Volume 29, Number 2, March 2012

Pages 241-254
Gérard Lizard, Olivier Rouaud, Jean Demarquoy, Mustapha Cherkaoui-Malki, Luigi Iuliano
Potential Roles of Peroxisomes in Alzheimer’s Disease and in Dementia of the Alzheimer’s Type
Abstract: In Alzheimer’s disease (AD) and dementia of the Alzheimer’s type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed.

Pages 255-273

JR Walton
Aluminum Disruption of Calcium Homeostasis and Signal Transduction Resembles Change that Occurs in Aging and Alzheimer’s Disease
Abstract: Most humans living in industrialized societies are routinely exposed to bioavailable aluminum salts in the form of additives—in commercially-prepared foods, alum-clarified drinking water, certain pharmaceuticals, sunscreens, and other topical applications. Minute amounts of this aluminum are absorbed into the circulation. Trace aluminum levels cross the blood-brain barrier and progressively accumulate in large pyramidal neurons of the hippocampus, cortex, and other brain regions vulnerable in Alzheimer’s disease. More aluminum enters the brain than leaves, resulting in a net increase in intraneuronal aluminum with advancing age. Aluminum is responsible for two main types of toxic damage in cells. As a pro-oxidant, aluminum causes oxidative damage both on its own and in synergy with iron. Aluminum also competes with, and substitutes for, essential metals—primarily Mg2+, iron and Ca2+ ions—in or on proteins and their co-factors. The author hypothesizes that intraneuronal aluminum interferes with Ca2+ metabolism in the aged brain and describes a way to test this hypothesis. This paper reviews: 1) major changes that occur in brain Ca2+ homeostasis and Ca2+ signaling, subtly with aging and more overtly in Alzheimer’s disease; and 2) evidence from the scientific literature that aluminum causes these same changes in neurons.

Pages 275-282
Amos D. Korczyn
Why Have We Failed to Cure Alzheimer’s Disease?
Abstract: There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer’s disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.

Pages 283-292
Stephen Deci, Susan K. Lemieux, Carrie A. Smith-Bell, D. Larry Sparks, Bernard G. Schreurs (Handling Associate Editor: Othman Ghribi)
Cholesterol Increases Ventricular Volume in a Rabbit Model of Alzheimer’s Disease
Abstract: One of the hallmarks of Alzheimer’s disease is a significant increase in ventricular volume. To date we and others have shown that a cholesterol-fed rabbit model of Alzheimer’s disease displays as many as fourteen different pathological markers of Alzheimer’s disease including amyloid-β accumulation, thioflavin-S staining, blood brain barrier breach, microglia activation, cerebrovasculature changes, and alterations in learning and memory. Using structural magnetic resonance imaging at 3T, we now report that cholesterol-fed rabbits also show a significant increase in ventricular volume following 10 weeks on a diet of 2% cholesterol. The increase in volume is attributable in large part to increases in the size of the third ventricle. These changes are accompanied by significant increases in the number of amyloid-β immuno-positive cells in the cortex and hippocampus. Increases in the number of amyloid-β neurons in the cortex also occurred with the addition of 0.24 ppm copper to the drinking water. Together with a list of other pathological markers, the current results add further validity to the value of the cholesterol-fed rabbit as a non-transgenic animal model of Alzheimer’s disease.

Pages 293-308
Slavica Krantic, Nathalie Isorce, Naguib Mechawar, Maria Antonietta Davoli, Erika Vignault, Marilia Albuquerque, Jean-Guy Chabot, Emmanuel Moyse, Jean-Pierre Chauvin, Isabelle Aubert, JoAnne McLaurin, Rémi Quirion
Hippocampal GABAergic Neurons are Susceptible to Amyloid-β Toxicity in vitro and are Decreased in Number in the Alzheimer’s Disease TgCRND8 Mouse Model
Abstract: The relevance of γ-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-β (Aβ) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Aβ42 (between 2 and 4 months) and accumulation of insoluble Aβ into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Aβ42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Aβ in vitro, GABAergic neurons are susceptible to Aβ42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Aβ load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5-2 month-old) TgCRND8 mice, it is likely that Aβ toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage.

