Journal of Alzheimer's Disease - Volume 37, issue 1

Authors: Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system. Objective: The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks. Methods: 20 patients with Alzheimer’s disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and …20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks. Results: All groups performed similarly on both the immediate and delayed recall of the word-list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups. Conclusion: The combined use of the prose and word-list tasks evidenced a “mesio-temporal” memory profile in AD patients as opposed to a “frontal” one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, Lewy body dementia, memory recall, subcortical ischemic vascular disease

DOI: 10.3233/JAD-130347

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 99-107, 2013

Authors: Lo, Adrian C. | Iscru, Emilia | Blum, David | Tesseur, Ina | Callaerts-Vegh, Zsuzsanna | Buée, Luc | De Strooper, Bart | Balschun, Detlef | D'Hooge, Rudi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a consequence of degenerative brain pathology with amyloid plaque deposition and neurofibrillary tangle formation. These distinct aspects of AD neuropathology have been suggested to induce a cascade of pathological events ultimately leading to neurodegeneration as well as cognitive and behavioral decline. Amyloid and tau neuropathology is known to develop along distinct stages and affect parts of the brain differentially. In this study, we examined two mouse AD lines (AβPPPS1-21 and Tau22 mice), which mimic different partial aspects of AD pathology, at comparable stages of their pathology. Since prefrontal cortex (PFC) is one of the first regions …to be affected in clinical AD, we compared long-term potentiation (LTP) of synaptic responses in medial PFC of AβPPPS1-21 and Tau22 mice. Frontal LTP was impaired in AβPPPS1-21 mice, but not in Tau22 mice. Consequently, we observed different behavioral defects between AβPPPS1-21 and Tau22 animals. Apart from spatial learning deficits, AβPPPS1-21 transgenic mice were impaired in fear learning, aversion learning, and extinction learning, whereas THY-Tau22 were impaired in appetitive responding. Discriminant function analysis identified critical behavioral variables that differentiated AβPPPS1-21 and THY-Tau22 mice from wild type littermates, and further confirmed that amyloid- versus tau-pathology differentially affects brain function. Show more

Keywords: Alzheimer's disease, amyloid, cognition, prefrontal cortex, synaptic plasticity, tau

DOI: 10.3233/JAD-122296

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 109-125, 2013

Authors: Raven, Erika P. | Lu, Po H. | Tishler, Todd A. | Heydari, Panthea | Bartzokis, George

Article Type: Research Article

Abstract: Background: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer’s disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. Objective: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. Methods: Thirty-one AD and sixty-eight healthy …control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2 ) was used as an index of tissue damage. Results: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated. Conclusion: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD. Show more

Keywords: Alzheimer's disease, chelation, dementia, ferritin, field dependent relaxation rate increase (FDRI), iron, magnetic resonance imagining (MRI), myelin, prevention, treatment

DOI: 10.3233/JAD-130209

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 127-136, 2013

Authors: Mez, Jesse | Cosentino, Stephanie | Brickman, Adam M. | Huey, Edward D. | Mayeux, Richard

Article Type: Research Article

Abstract: The study's objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer's disease (AD). 1,368 participants from the National Alzheimer's Coordinating Center database with a diagnosis of probable AD (CDR 0.5–1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language …and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype. Show more

Keywords: African Americans, age of onset, Alzheimer's disease, aphasia, apolipoprotein E4, focal onset Alzheimer's disease, demographic factors, language, longitudinal studies, memory

DOI: 10.3233/JAD-130320

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 137-146, 2013

Authors: Annweiler, Cedric | Montero-Odasso, Manuel | Llewellyn, David J. | Richard-Devantoy, Stéphane | Duque, Gustavo | Beauchet, Olivier

Article Type: Research Article

Abstract: Background: Hypovitaminosis D is associated with global cognitive impairment in adults. It remains unclear which domain-specific cognitive functions are affected with hypovitaminosis D. Objective. To systematically review and quantitatively synthesize the association of serum 25-hydroxyvitamin D (25OHD) concentrations with episodic memory and executive functions in adults. Methods: A Medline and PsycINFO® libraries search was conducted on May 2012, with no limit of date, using the Medical Subject Headings (MeSH) terms “Vitamin D” OR “Hydroxycholecalciferols” combined with the MeSH terms “Memory” OR “Memory Disorders” OR “Executive Function” OR “Attention” OR “Cognition” OR “Cognition disorders” OR “Dementia” OR “Alzheimer …disease” OR “Neuropsychological Tests”. Fixed-effects meta-analysis was performed from 12 eligible studies using an inverse-variance method. Results: Of the 285 selected studies, 14 observational studies (including 3 prospective cohort studies) and 3 interventional studies met the selection criteria. All were of good quality. The number of participants ranged from 44–5,692 community-dwellers (0–100% women). In the pooled analysis, although episodic memory disorders showed only modest association with lower 25OHD concentrations (summary effect size of the difference (ES) = −0.09 [95%CI:−0.16;−0.03]), associations of greater magnitude were found with executive dysfunctions (processing speed: mean difference of Trail Making Test (TMT)-A score = 4.0 [95%CI:1.20;6.83]; mental shifting: mean difference of TMT-B score = 12.47 [95%CI:6.78;18.16]; information updating tests: ES = −0.31 [95%CI:−0.5;−0.09]). The pooled risk of incident decline of TMT-B score was OR = 1.25 [95%CI:1.05;1.48] in case of initial lower 25OHD concentrations. Vitamin D repletion resulted in improved executive functions (ES = −0.50 [95%CI:−0.69;−0.32] for before-and-after comparison), but exhibited no difference with control groups (ES = 0.14 [95%CI:−0.04;0.32] for between-group comparison after intervention). Conclusion: Lower serum 25OHD concentrations predict executive dysfunctions, especially on mental shifting, information updating and processing speed. The association with episodic memory remains uncertain. Show more

Keywords: Aging, cognition, episodic memory, executive functions, meta-analysis, neuroendocrinology, vitamin D

DOI: 10.3233/JAD-130452

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 147-171, 2013

Authors: Ito, Kaori | Corrigan, Brian | Romero, Klaus | Anziano, Richard | Neville, Jon | Stephenson, Diane | Lalonde, Richard

Article Type: Research Article

Abstract: Background: The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer’s disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. Objectives: The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. Methods: The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in …various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. Results: The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug effect. Baseline cognitive function is an important covariate of disease progression, therefore, it is important to evaluate the baseline severity and predict disease progression accordingly when comparing trial results. Furthermore, study duration, sample size, and study design may affect the placebo response, all of which have the potential to confound understanding of study results. Conclusion: The recent failures in Phase III AD studies are not likely due to insufficient cognitive decline in the control groups. A meta-analytic approach using all available data provides a robust understanding of placebo effect, disease progression, and potential interpretation of treatment effects, and offers a useful tool to aid in both trial design and interpretation. Show more

Keywords: ADAS-cog, Alzheimer's disease, Coalition Against Major Diseases (CAMD), disease progression, meta-analysis, placebo response

DOI: 10.3233/JAD-130575

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 173-183, 2013

Authors: Gezen-Ak, Duygu | Dursun, Erdinç | Hanağası, Haşmet | Bilgiç, Başar | Lohman, Ebba | Araz, Ömür Selin | Atasoy, İrem L. | Alaylıoğlu, Merve | Önal, Burak | Gürvit, Hakan | Yılmazer, Selma

Article Type: Research Article

Abstract: Identifying early-detection biomarkers have become an increasingly important approach in the treatment and prevention of Alzheimer's disease (AD). In this study, we investigated the potential of brain-derived neurotrophic factor (BDNF), complement factor H (CFH), tumor necrosis factor-α (TNFα), interleukin 10 (IL-10), and heat shock protein 90 (Hsp90) as serum biomarkers for AD in a cohort of the Turkish population because they have been suggested to be associated with AD. Serum BDNF, CFH, TNFα, IL-10, and Hsp90 levels in three groups of patients, early-onset AD (EOAD; age of onset < 65; n = 22), late-onset AD (LOAD; age of onset > …65; n = 54), and mild cognitive impairment (MCI) (n = 30), were compared with age-matched healthy controls (age < 65, n = 18 and age > 65; n = 32) using ELISA. The serum BDNF levels significantly decreased and TNFα levels significantly increased in the EOAD and LOAD groups compared to the age-matched healthy controls. There was a correlation between serum TNFα and IL-10 levels in the LOAD and healthy control groups. Serum CFH levels in the LOAD and MCI patients were significantly decreased compared with controls. Serum Hsp90 levels in the EOAD, LOAD, and MCI patients were significantly decreased compared with controls. The protein misfolding, the inflammatory response, and decreased neurotrophic factor synthesis are all suggested to be related to AD type brain pathology, and our results indicate these alterations might be traced from serum samples. For accurate early diagnosis of AD, it is important to determine a profile of alterations in multiple biomarkers in large-scale population studies. Show more

Keywords: Alzheimer's disease, brain-derived neurotrophic factor (BDNF), complement factor H (CFH), ELISA, heat shock protein 90 (Hsp90), interleukin 10 (IL-10), mild cognitive impairment (MCI), tumor necrosis factor-α (TNFα)

DOI: 10.3233/JAD-130497

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 185-195, 2013

Authors: Smith, J. Carson | Nielson, Kristy A. | Antuono, Piero | Lyons, Jeri-Annette | Hanson, Ryan J. | Butts, Alissa M. | Hantke, Nathan C. | Verber, Matthew D.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer's disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants …and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD. Show more

Keywords: Alzheimer's disease, dementia, exercise, magnetic resonance imaging, memory, non-pharmacologic treatment, physical activity, physical fitness

DOI: 10.3233/JAD-130467

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 197-215, 2013

Authors: Natunen, Teemu | Parrado, Antonio R. | Helisalmi, Seppo | Pursiheimo, Juha-Pekka | Sarajärvi, Timo | Mäkinen, Petra | Kurkinen, Kaisa M.A. | Mullin, Kristina | Alafuzoff, Irina | Haapasalo, Annakaisa | Bertram, Lars | Soininen, Hilkka | Tanzi, Rudolph E. | Hiltunen, Mikko

Article Type: Research Article

Abstract: Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein (GGA3) is a central regulator of trafficking and degradation of BACE1 (β-site AβPP-cleaving enzyme), the rate-limiting enzyme in the production of amyloid-β (Aβ) in Alzheimer's disease (AD). Here, we assessed the potential role of GGA3 in AD pathogenesis using independent neuropathological, case-control, and family-based human sample cohorts. Increased BACE1 levels coincided with decreased GGA3 levels and with elevated phosphorylation status of eIF2α-Ser51 in the temporal cortex of AD patients as compared to age-matched controls. Severity of the disease did not alter mRNA or protein levels of GGA3 in the inferior temporal cortex of AD patients, …while a positive correlation between GGA3 and the levels of total, but not phosphorylated, tau was observed. Genetically, we did not observe consistent evidence for association between AD risk and common GGA3 polymorphisms across a number of independent sample cohorts. However, a nominally significant association was observed with rs2242230 (p < 0.05) among the Finnish case-control cohort. Accordingly, mRNA and protein levels of GGA3 in the inferior temporal cortex of AD patients did not significantly correlate with rs2242230 genotype status. While the present study indicates that GGA3 is involved in the cellular processes relevant for AD pathogenesis, the genetic data do not support the idea that common GGA3 polymorphisms would contribute to AD risk. Show more

Keywords: Alzheimer's disease, amyloid-β, β-secretase, Braak staging, eukaryotic translation initiation factor 2α, frozen brain tissue samples, Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein, polymorphism, protein stability, tau protein

DOI: 10.3233/JAD-130104

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 217-232, 2013

Authors: Wiesmann, Maximilian | Jansen, Diane | Zerbi, Valerio | Broersen, Laus M. | Garthe, Alexander | Kiliaan, Amanda J.

Article Type: Research Article

Abstract: There is accumulating evidence showing that lifestyle factors like diet may influence the onset and progression of Alzheimer's disease (AD). Our previous studies suggest that a multi-nutrient diet, Fortasyn, containing nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid, eicosapentaenoic acid, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium, has an ameliorating effect on cognitive deficits in an AD mouse model. In the present study we analyzed learning strategies and memory of 11-month-old AβPPswe/PS1dE9 (AβPP/PS1) mice in the Morris water maze (MWM) task performed after nine months of dietary intervention with a control diet or …a Fortasyn diet to characterize diet-induced changes in cognitive performance. The Fortasyn diet had no significant effect on MWM task acquisition. To assess hippocampus-dependent learning, the strategies that the mice used to find the hidden platform in the MWM were analyzed using the swim path data. During the fourth day of the MWM, AβPP/PS1 mice on control diet more often used the non-spatial random search strategy, while on the Fortasyn diet, the transgenic animals exhibited more chaining strategy than their wild-type littermates. During the probe trial, AβPP/PS1 mice displayed no clear preference for the target quadrant. Notably, in both transgenic and nontransgenic mice on Fortasyn diet, the latency to reach the former platform position was decreased compared to mice on the control diet. In conclusion, this specific nutrient combination showed a tendency to improve searching behavior in AβPP/PS1 mice by increasing the use of a more efficient search strategy and improving their swim efficiency by decreasing the latency to reach the former platform position. Show more

Keywords: Alzheimer's disease, cognition, docosahexaenoic acids, learning, memory, transgenic mice

DOI: 10.3233/JAD-130179

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 233-245, 2013