI: 10.3233/JAD-2012-111748

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 387-399, 2012

Authors: Cholerton, Brenna | Baker, Laura D. | Trittschuh, Emily H. | Crane, Paul K. | Larson, Eric B. | Arbuckle, Matthew | Saucedo, Hector Hernandez | McCurry, Susan M. | Bowen, James D. | McCormick, Wayne C. | Craft, Suzanne

Article Type: Research Article

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. Show more

Keywords: Age-related memory disorders, aging, Alzheimer's disease, cognition, dementia, hyperinsulinemia, insulin, vascular

DOI: 10.3233/JAD-2012-120202

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 401-410, 2012

Authors: Brodaty, Henry | Heffernan, Megan | Draper, Brian | Reppermund, Simone | Kochan, Nicole A. | Slavin, Melissa J. | Trollor, Julian N. | Sachdev, Perminder S.

Article Type: Research Article

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. Show more

Keywords: Cognitive deficits, dementia, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-2012-120169

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 411-420, 2012

Authors: Kamogawa, Kenji | Kohara, Katsuhiko | Tabara, Yasuharu | Takita, Rie | Miki, Tetsuro | Konno, Tomoko | Hata, Saori | Suzuki, Toshiharu

Article Type: Research Article

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. Show more

Keywords: Alcadein, Alzheimer's disease, amyloid-β, blood biomarker, mild cognitive impairment

DOI: 10.3233/JAD-2012-120601

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 421-428, 2012

Authors: Hall, James R. | Johnson, Leigh A. | Barber, Robert C. | Vo, Hoa T. | Winter, A. Scott | O'Bryant, Sid E. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, basic activities of daily living, biomarkers, gender

DOI: 10.3233/JAD-2012-111481

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 429-437, 2012

Authors: Wang, Li-San | Leung, Yuk Yee | Chang, Shu-Kai | Leight, Susan | Knapik-Czajka, Malgorzata | Baek, Young | Shaw, Leslie M. | Lee, Virginia M.-Y. | Trojanowski, John Q. | Clark, Christopher M.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, enzyme-linked immunosorbent assay

DOI: 10.3233/JAD-2012-120082

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 439-445, 2012

Authors: Arighi, Andrea | Fumagalli, Giorgio G. | Jacini, Francesca | Fenoglio, Chiara | Ghezzi, Laura | Pietroboni, Anna M. | De Riz, Milena | Serpente, Maria | Ridolfi, Elisa | Bonsi, Rossana | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

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 #num;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 #num;2, a woman with positive family history for dementia, developed behavioral disturbances, aggressiveness, and swearing at 57 years of age. Patient #num;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. Show more

Keywords: C9ORF72 hexanucleotide repeat expansion, delirium, dementia, frontotemporal lobar degeneration, psychosis

DOI: 10.3233/JAD-2012-120523

Citation: Journal of Alzheimer's Disease, vol. 31, no. 2, pp. 447-452, 2012