Pages 309-318
Blossom C.M. Stephan, Fiona E. Matthews, Brandy Ma, Graciela Muniz, Sally Hunter, Daniel Davis, Ian G. McKeith, Gill Foster, Paul G. Ince, Carol Brayne, the Medical Research Council Cognitive Function and Ageing Neuropathology Study
Alzheimer and Vascular Neuropathological Changes Associated with Different Cognitive States in a Non-Demented Sample
Abstract: The state between aging with no cognitive impairment and dementia has become a major focus for intervention. The neuropathological and neurobiological correlates of this intermediate state are therefore of considerable interest, particularly from population representative samples. Here we investigate the neuropathological profile associated with different cognitive ability levels measured using strata defined by Mini Mental State Examination (MMSE) scores. One hundred and fifty one individuals were stratified into three cognitive groups including: non-, mildly, and moderately impaired at death. Alzheimer’s disease, atrophy, and vascular pathologies were investigated. Mild impairment was associated with an increased risk of vascular pathologies including small vessel disease and lacunes. In contrast, the moderately impaired group showed a more extensive pattern of pathology, including tangles and neuritic plaques (entorhinal/hippocampus), atrophy (cortical and hippocampal), and vascular disease (small vessel disease, lacunes, and infarcts). In a population-based sample of older people, MMSE score defined strata are associated with multiple pathologies. The profile of AD and vascular changes becomes more complex with increased cognitive impairment and these changes are likely to constitute a major substrate for age associated cognitive impairment. The results highlight the need for rigorous investigation of both neurodegenerative and vascular risks factors in old age.

Supplementary Data for Stephan et al. article (PDF)

Pages 319-327
Ineke A. van Rossum, Pieter Jelle Visser, Dirk L. Knol, Wiesje M. van der Flier, Charlotte E. Teunissen, Frederik Barkhof, Marinus A. Blankenstein, Philip Scheltens (Handling Associate Editor: Henrik Zetterberg)
Injury Markers but not Amyloid Markers are Associated with Rapid Progression from Mild Cognitive Impairment to Dementia in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n=56), MTA (n=76), and APOE-genotype (n=63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p=0.004) and low MMSE score (HR 2.0 p=0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p=0.07) and p-tau (1.7, p=0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia.

Pages 329-340
Zhiheng Liu*, Haihao Zhu*, Guang Guang Fang, Kathryn Walsh, Mkaya Mwamburi, Benjamin Wolozin, Samer O. Abdul-Hay, Tsuneya Ikezu, Malcolm A. Leissring, Wei Qiao Qiu (Handling Associate Editor: Yong Shen) *These authors contributed equally to the manuscript.
Characterization of Insulin Degrading Enzyme and Other Amyloid-β Degrading Proteases in Human Serum: a Role in Alzheimer’s Disease?
Abstract: Sporadic Alzheimer’s disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.

Pages 341-350
Claudius Mueller*, Matthew Schrag*, Andrew Crofton, Jens Stolte, Martina U. Muckenthaler, Shino Magaki, Wolff Kirsch *These authors contributed equally to the study.
Altered Serum Iron and Copper Homeostasis Predicts Cognitive Decline in Mild Cognitive Impairment
Abstract: Alzheimer’s disease (AD) brain is marked by severe neuronal death which has been partly attributed to increased oxidative stress. The pathophysiology accounting for this free radical injury is not well-delineated at this point, but one hypothesis is that a derangement in transition metal metabolism contributes to the process. We tested the hypothesis that peripheral derangement of transition metal metabolism is present early in the dementing process. We analyzed non-heme iron and copper levels in serum from subjects with normal cognition, mild cognitive impairment, and early stage senile dementia and followed these subjects over 5 years. An increase in the ratio of serum copper to non-heme iron levels predicted which subjects with mild cognitive impairment would progress to dementia versus those that would remain cognitively stable. This increase did not correlate with changes in expression of iron regulatory protein 2 or selected downstream targets in peripheral lymphocytes. A cDNA-based microarray (IronChip) containing genes relevant to iron and copper metabolism was used to assess transition metal metabolism in circulating lymphocytes from cognitively normal and demented subjects. No gene was identified as being dysregulated more than 2-fold, and verification using quantitative RT-PCR demonstrated no significant changes in expression for ALAS2, FOS, and CTR1. The increased ratio of serum copper to serum iron prior to dementia has potential as a biomarker for cognitive decline and mirrors other changes in serum previously reported by others, but iron and copper metabolism pathways appear to be broadly unaffected in peripheral blood in Alzheimer’s disease.

