Journal of Alzheimer's Disease - Volume 40, issue 4

Authors: Walton, J.R.

Article Type: Review Article

Abstract: Industrialized societies produce many convenience foods with aluminum additives that enhance various food properties and use alum (aluminum sulfate or aluminum potassium sulfate) in water treatment to enable delivery of large volumes of drinking water to millions of urban consumers. The present causality analysis evaluates the extent to which the routine, life-long intake, and metabolism of aluminum compounds can account for Alzheimer's disease (AD), using Austin Bradford Hill's nine epidemiological and experimental causality criteria, including strength of the relationship, consistency, specificity, temporality, dose-dependent response, biological rationale, coherence with existing knowledge, experimental evidence, and analogy. Mechanisms that underlie the risk of …low concentrations of aluminum relate to (1) aluminum's absorption rates, allowing the impression that aluminum is safe to ingest and as an additive in food and drinking water treatment, (2) aluminum's slow progressive uptake into the brain over a long prodromal phase, and (3) aluminum's similarity to iron, in terms of ionic size, allows aluminum to use iron-evolved mechanisms to enter the highly-active, iron-dependent cells responsible for memory processing. Aluminum particularly accumulates in these iron-dependent cells to toxic levels, dysregulating iron homeostasis and causing microtubule depletion, eventually producing changes that result in disconnection of neuronal afferents and efferents, loss of function and regional atrophy consistent with MRI findings in AD brains. AD is a human form of chronic aluminum neurotoxicity. The causality analysis demonstrates that chronic aluminum intake causes AD. Show more

Keywords: Aluminum, Alzheimer's disease, amyloidogenesis, animal disease models, causality, disconnection, entorhinal cortex, microtubules, neurofibrillary tangles, transferrin receptors

DOI: 10.3233/JAD-132204

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 765-838, 2014

Authors: Silverstein, Jeffrey H.

Article Type: Review Article

Abstract: Since the finding in the 1880 s that elderly patients may experience cognitive decline following surgery, the search for an understanding of this phenomenon has been underway. In the last decade, evidence from biophysical (light scattering and nuclear magnetic resonance), in vitro, in vivo animal studies, retrospective evaluations of human registries, and recently prospective randomized trials have explored the idea that various anesthetic agents play a role in this phenomenon by interacting with the biochemical mechanisms that are also responsible for the development of Alzheimer's disease. In the current review, we examine the evidence available and conclude that there is …significant evidence to suggest an important role for this mechanism. Show more

Keywords: Alzheimer's disease, anesthetics, dementia

DOI: 10.3233/JAD-130815

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 839-848, 2014

Authors: Abbate, Carlo | Arosio, Beatrice | Galimberti, Daniela | Nicolini, Paola | Chiara, Lo Russo | Rossi, Paolo Dionigi | Ferri, Evelyn | Gussago, Cristina | Deriz, Milena | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Mari, Daniela

Article Type: Short Communication

Abstract: We describe a sporadic case of frontotemporal lobar degeneration, associated with the C9ORF72 mutation, with prominent behavioral changes and semantic deficits. Predominant deficits in naming, vocabulary, word comprehension, and face and object recognition emerged on neuropsychological assessment. Amnesia, behavioral changes, and isolated psychotic symptoms were also present. Hyposmia was an unspecific prodromal sign. Brain imaging showed basofrontal and temporopolar hypometabolism bilaterally, and predominantly left-sided atrophy. Levels of cerebrospinal fluid biomarkers (amyloid-β, tau and p-tau) were normal. This description further confirms the heterogeneous presentation of the C9ORF72 mutation.

Keywords: C9ORF72, frontotemporal lobar degeneration, hyposmia, phenotype, semantic dementia

DOI: 10.3233/JAD-132075

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 849-855, 2014

Authors: Troussière, Anne Cécile | Wallon, David | Mouton-Liger, François | Yatimi, Rachida | Robert, Philippe | Hugon, Jacques | Hannequin, Didier | Pasquier, Florence | Paquet, Claire

Article Type: Short Communication

Abstract: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are well validated in clinical research but less in clinical practice. Using a questionnaire, we evaluated the reasons for prescriptions and clinician's expectations concerning CSF biomarkers. The results show that CSF AD biomarkers are mainly required in case of atypical dementia and diagnosis uncertainty that are different from indications in clinical research. In the future, clinicians wish to get new biomarkers that could improve differential diagnosis and could have a good pronostic value. Further studies in routine practice are necessary to precise the role of these biomarkers in the management of patients.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, clinical practice

DOI: 10.3233/JAD-132672

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 857-861, 2014

Authors: Hu, Yueqing | Liang, Jingyao | Yu, Shengyuan

Article Type: Short Communication

Abstract: Huntington's disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband's daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM.

