Journal of Alzheimer's Disease - Volume 33, issue 3

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Alzheimer's disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine

DOI: 10.3233/JAD-2012-121537

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 547-658, 2013

Authors: Annweiler, Cedric | Llewellyn, David J. | Beauchet, Olivier

Article Type: Review Article

Abstract: Vitamin D has been investigated in association with cognitive function in older adults. It is unclear whether hypovitaminosis D could be associated with Alzheimer's disease (AD). Our objective was to systematically review and quantitatively synthesize the association of low serum 25-hydroxyvitamin D (25OHD) concentrations with AD in adults. A Medline and PsycINFO® search was conducted on May 2012, with no limit of date, using the MeSH terms “Vitamin D” OR “Hydroxycholecalciferols” combined with the MeSH terms “Alzheimer disease” OR “Dementia” OR “Cognition” OR “Cognition disorders” OR “Memory” OR “Memory Disorders” OR “Executive Function” OR “Attention” OR “Neuropsychological Tests”. Of …the 284 selected studies, 10 observational studies (including 9 case-controls and 1 cohort study) met the selection criteria. All were of good quality. The number of AD cases ranged from 20 to 211 (40%–100% female). Finally, 7 case-control studies were eligible for fixed and random-effects meta-analyses of bias-corrected effect size of the difference in serum 25OHD concentrations between AD cases and controls using an inverse-variance method. The pooled effect size in random-effects meta-analysis was 1.40 (95% CI: 0.26;2.54), a ‘large’ effect size that indicates that serum 25OHD concentrations were 1.4 standard deviation units lower in AD cases compared to cognitively healthy controls (p = 0.016). In conclusion, AD cases had lower serum vitamin D concentrations than matched controls. This reinforces the conceptualization of vitamin D as a ‘neurosteroid hormone’ and as a potential biomarker of AD. Show more

Keywords: Alzheimer's disease, cognition, meta-analysis, neuroendocrinology, vitamin D

DOI: 10.3233/JAD-2012-121432

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 659-674, 2013

Authors: Lim, Yen Ying | Pietrzak, Robert H. | Ellis, Kathryn A. | Jaeger, Judith | Harrington, Karra | Ashwood, Tim | Szoeke, Cassandra | Martins, Ralph N. | Bush, Ashley I. | Masters, Colin L. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Darby, David | Maruff, Paul

Article Type: Short Communication

Abstract: High levels of amyloid-β (Aβ) have been associated with greater rates of decline in episodic memory over 18 months in healthy older adults. Serial assessments over shorter time intervals may facilitate earlier detection of Aβ-related memory decline in healthy older adults. In forty-four healthy older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Rate of Change Sub-Study, we compared rates of change in cognition over six months in healthy older adults with high and low levels of Aβ. High Aβ was associated with greater decline in episodic memory measures over 6 months in healthy older adults.

Keywords: Alzheimer's disease, amyloid-β, cognitive decline, episodic memory, neuropsychological assessment

DOI: 10.3233/JAD-2012-121516

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 675-679, 2013

Authors: Davis, Katherine E. | Easton, Alexander | Eacott, Madeline J. | Gigg, John

Article Type: Research Article

Abstract: Episodic memory loss is a defining feature of early-stage Alzheimer's disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would …show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three-component task that can be solved without reliance on episodic recall (What-Where-When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, whereas, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non-episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model. Show more

Keywords: Allocentric, amyloid-β protein, egocentric, hippocampus, What-Where-When

DOI: 10.3233/JAD-2012-121543

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 681-698, 2013

Authors: Gu, Gucci Jijuan | Wu, Di | Lund, Harald | Sunnemark, Dan | Kvist, Alexander J. | Milner, Roy | Eckersley, Sonia | Nilsson, Lars N.G. | Agerman, Karin | Landegren, Ulf | Kamali-Moghaddam, Masood

Article Type: Research Article

Abstract: The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer's disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser262 is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser262 in vitro. In this study, we took advantage of the in situ proximity ligation …assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser262 in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser262 . Furthermore, we observed elevated interactions between MARK2 and tau in post-mortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate a specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser262 . Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression. Show more

Keywords: Alzheimer's disease, MARK, phosphorylation, proximity ligation assay, tau

DOI: 10.3233/JAD-2012-121357

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 699-713, 2013

Authors: Echávarri, Carmen | Burgmans, Saartje | Uylings, Harry | Cuesta, Manuel J. | Peralta, Victor | Kamphorst, Wouter | Rozemuller, Annemieke J.M. | Verhey, Frans R.J.

Article Type: Research Article

Abstract: Neuropsychiatric symptoms (NPSs) have a large impact on the quality of life of patients with dementia. A few studies have compared neuropsychiatric disturbances between dementia subtypes, but the results were conflicting. In the present study, we investigated whether the prevalence of NPSs differs between Alzheimer's disease (AD) and vascular dementia (VaD). The merit of our study is that we used clinical as well as histopathological information to differentiate between dementia subtypes. This retrospective descriptive study comprised 80 brains obtained from donors to the Netherlands Brain Bank between 1984 and 2010. These donors were diagnosed postmortem with AD (n = 40) …or VaD (n = 40). We assessed the presence of NPSs by reviewing the information found in the patients' medical files. The most prevalent symptom in the sample as a whole was agitation (45 cases, 57.0%), followed by depression (33, 41.2%) and anxiety (28, 35.4%). Our study tried to contribute to the discussion by including, for the first time in the literature, a sample of AD and VaD patients with neuropathologically confirmed diagnoses. Since no significant differences were found between AD and VaD patients, we suggest that the prevalence of NPSs cannot be predicted from the diagnosis of AD or VaD. Show more

Keywords: Alzheimer's disease, brain pathology, neuropsychiatry, vascular dementia

DOI: 10.3233/JAD-2012-121003

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 715-721, 2013

Authors: Selnes, Per | Aarsland, Dag | Bjørnerud, Atle | Gjerstad, Leif | Wallin, Anders | Hessen, Erik | Reinvang, Ivar | Grambaite, Ramune | Auning, Eirik | Kjærvik, Veslemøy Krohn | Due-Tønnessen, Paulina | Stenset, Vidar | Fladby, Tormod

Article Type: Research Article

Abstract: Neuropathological correlates of Alzheimer's disease (AD) emerge years before dementia. Biomarkers preceding cognitive decline and reflecting the causative processes can potentially aid early intervention and diagnosis. Diffusion tensor imaging (DTI) indirectly reflects tissue microstructure. To answer whether DTI is an early biomarker for AD and to explore the relationship between DTI and the established biomarkers of medial temporal lobe atrophy and cerebrospinal fluid (CSF) Aβ42 , T-tau, and P-tau, we longitudinally studied normal controls and patients with subjective (SCI) or mild (MCI) cognitive impairment. 21 controls and 64 SCI or MCI cases recruited from a university-hospital based memory clinic were …re-examined after two to three years. FreeSurfer was used for longitudinal processing of morphometric data, and DTI derived fractional anisotropy, radial diffusivity, and mean diffusivity were analyzed in Tract-Based Spatial Statistics. Using regression models, we explored and compared the predictive powers of DTI and CSF biomarkers in regard to cognitive change and atrophy of the medial temporal lobe. Both DTI and CSF biomarkers significantly predicted cognitive decline and atrophy in the medial temporal lobe. In this population, however, DTI was a better predictor of dementia and AD-specific medial temporal lobe atrophy than the CSF biomarkers. The case for DTI as an early biomarker for AD is strengthened, but further studies are needed to confirm these results. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, diffusion tensor imaging, longitudinal study, magnetic resonance brain imaging, mild cognitive impairment, preclinical Alzheimer's disease, subjective cognitive impairment

DOI: 10.3233/JAD-2012-121603

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 723-736, 2013

Authors: Lunnon, Katie | Sattlecker, Martina | Furney, Simon J. | Coppola, Giovanni | Simmons, Andrew | Proitsi, Petroula | Lupton, Michelle K. | Lourdusamy, Anbarasu | Johnston, Caroline | Soininen, Hilkka | Kłoszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Geschwind, Daniel | Lovestone, Simon | Dobson, Richard | Hodges, Angela | On behalf of the AddNeuroMed Consortium