Pages 351-359
Haijing Lang, Xudong Huang, Yongliang Yang
Identification of Putative Molecular Imaging Probes for BACE-1 by Accounting for Protein Flexibility in Virtual Screening
Abstract: β-secretase (BACE-1), an enzyme critical in the process of amyloid-β (Aβ) peptides deposition in human brain, is closely associated with the onset and progression of Alzheimer’s disease (AD). A strong need exists, therefore, to identify molecular imaging probes homing at BACE-1 for use with positron emission tomography (PET) that is recognized as an effective tool for detecting AD. Through this imaging, an early diagnosis of AD could be made. Herein, to identify suitable molecular probes for use with PET, we searched the Molecular Imaging and Contrast Agent Database (MICAD), an online database warehousing scientific information regarding molecular imaging and contrast agents, and applied a virtual screening approach against the different confirmations of BACE-1 obtained from the World Wide Protein Database.The lack of considering receptor flexibility is a key drawback in virtual screening for drug discovery. Therefore, we incorporated protein flexibility into the virtual screening by using an ensemble of 143 experimental BACE-1 structures derived from the Protein Data Bank. Finally, the best performing affinity was recorded and used in the ranking of each ligand. To the best of our knowledge, this is the first virtual screening approach used to identify four new molecular probes that could target BACE-1 with favorable affinity, a discovery that can lead to the development of new PET probes for the early detection and therapy of AD. However, the actual utility of these probes can only be ascertained after in vitro and in vivo investigations.

Supplementary Data for Lang et al. article (PDF)
Supplementary Data for Lang et al. article (Excel file)

Pages 361-371
Vivek Venkataramani, Oliver Wirths, Herbert Budka, Wolfgang Härtig, Gabor G. Kovacs, Thomas A. Bayer (Handling Associate Editor: Irina Alafuzoff)
Antibody 9D5 Recognizes Oligomeric Pyroglutamate Amyloid-β in a Fraction of Amyloid-β Deposits in Alzheimer’s Disease without Cross-Reactivity with other Protein Aggregates
Abstract: Recent evidence suggests that soluble oligomeric amyloid-β (Aβ) assemblies are critically involved in the pathogenesis of Alzheimer’s disease (AD). We have generated a conformation-dependent monoclonal antibody (9D5) that selectively recognizes low-molecular weight AβpE3 oligomers, and demonstrated its diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a spectrum of neurodegeneration-related protein deposits for cross-reactivity, and by comparing the staining pattern of 9D5 with a generic Aβ antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent Aβ antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5 antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43 inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the specificity of 9D5 for Aβ deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total Aβ plaque load in the entorhinal cortex, the CA1 region, and the temporal neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of an epitope found only in oligomeric assemblies of AβpE3 of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of Aβ deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits.

Supplementary Data for Venkataramani et al. article (PDF)

Pages 373-377
Akio Kimura, Takeo Sakurai, Megumi Yamada, Akihiro Koumura, Yuichi Hayashi, Yuji Tanaka, Isao Hozumi, Hirofumi Ohtaki, Mitsuhiro Chousa, Masao Takemura, Mitsuru Seishima, Takashi Inuzuka
Antibodies Against the Tom40 Subunit of the Translocase of the Outer Mitochondrial Membrane Complex and Cognitive Impairment in Alzheimer’s Disease
Abstract: Recent studies suggest that microvascular abnormalities are involved in pathology and progression of Alzheimer’s disease. The purpose of this study was to examine the presence of antibodies against cerebral microvascular endothelial cells specific for Alzheimer’s disease, and to evaluate the association of these antibodies with cognitive impairment. The study included patients with Alzheimer’s disease (age ≥ 60 years; 24 patients), control subjects without neurological diseases (age ≥ 60 years; 19 subjects), patients with multiple sclerosis (all ages; 17 patients), and healthy control subjects (age < 40 years; 18 subjects). Serum was analyzed with 2-dimensional electrophoresis and Western blot, with cultured human brain microvascular endothelial cells as the antigen source. The anti-Tom40 antibody was identified significantly more frequently in patients with Alzheimer’s disease than control subjects or patients with multiple sclerosis. In patients with Alzheimer’s disease, the mean scores for the Mini-Mental State Examination were significantly lower for patients who were positive for anti-Tom40 antibody than those who were negative for anti-Tom40 antibody. In summary, the anti-Tom40 antibody is significantly associated with cognitive impairment in patients with Alzheimer’s disease.

