Journal of Alzheimer's Disease - Volume 38, issue 2

Authors: Narme, Pauline | Clément, Sylvain | Ehrlé, Nathalie | Schiaratura, Loris | Vachez, Sylvie | Courtaigne, Bruno | Munsch, Frédéric | Samson, Séverine

Article Type: Research Article

Abstract: Although musical interventions have recently gained popularity as a non-pharmacological treatment in dementia, there is still insufficient evidence of their effectiveness. To investigate this issue, a single-center randomized controlled trial was conducted with forty-eight patients with Alzheimer's disease or mixed dementia to compare the effects of music versus cooking interventions in the emotional, cognitive, and behavioral domain, as well as on professional caregiver distress. Each intervention lasted four weeks (two one-hour sessions a week). Multi-component evaluations (with blind assessors) were conducted before, during, and after the interventions to assess their short and long-term effects (up to four weeks post interventions). …Analyses revealed that both music and cooking interventions led to positive changes in the patients' emotional state and decreased the severity of their behavioral disorders, as well as reduced caregiver distress. However, no benefit on the cognitive status of the patients was seen. While results did not demonstrate a specific benefit of music on any of the considered measures, the present study suggests the efficacy of two pleasant non-pharmacological treatments in patients with moderate to severe dementia. Our findings highlight the potential of such interventions in improving the well-being of patients living in residential care, as well as reducing caregiver distress. Show more

Keywords: Behavioral disorders, caregiver distress, cooking, dementia, mood, music, non-pharmacological treatment, nursing

DOI: 10.3233/JAD-130893

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 359-369, 2014

Authors: Pákáski, Magdolna | Fehér, Ágnes | Juhász, Anna | Drótos, Gergely | Fazekas, Örsike Csilla | Kovács, János | Janka, Zoltán | Kálmán, János

Article Type: Research Article

Abstract: Neurotransmitter enhancement therapy with acetylcholinesterase inhibitors (AChEIs) is a clinically proven approach for patients with Alzheimer's disease (AD). Donepezil is one of the three currently approved AChEIs for treating AD symptoms delaying the decline in cognitive function. In addition to cholinergic hypofunction, there are several factors in AD pathogenesis. For example, adipocytokines released from adipose tissue are also thought to play a role in the progress of dementia. Adipokines, i.e., leptin and adiponectin, are involved in the modulation of certain cognitive functions in the brain. The goal of our study was to elucidate effects of donepezil therapy on the serum …levels of certain adipokines, such as leptin and adiponectin in AD patients. Clinically diagnosed mild-to-moderate AD patients (n = 26) were involved in this open-labeled, single-center, prospective self-control study. ApoE polymorphism, serum adiponectin, leptin, LDL, HDL, triglyceride levels, and BMI were determined before and at 12 and 24 weeks intervals of donepezil treatment, respectively. Twenty-four weeks of donepezil treatment induced a linear decrease of serum leptin levels (p = 0.013) and a linear elevation of serum adiponectin levels (p = 0.007). BMI (p < 0.001) and abdominal circumference (p = 0.017) were significantly lower at 24 weeks as compared to control values. None of the other examined metabolic parameters were changed during the treatment period. This previously unrecognized serum adipokine regulating potential of donepezil may be relevant in its therapeutic, disease modifying effect in AD by transferring protective (by increasing serum adiponectin levels) and detrimental (by decreasing serum leptin levels) effects onto the neurodegenerative process at the same time. Show more

Keywords: Acetylcholinesterase inhibitor, adipokine, adiponectin, Alzheimer's disease, apolipoprotein E, body weight, dementia, donepezil, leptin

DOI: 10.3233/JAD-131139

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 371-377, 2014

Authors: Müller, Stephan | Mychajliw, Christian | Hautzinger, Martin | Fallgatter, Andreas J. | Saur, Ralf | Leyhe, Thomas

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by retrograde memory deficits primarily caused by dysfunction of the hippocampal complex. Unresolved questions exist concerning the time course of hippocampal involvement in conscious recollection of declarative knowledge, as reports of temporal gradients of retrograde amnesia have been inconclusive. The aim of this study was to examine whether the extent and severity of retrograde amnesia is mediated by retrieval frequency or, in contrast, whether it depends on the age of the memory according to the assumptions of the main current theories of memory formation. We compared recall of past public events in patients with AD …and healthy control (HC) individuals using the Historic Events Test (HET). The HET assesses knowledge about famous public events of the past 60 years divided into four time segments and consists of subjective memory rating, dating accuracy, and contextual memory tasks. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. As AD and HC groups derived similar benefits from greater retrieval frequency, cortical structures other than the hippocampal complex may mediate memory retrieval. These findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early damage of AD. This could explain why cognitive activity may delay the onset of memory decline in persons who develop AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, historic events test, multiple trace theory, retrieval frequency, standard model of memory consolidation

DOI: 10.3233/JAD-130923

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 379-390, 2014

Authors: Serra, Laura | Fadda, Lucia | Perri, Roberta | Spanò, Barbara | Marra, Camillo | Castelli, Diana | Torso, Mario | Makovac, Elena | Cercignani, Mara | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess …the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy. Show more

Keywords: Alzheimer's disease, constructional praxis, drawing tasks, voxel-based morphometry

DOI: 10.3233/JAD-130656

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 391-402, 2014

Authors: Saresella, Marina | Marventano, Ivana | Calabrese, Elena | Piancone, Federica | Rainone, Veronica | Gatti, Andrea | Alberoni, Margherita | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: An impairment of the microglial catabolic mechanisms allows amyloid-β (Aβ) accumulation in plaques within the brain in Alzheimer's disease (AD). Monocytes/macrophages (M/M) are activated in AD and migrate thorough the blood-brain barrier (BBB) trying to improve Aβ clearing. In the attempt to shed light on the role of M/M in AD, these cells were analyzed in patients with AD or mild cognitive impairment (MCI) and in age-matched healthy controls. Results obtained in Aβ42 -stimulated cell cultures showed that significantly higher percentages of inflammatory M/M (CD14+ CD16− CCR2++ CX3CR1low ) expressing toll like receptors (TLR) 2 and 4, as well as …IL-6 and CCR2, a chemokine favoring M/M migration through the BBB, are seen in AD. Confocal microscopy suggested the presence of MHC-II/Aβ42 complexes on AD M/M alone. Finally, TRL3- and TLR8-expressing and IL-23-producing M/M were increased in both AD and MCI compared to HC. These data indicate that M/M in AD are characterized by an inflammatory profile and are involved in the induction of both innate immune responses via TLR stimulation and of acquired immunity possibly secondarily to the presentation of Aβ peptides in an MHC-restricted fashion. Therapeutic approaches designed to interrupt these mechanism might prove beneficial. Show more

Keywords: Alzheimer's disease, cytokines, monocytes, neuroinflammation, toll-like receptors

DOI: 10.3233/JAD-131160

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 403-413, 2014

Authors: Parham, Christi | Auckland, Lisa | Rachwal, Jessica | Clarke, Douglas | Bix, Gregory

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), amyloid-β (Aβ) deposits in the cerebrovasculature can result in neurovascular dysfunction and/or cerebral amyloid angiopathy. The accumulation of Aβ in blood vessels can cause endothelial cell damage, resulting in impaired Aβ clearance by the blood-brain barrier. Additionally, impaired endothelial cell function can result in decreased angiogenesis in the brains of AD patients, affecting cognitive function. VEGF is a crucial mediator of angiogenesis and is deficient in AD brains thus promoting angiogenesis could be an important component of successful AD treatment. The C-terminal portion of the extracellular matrix proteoglycan perlecan, Domain V (DV), promotes brain-derived endothelial cell …proliferation and is proangiogenic in that it increases VEGFR2 expression and production of VEGF. In this study, we show that Aβ25-35 reduces proliferation of a mouse brain microvascular endothelial cell line (MBEC) in vitro and that DV and mouse LG3 (C-terminal fragment of DV) block these effects of Aβ25-35 . Additionally, we show that DV restores the ability of MBECs to form tube-like structures on Matrigel in the presence of Aβ25-35 and that this is α5β1 dependent. Interestingly, the reduction in tube-like structure formation by Aβ25-35 was not due to endothelial cell death, suggesting that Aβ25-35 induces the downregulation of a cell surface molecule required for adhesion events critical to the angiogenic process. We propose a model suggesting that DV works through both the α5β1 integrin receptor and VEGFR2 to increase VEGF production, causing competition with Aβ25-35 for VEGFR2 binding, thus ultimately increasing VEGF expression and restoring angiogenesis. This supports DV as a potential anti-amyloid therapy. Show more

Keywords: Alzheimer's disease, amyloid-β25-35, blood-brain barrier, extracellular matrix, integrins, perlecan

DOI: 10.3233/JAD-130683

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 415-423, 2014

Authors: Bobkova, Natalia V. | Garbuz, David G. | Nesterova, Inna | Medvinskaya, Natalia | Samokhin, Alexander | Alexandrova, Irina | Yashin, Valerii | Karpov, Vadim | Kukharsky, Michail S. | Ninkina, Natalia N. | Smirnov, Andrey A. | Nudler, Evgeny | Evgen'ev, Michael

Article Type: Research Article

Abstract: Brain deterioration resulting from “protein folding” diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted …brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-β (Aβ) peptide and, in the case of 5XFAD mice, reduces Aβ plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed. Show more

Keywords: 5XFAD mice, Alzheimer's disease, amyloid-β, bulbectomized mice, Hsp70

DOI: 10.3233/JAD-130779

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 425-435, 2014

Authors: Sun, Yong-Xin | Ji, Xunming | Mao, XiaoOu | Xie, Lin | Jia, Jianping | Galvan, Veronica | Greenberg, David A. | Jin, Kunlin

Article Type: Research Article

Abstract: Mammalian target of rapamycin (mTOR) signaling has been suggested to be effective in modifying cognitive status in animal models of Alzheimer's disease (AD), but little is known about its role in AD patients. We hereby tested whether mTOR signaling was activated and whether activated mTOR signaling was related to the degree of cognitive deficits in patients with AD. Autopsy brain hippocampal tissues were obtained from controls and patients with AD and Western blots were performed using antibodies against mTOR signaling molecules and RagC, an upstream component of mTOR complex 1 (mTORC1) signaling. We found that expression of mTOR/p-mTOR and its …downstream targets S6/p-S6 and Raptor/p-Raptor were expressed in the control and AD hippocampus. The expression levels of these signaling molecules were significantly increased in the hippocampus at the severe stages of AD, compared to controls and other stages of AD. Interestingly, Rictor expression level was unaltered. In addition, RagC was increased in the hippocampus at the early, moderate, and severe stages of AD. Our data indicate that mTORC1, but not mTORC2, was activated in the AD brains and that the level of mTOR signaling activation was correlated with cognitive severity of AD patients. Show more

Keywords: Alzheimer's disease, cognitive impairment, mTOR, RagC, rapamycin

DOI: 10.3233/JAD-131124

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 437-444, 2014

Authors: Buratti, Laura | Viticchi, Giovanna | Falsetti, Lorenzo | Cagnetti, Claudia | Luzzi, Simona | Bartolini, Marco | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Epidemiological studies have suggested a pathophysiological link between obstructive sleep apnea syndrome (OSAS) and Alzheimer's disease (AD). The mechanism by which sleep disturbance can affect cognitive impairment is not clear. The aim of this study was to investigate whether AD patients with OSAS have an impairment in cerebrovascular disease markers. We included 69 patients without OSAS and 93 patients with OSAS. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). Pathological values of IMT and BHI were …significantly associated with the presence of OSAS (IMT > 1.0 mm: OR 2.98, 95%CI: 1.37–6.46; p < 0.05; BHI < 0.69: OR 5.25, 95%CI: 2.35–11.74; p < 0.05, multivariate adjusted analysis). Furthermore, the extent of cerebrovascular impairment was correlated with the severity of OSAS. The finding of alterations of cerebral vessel functional and anatomic status in AD patients with OSAS suggests the potential for effective treatment for sleep-related disturbances in a subgroup of AD patients. Show more

Keywords: Alzheimer's disease, carotid atherosclerosis, cerebral hemodynamics, obstructive sleep apnea, ultrasound

DOI: 10.3233/JAD-131046

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 445-453, 2014

Article Type: Other

DOI: 10.3233/JAD-131047

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 455-457, 2014