Keywords: Diabetes mellitus, genes, Huntington disease, pathogenesis

DOI: 10.3233/JAD-131847

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 863-868, 2014

Authors: Yakhia, Maja | König, Alexandra | van der Flier, Wiesje M. | Friedman, Leah | Robert, Philippe H. | David, Renaud

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) may exhibit changes in motor activity in conducting their activities of daily living. Depression, one of the most frequent neuropsychiatric symptoms, might affect motor activity in MCI. Objective: To assess motor activity in MCI subjects carrying out short functional activity tasks using ambulatory actigraphy. Secondly, we sought to investigate the influence of depressive symptoms on motor activity. Methods: 20 MCI and 14 healthy subjects carried out a 30-minute standardized scenario while wearing a chest actigraph. The protocol consisted of directed activities (execution of motor tasks), semi-directed activities (execution of …Instrumental Activities of Daily Living, IADL), and undirected ‘free’ activities. Several common assessment scales (GDS, MADRS, and NPI) were used to diagnose depression. Results: MCI subjects had significantly reduced mean motor activity while carrying out directed and semi-directed activities, compared to healthy control subjects. No difference was found in motor activity between MCI subjects with or without depression. Conclusion: Actigraphic measurement of motor activity during the evaluation of IADLs and motor tasks is a potential objective tool in detecting early changes in MCI. Depressive symptoms seem not to be associated with motor activity in MCI subjects. Show more

Keywords: Actigraphy, depressive symptoms, mild cognitive impairment, motor activity

DOI: 10.3233/JAD-131691

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 869-875, 2014

Authors: Noh, Young | Seo, Sang Won | Jeon, Seun | Lee, Jong Min | Kim, Jung-Hyun | Kim, Geon Ha | Cho, Hanna | Yoon, Cindy W. | Kim, Hee Jin | Ye, Byoung Seok | Kim, Sung Tae | Choe, Yearn Seong | Lee, Kyung-Han | Kim, Jae Seung | Ewers, Michael | Weiner, Michael W. | Lee, Jae-Hong | Werring, David J. | Kang, Dae Ryong | Kim, Chang Soo | Na, Duk L.

Article Type: Research Article

Abstract: Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11 C-Pittsburgh compound B (PiB) PET. We recruited …53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10−3 , p = 0.034) while no significant correlation was found in APOE4 carriers (β = −9.0 × 10−3 , p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD. Show more

Keywords: Alzheimer's disease, amyloid burden, apolipoprotein E4, cerebrovascular disease

DOI: 10.3233/JAD-130461

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 877-886, 2014

Authors: Hall, James R. | Wiechmann, April R. | Johnson, Leigh A. | Edwards, Melissa | Barber, Robert C. | Cunningham, Rebecca | Singh, Meharvan | O'Bryant, Sid E. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: Research on the link between APOEε4 and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) has been inconsistent. Previous work has shown a relationship between serum biomarkers of vascular risk and inflammation and NPS in AD. The current study investigated the impact of APOEε4 status on the relationship between biomarkers of cardiovascular risk, systemic inflammation, and NPS. The sample was drawn from the TARCC Longitudinal Research Cohort; the final sample of 190 consisted of 124 females and 66 males meeting the diagnostic criteria for mild to moderate AD. 115 individuals were APOEε4 carriers and 75 were non-carriers. Serum-based clinical biomarkers of …vascular risk and biomarkers of inflammation related to AD were analyzed. NPS data was gathered from caretakers/family members using the Neuropsychiatric Inventory. The significant biomarkers differed for carriers and non-carriers with IL15 being a negative biomarker of total NPS accounting for 12% of the variance for carriers and IL18 and TNFα negative predictors for non-carriers (18% of variance). Patterns related to specific symptoms were similar. Stratification by gender revealed significant biomarkers of total NPS for female carriers were negative IL15 and IL1ra (18% of variance) and for female non-carriers were negative IL18 and positive homocysteine. Total cholesterol was a positive biomarker of total NPS for both male carriers (36% of variance) and non-carriers (negative TNFα and total cholesterol, 32% of variance). These findings suggest that dysregulation of inflammatory activity is related to NPS, that cholesterol is a significant factor in the occurrence of NPS, and that gender and APOE status need to be considered. Show more