Article Type: Research Article

Abstract: A marker of Alzheimer's disease (AD) that can accurately diagnose disease at the earliest stage would significantly support efforts to develop treatments for early intervention. We have sought to determine the sensitivity and specificity of peripheral blood gene expression as a diagnostic marker of AD using data generated on HT-12v3 BeadChips. We first developed an AD diagnostic classifier in a training cohort of 78 AD and 78 control blood samples and then tested its performance in a validation group of 26 AD and 26 control and 118 mild cognitive impairment (MCI) subjects who were likely to have an AD-endpoint. A …48 gene classifier achieved an accuracy of 75% in the AD and control validation group. Comparisons were made with a classifier developed using structural MRI measures, where both measures were available in the same individuals. In AD and control subjects, the gene expression classifier achieved an accuracy of 70% compared to 85% using MRI. Bootstrapping validation produced expression and MRI classifiers with mean accuracies of 76% and 82%, respectively, demonstrating better concordance between these two classifiers than achieved in a single validation population. We conclude there is potential for blood expression to be a marker for AD. The classifier also predicts a large number of people with MCI, who are likely to develop AD, are more AD-like than normal with 76% of subjects classified as AD rather than control. Many of these people do not have overt brain atrophy, which is known to emerge around the time of AD diagnosis, suggesting the expression classifier may detect AD earlier in the prodromal phase. However, we accept these results could also represent a marker of diseases sharing common etiology. Show more

Keywords: Alzheimer's disease, biomarkers, blood, diagnosis, gene expression pattern analysis, leukocytes, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2012-121363

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 737-753, 2013

Authors: Velayudhan, Latha | Proitsi, Petroula | Westman, Eric | Muehlboeck, J-Sebastian | Mecocci, Patrizia | Vellas, Bruno | Tsolaki, Magda | Kłoszewska, Iwona | Soininen, Hilkka | Spenger, Christian | Hodges, Angela | Powell, John | Lovestone, Simon | Simmons, Andrew | AddNeuroMed consortium

Article Type: Research Article

Abstract: Biomarkers for Alzheimer's disease (AD) based on non-invasive methods are highly desirable for diagnosis, disease progression, and monitoring therapeutics. We aimed to study the use of hippocampal volume, entorhinal cortex (ERC) thickness, and whole brain volume (WBV) as predictors of cognitive change in patients with AD. 120 AD subjects, 106 mild cognitive impairment (MCI), and 99 non demented controls (NDC) from the multi-center pan-European AddNeuroMed study underwent MRI scanning at baseline and clinical evaluations at quarterly follow-up up to 1 year. The rate of cognitive decline was estimated using cognitive outcomes, Mini-Mental State Examination (MMSE) and Alzheimer disease assessment scale–cognitive …(ADAS-cog) by fitting a random intercept and slope model. AD subjects had smaller ERC thickness and hippocampal and WBV volumes compared to MCI and NDC subjects. Within the AD group, ERC > WBV was significantly associated with baseline cognition (MMSE, ADAS-cog) and disease severity (Clinical Dementia Rating). Baseline ERC thickness was associated with both longitudinal MMSE and ADAS-cog score changes and WBV with ADAS-cog decline. These data indicate that AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive decline at one year follow up. ERC is a region known to be affected early in the disease. Therefore, the rate of atrophy in this structure is expected to be higher since neurodegeneration begins earlier. Focusing on structural analyses that predict decline can identify those individuals at greatest risk for future cognitive loss. This may have potential for increasing the efficacy of early intervention. Show more

Keywords: Alzheimer's disease, biomarker, cognitive decline, entorhinal cortex, hippocampus, whole brain volume

DOI: 10.3233/JAD-2012-121408

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 755-766, 2013

Authors: Rocco, Maria Luisa | Pristerà, Andrea | Pistillo, Luana | Aloe, Luigi | Canu, Nadia | Manni, Luigi

Article Type: Research Article

Abstract: Diabetes often correlates with tau phosphorylation and the development of Alzheimer's disease. Both are associated with brain cholinergic dysfunction that could benefit from nerve growth factor (NGF)-based therapies. Electroacupuncture (EA) improves brain NGF availability and action. Here we assessed the variations of NGF and tau phosphorylation in the cortex and hippocampus, as well as the expression of choline acetyltransferase in the basal forebrain following diabetes induction and EA in adult rats. We found that EA counteracts diabetes-associated tau hyperphosphorylation and decreases in NGF and choline acetyltransferase, suggesting a possible beneficial effect of EA on brain cholinergic system in diabetes.

Keywords: Choline acetyltransferase, diabetes, electroacupuncture, nerve growth factor, tau phosphorylation

DOI: 10.3233/JAD-2012-121309

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 767-773, 2013