Journal of Alzheimer's Disease - Volume 18, issue 3

Authors: Mrak, Robert E.

Article Type: Review Article

Abstract: A role for innate immunity in neurodegenerative diseases is now widely accepted, although debate continues over the relative contributions of these processes to disease progression and/or to disease amelioration. The idea that microglia and cytokines are important in neurodegeneration arose from neuropathological observations, especially in Alzheimer's disease. Microglia are invariant components of the Aβ plaques of Alzheimer's disease, where they show a waxing and waning of numbers, activation state, and cytokine expression during plaque progression. This is in contrast to diffuse Aβ deposits sometimes found in abundance in the brain of non-demented elderly individuals, which do not contain activated microglia. …In Alzheimer's disease, plaque-associated astrocytes, which also produce paracrine mediators, show a pattern similar to that of microglia; and the associated plaque progression is accompanied by progressive damage to and loss of adjacent neurons. Further, activated microglia and astrocytes show a progressive pattern of association with neurofibrillary tangles. These observations, together with known functions of the involved cytokines, originally suggested a central role for immunological phenomena in driving disease progression in Alzheimer's disease. Further observations have extended these ideas to α-synuclein-based diseases (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions. Show more

Keywords: Alzheimer's disease, amyloid-β plaques, astrocytes, cytokines, interleukin-1, Lewy bodies, microglia, neurofibrillary tangles, neuroinflammation, S100B

DOI: 10.3233/JAD-2009-1158

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 473-481, 2009

Authors: Cardoso, Susana | Correia, Sónia | Santos, Renato X. | Carvalho, Cristina | Santos, Maria S. | Oliveira, Catarina R. | Perry, George | Smith, Mark A. | Zhu, Xiongwei | Moreira, Paula I.

Article Type: Review Article

Abstract: Insulin, long known as an important regulator of blood glucose levels, plays important and multifaceted roles in the brain. It has been reported that insulin is an important neuromodulator, contributing to several neurobiological processes in particular energy homeostasis and cognition. Dysregulation of insulin signaling has been linked to aging and metabolic and neurodegenerative disorders. The first part of this review is devoted to discussion of the critical role of insulin signaling in normal brain function. Then the involvement of impaired insulin signaling in the pathophysiology of diabetes, Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis will be discussed. Finally, …the potential therapeutic effect of insulin and insulin sensitizers will be examined. Show more

Keywords: Brain, insulin, insulin sensitizers, insulin signaling, neurodegenerative disorders

DOI: 10.3233/JAD-2009-1155

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 483-507, 2009

Authors: Glodzik, Lidia | De Santi, Susan | Rich, Kenneth E. | Brys, Miroslaw | Pirraglia, Elizabeth | Mistur, Rachel | Switalski, Remigiusz | Mosconi, Lisa | Sadowski, Martin | Zetterberg, Henrik | Blennow, Kaj | de Leon, Mony J.

Article Type: Short Communication

Abstract: Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, memantine, phosphorylated tau, total tau

DOI: 10.3233/JAD-2009-1183

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 509-513, 2009

Authors: Jiang, Xu | Zhang, Dongli | Shi, Jianting | Chen, Yiqun | Zhang, Ping | Mei, Bing

Article Type: Research Article

Abstract: It has been reported that conditional double knockout of presenilin-1 and presenilin-2 in forebrain of mice (dKO mice) induce symptoms most analogous to that of neurodegenerative diseases, especially Alzheimer's disease, however, there is no deposition of extra amyloid-β (Aβ40 or Aβ42 ) in dKO brain. In the present study, we thoroughly measured the inflammatory response in dKO mice, which is another global symptom in neurodegenerative diseases. We demonstrated that glial cells were dramatically activated from early age (3 months) in dKO brain when compared with control mice. In addition, complement C1qα and C4, the key components in the classical …complement pathway, were also stimulated in dKO mice brain. Antibody array and ELISA analysis indicated that cytokine and chemokine levels were also significantly increased in dKO brain. Moreover, we found that leukocytes were elevated beginning at 6 months of age, and multiple inflammatory mediators changed in dKO mice serum at 9 months, showing that the inflammatory responses gradually expanded to systemic tissue. These findings confirm that presenilins double knockout results in robust inflammatory response both in brain and in periphery and suggest that dKO mice may be useful to further understand the effects of inflammation on the pathological processes of neurodegenerative diseases. Show more

Keywords: Antibody array, inflammatory response, neurodegenerative disease, presenilins

DOI: 10.3233/JAD-2009-1164

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 515-523, 2009

Authors: Seidl, Ulrich | Thomann, Philipp A. | Schröder, Johannes

Article Type: Research Article

Abstract: Neurological soft signs (NSS), i.e., minor motor and sensory changes, are a common feature in psychiatric disorders related to brain changes. Nevertheless, they have rarely been investigated in patients with Alzheimer's disease (AD). NSS were examined in 104 nursing home residents with AD with respect to dementia severity, neuropsychiatric symptoms, and Parkinsonian signs as well as potential medication effects. 16 cognitively unimpaired residents served as a control group. NSS scores were significantly higher in residents with AD and were associated with both severity of cognitive deficits and non-cognitive symptoms, in particular apathy, but neither with Parkinsonian signs nor with antipsychotic …medication. Our results demonstrate that NSS increase with progression of AD and one may hypothesize that they are linked to degenerative cerebellar changes. NSS in AD are clinically significant and thus, besides other neurological symptoms, are to be considered in diagnostics and therapy. Show more

Keywords: Alzheimer's disease, antipsychotic medication, neurological soft signs, neuropsychiatric symptoms, Parkinsonian signs

DOI: 10.3233/JAD-2009-1159

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 525-532, 2009

Authors: Carrión-Baralt, José R. | Meléndez-Cabrero, Josefina | Rodríguez-Ubiñas, Heide | Schmeidler, James | Beeri, Michal Schnaider | Angelo, Gary | Sano, Mary | Silverman, Jeremy M.

Article Type: Research Article

Abstract: APOE ε4 is a major risk factor for Alzheimer's disease. It has also been associated with cognitive impairment and cognitive decline in young-olds, but the impact of the ε4 allele on cognitive function in very late life is still unclear. The object of this study was to evaluate the association of the ε4 allele of APOE with the cognitive performance of a sample of non-demented oldest-olds. Eighty-seven Spanish-speaking Puerto Rican non-demented nonagenarians were administered a complete neuropsychological assessment and provided a blood sample used for APOE genotyping. A factor analysis generated two factors: 1) verbal memory; and 2) visuo-spatial, naming …and attention tasks, accounting for 43.6% of the overall variance in the 13 original neuropsychological variables. The multivariate analysis reflected, after controlling for gender, education, and age, the APOE ε4 carriers performed better in overall cognition (both factors analyzed together) than non-carriers (T2 = 0.082, F(2,80) = 3.289, p = 0.042). Neither gender nor the gender by APOE ε4 status interaction was associated with differences in cognition. In conclusion, the results of this study suggest that, among these Puerto Rican non-demented nonagenarians, being an APOE ε4 allele carrier is associated with better cognition. Show more

Keywords: APOE, cognition, Hispanic, nonagenarian

DOI: 10.3233/JAD-2009-1160

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 533-540, 2009

Authors: García-Rodríguez, Beatriz | Fusari, Anna | Rodríguez, Beatriz | Hernández, José Martín Zurdo | Ellgring, Heiner

Article Type: Research Article

Abstract: Implicit memory for emotional facial expressions (EFEs) was investigated in young adults, healthy old adults, and mild Alzheimer's disease (AD) patients. Implicit memory is revealed by the effect of experience on performance by studying previously encoded versus novel stimuli, a phenomenon referred to as perceptual priming. The aim was to assess the changes in the patterns of priming as a function of aging and dementia. Participants identified EFEs taken from the Facial Action Coding System and the stimuli used represented the emotions of happiness, sadness, surprise, fear, anger, and disgust. In the study phase, participants rated the pleasantness of 36 …faces using a Likert-type scale. Subsequently, the response to the 36 previously studied and 36 novel EFEs was tested when they were randomly presented in a cued naming task. The results showed that implicit memory for EFEs is preserved in AD and aging, and no specific age-related effects on implicit memory for EFEs were observed. However, different priming patterns were evident in AD patients that may reflect pathological brain damage and the effect of stimulus complexity. These findings provide evidence of how progressive neuropathological changes in the temporal and frontal areas may affect emotional processing in more advanced stages of the disease. Show more

Keywords: Aging, Alzheimer's disease, emotional facial expression identification, implicit memory, priming

DOI: 10.3233/JAD-2009-1161

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 541-551, 2009

Authors: Honea, Robyn A. | Vidoni, Eric | Harsha, Amith | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Neuroimaging studies of apolipoprotein E (ApoE4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess ApoE4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with ApoE4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the E4 allele, cognitive performance was reduced, and atrophy was …present in the hippocampus and amygdala compared to ApoE4 negative participants. We also report that E4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an ApoE4 allele in nondemented older adults is associated with decreases in cognition and gray and white matter changes in the medial temporal cortex. Overall we provide further evidence of the effects of genetic variance related to imaging and cognitive measures of risk for Alzheimer's disease. Show more

Keywords: Aging, Alzheimer's disease, apolipoprotein (APOE), cognition, dementia, diffusion tensor imaging (DTI), fractional anisotropy (FA), genetics, hippocampus, voxel-based morphometry (VBM)

DOI: 10.3233/JAD-2009-1163

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 553-564, 2009

Authors: Linkous, David H. | Adlard, Paul A. | Wanschura, Patricia B. | Conko, Kathryn M. | Flinn, Jane M.

Article Type: Research Article

Abstract: There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, there remain few studies that have examined the behavioral consequences of elevated dietary metals in wild type and Alzheimer's disease animals. To further investigate this in the current study, two separate transgenic models of AD (Tg2576 and TgCRND8), together with wild type littermates were administered 10 ppm (0.153 mM) Zn. Tg2576 animals were maintained on a zinc-enriched diet both pre- and postnatally until 11 months of …age, while TgCRND8 animals were treated for five months following weaning. Behavioral testing, consisting of “Atlantis” and “moving” platform versions of the Morris water maze, were conducted at the end of the study, and tissues were collected for immunohistochemical analysis of amyloid-β burden. Our data demonstrate that the provision of a zinc-enriched diet potentiated Alzheimer-like spatial memory impairments in the transgenic animals and was associated with reduced hippocampal amyloid-β plaque deposits. Zinc-related behavioral deficits were also demonstrated in wild type mice, which were sometimes as great as those present in the transgenic animals. However, zinc-related cognitive impairments in transgenic mice were greater than the summation of zinc effects in the wild type mice and the transgene effects. Show more

Keywords: Alzheimer's disease, amyloid plaques, metals, Morris water maze, nutrition, spatial memory, Tg2576, transgenic mice, Westaway, zinc

DOI: 10.3233/JAD-2009-1162

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 565-579, 2009

Authors: Zhu, Ying-Ying | Ni, Dao-Feng | Xu, Cai-Min

Article Type: Research Article

Abstract: Abnormalities and impaired functions of the olfactory system have been reported in Alzheimer's disease (AD), and these changes may appear much earlier than other clinical symptoms of AD. However, little is known about these abnormalities at the level of gene expression. In this study, we investigated alterations of expression of 22,012 genes in the olfactory bulbs of a rat model of AD by using a microarray approach. The rat model was produced by intracerebroventricular injection of amyloid-β25-35 , which demonstrated pathological changes in olfactory bulbs and memory impairment in the Morris water maze test. We found that expression of 811 …genes among the 22,012 genes was altered by more than 1.5-fold in the amyloid-β-injected rats as compared with control injected rats. We analyzed the distribution of the 811 altered genes according to the Affymetrix criteria and found that the majority of these genes were related to cellular processes, binding, and enzyme activities. The alterations of three of these genes, i.e., calcineurin, olfactory receptor, and protein kinase C, were also confirmed by RT-PCR and Western blots. These studies provide new insight into the abnormalities of the olfactory system in AD and might help to further the understanding of the molecular mechanisms of AD. Show more

Keywords: Alzheimer's disease, gene expression profile, microarray, olfactory bulb, rat

DOI: 10.3233/JAD-2009-1201

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 581-593, 2009