Pages 379-391
Ying Peng*, Yanli Hu* , Shaofeng Xu, Pingping Li, Jiang Li, Li Lu, Hongyan Yang, Nan Feng, Ling Wang, Xiaoliang Wang (Handling Associate Editor: Jianzhi Wang) *These authors contributed equally to this work.
L-3-n-butylphthalide Reduces Tau Phosphorylation and Improves Cognitive Deficits in AβPP/PS1-Alzheimer’s Transgenic Mice
Abstract: L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and amyloid-β (Aβ)-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation, regulating amyloid-β protein precursor (AβPP) processing and reducing Aβ generation. The aim of the present study was to examine the effect of L-NBP on learning and memory in AβPP and presenilin 1 (PS1) double-transgenic AD mouse model (AβPP/PS1) and the mechanisms of L-NBP in reducing Aβ accumulation and tau phosphorylation. Twelve-month old AβPP/PS1 mice were given 15 mg/kg L-NBP by oral gavage for 3 months. L-NBP treatment significantly improved the spatial learning and memory deficits compared to the vehicle-treated AβPP/PS1 mice, whereas L-NBP treatment had no effect on cerebral Aβ plaque deposition and Aβ levels in brain homogenates. However, we found an L-NBP-induced reduction of tau hyperphosphorylation at Ser199, Thr205, Ser396, and Ser404 sites in AβPP/PS1 mice. Additionally, the expressions of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in tau phosphorylation, were markedly decreased by L-NBP treatment. The effects of L-NBP on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human AβPP695 (SK-N-SH AβPPwt). L-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of Alzheimer’s disease.

Pages 393-403
Barbara Caracciolo, Margaret Gatz, Weili Xu, Nancy L. Pedersen, Laura Fratiglioni (Handling Associate Editor: Julián Benito-León)
Differential Distribution of Subjective and Objective Cognitive Impairment in the Population: A Nation-Wide Twin-Study
Abstract: We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥ 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38-39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND.

Pages 405-429
Lies Clerx, Pieter Jelle Visser, Frans Verhey, Pauline Aalten (Handling Associate Editor: Tânia Alves)
New MRI Markers for Alzheimer’s Disease: A Meta-Analysis of Diffusion Tensor Imaging and a Comparison with Medial Temporal Lobe Measurements
Abstract: The aim of the present study is to evaluate the diagnostic value of diffusion tensor imaging (DTI) for early Alzheimer’s disease (AD) in comparison to widely accepted medial temporal lobe (MTL) atrophy measurements. A systematic literature research was performed into DTI and MTL atrophy in AD and mild cognitive impairment (MCI). We included seventy-six studies on MTL atrophy including 8,122 subjects and fifty-five DTI studies including 2,791 subjects. Outcome measure was the effect size (ES) expressed as Hedges g. In volumetric studies, atrophy of the MTL significantly differentiated between AD and controls (ES 1.32-1.98) and MCI and controls (ES 0.61-1.46). In DTI-Fractional anisotropy (FA) studies, the total cingulum differentiated best between AD and controls (ES=1.73) and the parahippocampal cingulum between MCI and controls (ES=0.97). In DTI-Mean diffusivity (MD) studies, the hippocampus differentiated best between AD and controls (ES=-1.17) and between MCI and controls (ES=-1.00). We can conclude that in general, the ES of volumetric MTL atrophy measurements was equal or larger than that of DTI measurements. However, for the comparison between controls and MCI-patients, ES of hippocampal MD was larger than ES of hippocampal volume. Furthermore, it seems that MD values have somewhat more discriminative power than FA values with higher ES in the frontal, parietal, occipital and temporal lobe.

Supplementary Data for Clerx et al. article (PDF)

Pages 431-439
Anne E Afgin, Magda Massarwa, Edna Schechtman, Simon D. Israeli-Korn, Rosa Strugatsky, Amin Abuful, Lindsay A. Farrer, Robert P. Friedland, Rivka Inzelberg
High Prevalence of Mild Cognitive Impairment and Alzheimer's Disease in Arabic Villages in Northern Israel: Impact of Gender and Education
Abstract: The prevalence of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) have not been well been studied in Arab populations. In a door-to-door study of all residents aged ≥65 years in Wadi-Ara, an Arab community in northern Israel, we estimated the prevalence of AD, MCI, and the risk of conversion to AD. Subjects were classified as cognitively normal, MCI, AD, or other based on neurological and cognitive examination (in Arabic). MCI subjects were re-examined (interval ≥1 year) to determine conversion to AD and contributions of age, gender, and education to the probability of conversion. Of the 944 participants (96.6% of those approached; 49.4% men), 92 (9.8%) had AD. An unusually high prevalence of MCI (n=303, 32.1%) was observed. Since the majority of women (77.2%) had no schooling, we estimated the effect of gender on the risk of AD and MCI among subjects without schooling and of school years among men. Among subjects with no schooling (n=452), age (p=0.02) and female gender (p<0.0001) were significant predictors of AD, whereas risk of MCI increased only with age (p=0.0001). Among men (n=318), age increased the risk (p<0.0001), school years reduced the risk of AD (p=0.039) and similarly for MCI [age (p=0.0001); school years (p=0.0007)]. Age (p=0.013), but not gender or school years, was a significant predictor of conversion from MCI to AD (annual rate 5.7%). The prevalence of MCI and AD are unusually high in Wadi Ara, while the rate of conversion from MCI to AD is low. Yet unidentified genetic factors might underlie this observation.