Keywords: Alzheimer's disease, APOE, gender, neuropsychiatric symptoms

DOI: 10.3233/JAD-131724

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 887-896, 2014

Authors: Walterfang, Mark | Luders, Eileen | Looi, Jeffrey C.L. | Rajagopalan, Priya | Velakoulis, Dennis | Thompson, Paul M. | Lindberg, Olof | Östberg, Per | Nordin, Love E. | Svensson, Leif | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: Morphology of the corpus callosum is a useful biomarker of neuronal loss, as different patterns of cortical atrophy help to distinguish between dementias such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We used a sophisticated morphometric analysis of the corpus callosum in FTLD subtypes including frontotemporal dementia (FTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA), and compared them to AD patients and 27 matched controls. FTLD patient subgroups diverged in their callosal morphology profiles, with FTD patients showing marked widespread differences, PNFA patients with differences largely in the anterior half of the callosum, and SD patients differences …in a small segment of the genu. AD patients showed differences in predominantly posterior callosal regions. This study is consistent with our previous findings showing significant cortical and subcortical regional atrophy across FTLD subtypes, and suggests that callosal atrophy patterns differentiate AD from FTLD, and FTLD subtypes. Show more

Keywords: Alzheimer's disease, corpus callosum, frontotemporal dementia, white matter

DOI: 10.3233/JAD-131853

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 897-906, 2014

Authors: Gharbiya, Magda | Trebbastoni, Alessandro | Parisi, Francesco | Manganiello, Silvia | Cruciani, Filippo | D'Antonio, Fabrizia | De Vico, Umberto | Imbriano, Letizia | Campanelli, Alessandra | De Lena, Carlo

Article Type: Research Article

Abstract: Background: The involvement of retina and its vasculature has been recently described in Alzheimer’s disease (AD). However, none of the previous works have yet investigated the choroid in vivo. Objective: Spectral domain optical coherence tomography (SD-OCT) and enhanced depth imaging (EDI) technique is non-invasively used to assess choroidal thickness in patients with AD and to determine whether the peripapillary retinal nerve fiber layer (RNFL) and central retinal thickness are reduced compared to normal subjects. Methods: Forty-two eyes of 21 patients (mean age, 73.1 ± 6.9 years) with a diagnosis of mild to moderate AD and 42 …eyes of 21 age-matched control subjects (mean age, 70.3 ± 7.3 years) were included in this prospective, cross-sectional study. All the subjects underwent neuropsychological (MMSE, ADAS-Cog, and CDR) and ophthalmological evaluation. The SD-OCT images of the choroid were obtained by EDI modality. Choroidal thickness was assessed by manual measurement. The following parameters, measured automatically by the OCT software, were also analyzed for each eye: 1-mm central subfield (CSF) retinal thickness, peripapillary RNFL thickness. Results: Choroidal thickness was significantly thinner in AD than in control eyes (p < 0.05). No difference in CSF retinal thickness was found between groups (p > 0.05). Mean peripapillary RNFL thickness in all four quadrants was similar between groups (p > 0.05). OCT measurements were not correlated with any of the tested psychometric parameters (p > 0.05). Conclusion: Compared with healthy subjects, patients with AD showed a significant reduction in choroidal thickness. Choroidal thinning may represent an adjunctive biomarker for the diagnosis and follow-up of this disease. Show more

Keywords: Age-related macular degeneration, Alzheimer's disease, biomarker, choroid, choroidal thickness, enhanced depth imaging, optical coherence tomography, peripapillary RNFL thickness, retinal thickness, SD-OCT

DOI: 10.3233/JAD-132039

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 907-917, 2014