Journal of Alzheimer's Disease - Volume 42, issue 2

Authors: Eichler, Tilly | Thyrian, Jochen René | Hertel, Johannes | Köhler, Leonore | Wucherer, Diana | Dreier, Adina | Michalowsky, Bernhard | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Primary data about rates of formal diagnosis of dementia in the German primary care sector are widely lacking. Objectives: Main objectives are to analyze the rate of syndrome diagnosis in primary care patients who screened positive for dementia, the distribution of differential diagnoses, and factors associated with undiagnosed dementia. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is an ongoing general practitioner (GP)-based, randomized, controlled intervention trial. A total of 4,064 patients (≥70 years, living at home) recruited from 108 participating GP practices were screened for dementia (DemTect < 9). Of 692 eligible …patients (17%), a total of 406 subjects (59%) provided informed consent. Present analyses are based on the data of 243 patients with complete baseline assessment on January 1, 2014 (preliminary data). Formal diagnoses were retrieved from the medical records of the treating GPs. A conditional fixed effect regression analysis was performed to analyze factors associated with undiagnosed dementia. Results: A total of 40% of patients who screened positive for dementia had been formally diagnosed with dementia. Unspecified dementia was diagnosed in 53%, vascular dementia in 24%, and Alzheimer’s disease in 19% of these patients. Undiagnosed dementia was significantly associated with a higher mean score in the Mini-Mental State Examination (odds ratio, 1.11; p < 0.01, 95% confidence interval 1.04–1.18). Conclusions: The diagnosis rate of dementia in German primary care (40%) is well within the range of the international data (20–50%). The results emphasize the need for action to enhance recognition and differential diagnosis of dementia. Show more

Keywords: Dementia, differential diagnosis, early diagnosis, primary health care, screening

DOI: 10.3233/JAD-140354

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 451-458, 2014

Authors: Nguyen, Thuy-Vi V. | Shen, Lin | Vander Griend, Lilith | Quach, Lisa N. | Belichenko, Nadia P. | Saw, Nay | Yang, Tao | Shamloo, Mehrdad | Wyss-Coray, Tony | Massa, Stephen M. | Longo, Frank M.

Article Type: Research Article

Abstract: The p75 neurotrophin receptor (p75NTR ) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these …in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds. Show more

Keywords: Alzheimer's disease, LM11A-31, LM11A-24, p75 neurotrophin receptor

DOI: 10.3233/JAD-140036

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 459-483, 2014

Authors: Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Graff-Guerrero, Ariel | Mimura, Masaru | Nakayama, Kazuhiko | Miller, Bruce L.

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, “psychosis”, “schizophreni* ”, “psychotic symptoms”, “hallucinations”, and “delusions”, and it identified 122 …articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders. Show more

Keywords: Frontotemporal dementia, gene mutation, neuropathology, psychosis, schizophrenia

DOI: 10.3233/JAD-140312

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 485-499, 2014

Authors: Oosterveld, Saskia M. | Kessels, Roy P.C. | Hamel, Renske | Ramakers, Inez H.G.B. | Aalten, Pauline | Verhey, Frans R.J. | Sistermans, Nicole | Smits, Lieke L. | Pijnenburg, Yolande A. | van der Flier, Wiesje M. | Olde Rikkert, Marcel G.M. | Melis, René J.F.

Article Type: Research Article

Abstract: Co-morbidity and frailty are common in Alzheimer's disease (AD) and may contribute to the heterogeneity in clinical manifestations of the disease. We cross-sectionally investigated whether co-morbidity and frailty were independently associated with the clinical manifestation of AD in the 4C–Dementia study; a multicenter, longitudinal study in newly diagnosed AD patients. Clinical manifestation was operationalized using a composite of cognitive performance (neuropsychological assessment), activities of daily living (Disability Assessment for Dementia; DAD) and neuropsychiatric symptoms (Neuropsychiatric Inventory). As predictors of prime interest, co-morbidity was determined using the Cumulative Illness Rating Scale (CIRS-G) and frailty by the Fried criteria. In total, 213 …AD patients participated (mean age 75 ± 10 years; 58% females). In linear regression models adjusted for age, gender, education, and disease duration, CIRS-G (β = −0.21, p < 0.01) and frailty (β = −0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (β = −0.12, p = 0.12) lost statistical significance when both were combined (frailty: β = −0.31, p < 0.001). Models with the individual components of clinical AD manifestation as dependent variables show significant associations between cognitive performance and CIRS-G (β = −0.22, p = 0.01), and between DAD and frailty (β = −0.37, p < 0.001). Our findings indicate that physical health and clinical AD manifestation are associated. This association may be responsible for part of the heterogeneity in the presentation of AD. This emphasizes the importance of adequate assessment of co-morbid medical conditions and frailty in patients with AD. Show more

Keywords: Activities of daily living, Alzheimer's disease, co-morbidity, cognitive performance, dementia, frailty

DOI: 10.3233/JAD-140138

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 501-509, 2014

Authors: Tian, Li | Zhang, Ke | Tian, Zhi-Ying | Wang, Tao | Shang, De-Shu | Li, Bo | Liu, Dong-Xin | Fang, Wen-Gang | Wang, Zhan-You | Chen, Yu-Hua

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by pathological senile plaques composed of amyloid-β (Aβ) in the cerebral cortex and hippocampus. Bone marrow-derived monocytes of patients with AD migrate across the blood-brain barrier into the brain, but are defective at clearing Aβ in the neuritic plaques. However, the underlying mechanisms remain unclear. Here, in patients with AD, we found that cathepsin D, a major lysosomal aspartic protease, was underexpressed in monocytes, resulting in the defective degradation of Aβ by monocytes/macrophages. Further, downregulation of cathepsin D in THP-1 cells significantly reduced the clearance of amyloid plaques in the brain …sections of AβPP/PS1 mice. The clearance ability was recovered by the overexpression of cathepsin D in AD monocytes. These results suggest that decreased expression of cathepsin D in the peripheral monocytes is a potential signature of AD, and that this decreased expression is involved in Aβ degradation and AD pathogenesis. Show more

Keywords: Alzheimer's disease, amyloid-β, cathepsin D, monocyte

DOI: 10.3233/JAD-132192

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 511-520, 2014

Authors: Trujillo-Estrada, Laura | Dávila, José Carlos | Sánchez-Mejias, Elisabeth | Sánchez-Varo, Raquel | Gomez-Arboledas, Angela | Vizuete, Marisa | Vitorica, Javier | Gutiérrez, Antonia

Article Type: Research Article

Abstract: The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, …a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex. Our results indicate that the subiculum is the earliest affected region in the hippocampus, showing a selective early loss of both principal neurons (28%) and SOM-positive interneurons (69%). In addition, our data demonstrate the existence of an early axonal and synaptic pathology, which may represent the beginning of the synaptic disruption and loss. These neurodegenerative processes occur in parallel, and closely related, with the onset and accelerated progression of the extracellular amyloid-β deposition, thus suggesting plaques as major contributors of neuronal/axonal damage. Data reported here indicate that this AD model displays a selective AD-like neurodegenerative phenotype in highly vulnerable regions, including the subiculum, and therefore can be a very useful model for testing the therapeutic ability of potential compounds to protect neurons and ameliorate disease symptoms. Show more

Keywords: Alzheimer's disease, amyloid-β plaques, axonal damage, hippocampus, neuronal loss, subiculum, transgenic mice

DOI: 10.3233/JAD-140495

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 521-541, 2014

Authors: Sun, Lin | Guo, Chunni | Wang, Tao | Li, Xia | Li, Guanjun | Luo, Yanli | Xiao, Shifu

Article Type: Research Article

Abstract: Bone morphogenetic protein 6 (BMP6) has neuroprotective effects against various neuronal injuries, but its effect on amyloid-β (Aβ)-induced neurotoxicity remains unclear. We exposed rat hippocampal neurons to different concentrations of Aβ25-35 to induce neurotoxicity, and then treated cells with BMP6 to assess the neuroprotective effects. In vivo, we bilaterally injected Aβ1-40 into basal forebrain to simulate the neuropathological process of Alzheimer's disease (AD), and explored changes in the expression of BMP6 and LIMK1. Our data demonstrated that BMP6 prevented apoptosis induced by a high dose of Aβ25-35 , and inhibited rod formation induced by low dose of Aβ25-35 …in hippocampal neurons. Forebrain injection of Aβ1-40 led to a significant downregulation of BMP6, and inactivation of LIMK1 pathway in basal forebrain, whereas the opposite changes were observed in hippocampus. Our results suggest that BMP6 has neuroprotective effects against Aβ25-35 . The BMP6 and LIMK1 pathways may have different expression patterns at different stages of AD, and be self-regulating via a negative feedback mechanism between different brain regions. Show more

Keywords: actin, Alzheimer's disease, amyloid-β, bone morphogenetic protein, rod

DOI: 10.3233/JAD-140231

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 543-554, 2014

Authors: Qiu, Wei Qiao | Au, Rhoda | Zhu, Haihao | Wallack, Max | Liebson, Elizabeth | Li, Huajie | Rosenzweig, James | Mwamburi, Mkaya | Stern, Robert A.

Article Type: Research Article

Abstract: Our recent study reported that amylin, a pancreatic peptide that readily crosses the blood-brain barrier, improves learning and memory in Alzheimer's disease mouse models. However, the relationship between peripheral amylin and cognition in humans is unknown. In this follow-up study, using a cross-sectional, homebound elderly population, improvement in cognitive function with increasing quartiles of plasma amylin was suggested by positive association with verbal memory (p = 0.0002) and visuoconstruction tasks (p = 0.004), and inverse association with timed measures of attention (p < 0.0001) and executive function (p = 0.04). After adjusting for demographic information, apolipoprotein E4 allele, diabetes, stroke, …kidney function, and lipid profile, log10 of plasma amylin remained associated with these cognitive domains. In contrast, plasma amyloid-β peptide was not associated with these specific cognitive domains. Our study suggests that peripheral amylin may be protective for cognitive decline, especially in the domains affected by Alzheimer's disease. Show more

Keywords: Amylin, cognition, memory, visuospatial and executive function

DOI: 10.3233/JAD-140210

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 555-563, 2014

Authors: Ma, Ling-Li | Yu, Jin-Tai | Wang, Hui-Fu | Meng, Xiang-Fei | Tan, Chen-Chen | Wang, Chong | Tan, Lan

Article Type: Research Article

Abstract: This study examined the association between cancer and Alzheimer's disease (AD) by a quantitative meta-analysis of cohort studies. Studies were identified by searching PubMed database through 1966 to December 2013 using the terms “Alzheimer's disease”, “neoplasm”, and “cancer”. Six studies met the inclusion criteria in the overall meta-analysis. We pooled effect sizes using fixed-effects and random-effects models. Furthermore, we also tested for heterogeneity and publication bias. The results suggested that individuals diagnosed with AD had a decreased risk for incident cancer by 42% (95% CI, 0.40–0.86; p < 0.05), and patients with a history of cancer had a 37% decreased …risk of AD (RR = 0.63; 95% CI, 0.56–0.72; p = 0.495). The Egger's test for publication bias (p = 0.280) showed no significant evidence for bias in the data from studies on AD and cancer risk. In summary, our meta-analysis demonstrated an inverse association between cancer and AD. Show more

Keywords: Alzheimer's disease, cancer, meta-analysis, neoplasm

DOI: 10.3233/JAD-140168

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 565-573, 2014

Authors: Imtiaz, Bushra | Tuppurainen, Marjo | Tiihonen, Miia | Kivipelto, Miia | Soininen, Hilkka | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Association between oophorectomy and/or hysterectomy and dementia in context of hormone therapy (HT) use is ambiguous. Objective: To assess whether oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy are related to risk of Alzheimer’s disease (AD), whether the possible indication for surgery plays a role, and if the associations are modified by HT. Methods: Our nationwide register based case–control (1 : 1) study included all women with clinically-verified AD diagnoses, residing in Finland on December 31, 2005 (n of cases = 19,043, n of controls = 19,043). AD cases, diagnosed according to NINCS-ADRDA and the DSM-IV …criteria, were identified from Special Reimbursement Register. Information on HT use was collected from national prescription register, and data on surgery and uterine/ovarian/cervical cancer were obtained from the hospital discharge register. Most of the women (91.8%) were over 51 years of age when the surgery was performed. Results: Oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy were associated with lower risk of AD (OR/95% CI: 0.85/0.75–0.97, 0.89/0.81–0.97 and 0.85/0.75–0.98, respectively) among women without the history of uterine/ovarian/cervical cancer, although the absolute risk difference was small. The association was not evident in women with uterine/ovarian/cervical cancer history (3.00/0.20–44.87 for all surgeries). The associations were not modified by HT use, which was independently associated with AD risk, with longer use showing protective association. Conclusion: Our findings indicate that oophorectomy with or without hysterectomy after commencement of natural menopause is not an important determinant of AD risk in older age and support the critical window hypothesis for HT use. Show more

Keywords: Alzheimer's disease, cognition, dementia, estrogen, hormone therapy, hysterectomy, menopause, oophorectomy, radical hysterectomy

DOI: 10.3233/JAD-140336

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 575-581, 2014