Pages 441-448
Yen-Ti Lee, Ming-Chyi Pai (Handling Associate Editor: Pei-Jung Frank Lu)
Recognition of Personally Familiar Scenes in Patients with Very Mild Alzheimer’s Disease: Effects of Spatial Frequency and Luminance
Abstract: Many community-residing patients with Alzheimer’s disease (AD) have way-finding problems, particularly at twilight or on rainy days. In an attempt to understand the mechanism, we prepared pictures of street scenes, including 8 personally familiar and 8 unfamiliar, divided into Low Spatial Frequency (LSF) and Low Luminance (LL) conditions to simulate foggy or rainy days and nighttime. Each picture was presented from the most difficult (level 10) to the easiest (level 1). The participants, including 20 very mild AD patients and 20 normal controls (NC) with equal basic visual acuity, were asked to judge whether a picture was familiar or not and to describe how they came to that conclusion. The accuracy of familiar scene recognition was measured by the number of pictures successfully recognized and the ability thereof by the level needed. Compared with NC, AD patients showed poorer accuracy (2.7±0.2 versus 3.6±0.1, mean±SEM, p= 0.003 under LSF; 2.8±0.2 versus 3.8±0.1, p= 0.001 under LL) and poorer ability (2.2±0.4 versus 4.3±0.4 p= 0.000 under LSF; 2.9±0.3 versus 5.2±0.5, p= 0.000 under LL) for both conditions. The AD patients used a global element to help judge when personally familiar scenes were displayed, which was the method NC usually adopted when presented with novel scenes. In summary, this study demonstrated poorer recognition ability in very mild AD patients when personally familiar street scenes were displayed, and the underlying mechanisms may include impaired visual search performance and efficiency. The deficits also reflect their difficulty in real life situations when their familiar environments become blurred or dark.

Pages 449-457
William G. Tharp, Yong-Ho Lee, Shane M. Greene, Elise Vincellete, Thomas G. Beach, Richard E. Pratley (Handling Associate Editor: Anders Lonneborg)
Measurement of Altered AβPP Isoform Expression in Frontal Cortex of Patients with Alzheimer’s Disease by Absolute Quantification Real-Time PCR
Abstract: Enzymatic cleavage of amyloid-β protein precursor (AβPP) produces amyloid-β (Aβ) peptides which form the insoluble cortical plaques characteristic of Alzheimer’s disease (AD). AβPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AβPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AβPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AβPP and all three major isoforms (AβPP695, AβPP751, and AβPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n=12) and without AD (n=10). Both total AβPP and AβPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p=0.037 and p=0.034, respectively). AβPP751 and AβPP770 transcripts numbers were not significantly different between AD and control (p>0.15). There was trend for decreased percentage AβPP695 (p=0.051) and increased percentage AβPP770 (p=0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p=0.005). Decreasing total AβPP and AβPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AβPP isoform transcripts by real-time PCR and confirm previous studies showing altered AβPP isoform expression patterns in AD.

Supplementary Data for Tharp et al. article (PDF)

Pages 459-469
David Wilkinson, Nick C Fox, Frederik Barkhof, Ravinder Phul, Ole Lemming, Philip Scheltens; for the Study 10112 investigators
Memantine and Brain Atrophy in Alzheimer’s Disease: A 1-year Randomized Controlled Trial
Abstract: The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer’s disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1:1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (-0.04 mL/year [(95% CI: -2.60, 2.52), p=0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes.

Pages 471-483
Julien Giustiniani, Marlène Sineus, Elodie Sardin, Omar Dounane, Maï Panchal, Véronique Sazdovitch, Charles Duyckaerts, Béatrice Chambraud*, Etienne-Emile Baulieu* (Handling Associate Editor: Marie Pardon) *These authors contributed equally to this work.
Decrease of the Immunophilin FKBP52 Accumulation in Human Brains of Alzheimer’s Disease and FTDP-17
Abstract: Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or “tauopathies”, include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed.