Volume 31, Number 3, August 2012

Pages 459-474
Mortimer Mamelak (Handling Associate Editor: D. Allan Butterfield)
Sporadic Alzheimer’s Disease: The Starving Brain
Abstract: A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimer’s disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimer’s disease.

Pages 475-492
Teng Jiang, Jin-Tai Yu, Lan Tan (Handling Associate Editor: Benedetta Nacmias)
Novel Disease-Modifying Therapies for Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common progressive dementia in the elderly and places an enormous burden on the individual and society. Presently, the treatments for AD are only symptomatic and do not halt the progression of the disease. With the recent advances in the understanding of the pathogenesis of AD in past years, numerous therapies which could modify the disease process are under active investigation. These therapies could attenuate or even reverse the neurodegenerative process by interfering with the underlying pathogenesis including amyloid-β production, tau hyperphosphorylation, oxidative stress, inflammation, and excitotoxicity. In this review, new disease-modifying therapies which reduce amyloid-β production, prevent tau hyperphosphorylation, and provide neuroprotective effects are described, including the results of in vitro and in vivo studies and clinical trials. Some typical therapies with disease-modifying effects have also been discussed.

Pages 493-506
Shingo Ito, Michel Ménard, Trevor Atkinson, Chantal Gaudet, Leslie Brown, James Whitfield, Balu Chakravarthy (Handling Associate Editor: Ottavio Arancio)
Involvement of Insulin-Like Growth Factor 1 Receptor Signaling in the Amyloid-β Peptide Oligomers-Induced p75 Neurotrophin Receptor Protein Expression in Mouse Hippocampus
Abstract: The p75 neurotrophin receptor (p75NTR) has been thought to play a critical role in amyloid-β peptide (Aβ)-mediated neurodegeneration and Aβ metabolism in Alzheimer’s disease (AD) brains. Our previous report showed that membrane-associated p75NTR protein expression was significantly increased in the hippocampi of two different strains of transgenic AD mice and was associated with the age-dependent elevation of Aβ1-42 levels. Here, we provide evidence that the Aβ1-42 oligomers known as ADDLs (Aβ-derived diffusible ligands) induce p75NTR protein expression through insulin-like growth factor 1 receptor (IGF-1R) phosphorylation in SH-SY5Y human neuroblastoma cells. An in vivo microinjection study demonstrated that microinjected ADDLs increased the p75NTR protein expression by 1.4-fold in the ipsilateral hippocampus compared to the contralateral hippocampus. In addition, ADDLs microinjected into mouse hippocampi facilitated IGF-1R phosphorylation within 30 min and the co-administration of picropodophyllin, an IGF-1R kinase inhibitor, blocked ADDLs-induced p75NTR expression. We examined the possible involvement of IGF-1R in the increased p75NTR protein expression in the hippocampi of 6-month-old AβPPswe/PS1dE9 AD model mice that had accumulated significant amounts of Aβ1-42 and showed significantly higher p75NTR expression than age-matched wild-type mice. We found that IGF-1R phosphorylation in these transgenic mice was higher than that in the wild-type mice. These findings indicate that Aβ1-42 oligomers stimulate the p75NTR protein expression in the hippocampus through IGF-1R signaling. Thus, Aβ1-42 oligomers-mediated IGF-1R activation may trigger an increase in p75NTR protein expression in the hippocampus of AD brain during the early stages of disease development.

Pages 507-516
Timothy Schultz, Eric Yang, Michael Farnum, Victor Lobanov, Rudi Verbeeck, Nandini Raghavan, Mahesh N. Samtani, Gerald Novak, Yingqi Shi, Vaibhav Narayan, Allitia DiBernardo
A Novel Subject Synchronization Clinical Trial Design for Alzheimer’s Disease
Abstract: One of the challenges in developing a viable therapy for Alzheimer’s disease has been demonstrating efficacy within a clinical trial. Using this as motivation, we sought to re-examine conventional clinical trial practices in order to determine whether efficacy can be better shown through alternative trial designs and novel analysis methods. In this work, we hypothesize that the confounding factors which hamper the ability to discern a treatment signal are the variability in observations as well as the insidious nature of the disease. We demonstrate that a two-phase trial design in which drug dosing is administered after a certain level of disease severity has been reached, coupled with a method to account more accurately for the progression of the disease, may allow us to compensate for these factors, and thus enable us to make treatment effects more apparent. Utilizing data from two previously failed trials which involved the evaluation of galantamine for indication in mild cognitive impairment, we were able to demonstrate that a clear treatment effect can be realized through both visual and statistical means, and propose that future trials may be more likely to show success if similar methods are utilized.

Pages 517-526
Lorena Rami, Roser Sala-Llonch, Cristina Solé-Padullés, Juan Fortea, Jaume Olives, Albert Lladó, Cleofe Peña-Gómez, Mircea Balasa, Bea Bosch, Anna Antonell, Raquel Sanchez-Valle, David Bartrés-Faz, Jose L. Molinuevo
Distinct Functional Activity of the Precuneus and Posterior Cingulate Cortex During Encoding in the Preclinical Stage of Alzheimer’s Disease
Abstract: In this study functional magnetic resonance imaging (fMRI) is used to investigate the functional brain activation pattern in the preclinical stage of AD (pre-AD) subjects during a visual encoding memory task. Thirty subjects, eleven in the pre-AD stage, with decreased cerebrospinal fluid levels of Aβ42 (<500 pg/ml), and 19 controls with normal Aβ42 levels (CTR) were included. fMRI was acquired during a visual encoding task. Data were analyzed through an Independent Component Analysis (ICA) and region-of-interest-based univariate analysis of task-related BOLD signal change. From the ICA decomposition, we identified the main task-related component, which included the activation of visual associative areas and prefrontal executive regions, and the deactivation of the default-mode network. The activation was positively correlated with task performance in the CTR group (p <0.0054). Within this pattern, subjects in the pre-AD stage had significantly greater activation of the precuneus and posterior cingulate cortex during encoding. Subjects in the pre-AD stage present distinct functional neural activity before the appearance of clinical symptomatology. These findings may represent that subtle changes in functional brain activity precede clinical and cognitive symptoms in the AD continuum. Present findings provide evidence suggesting that fMRI may be a suitable biomarker of preclinical AD.

Supplementary Data for Rami et al. article (PDF)

Pages 527-536
Louise Hedskog, Jesper Brohede, Birgitta Wiehager, Catarina Moreira Pinho, Priya Revathikumar, Lena Lilius, Elzbieta Glaser, Caroline Graff, Helena Karlström, Maria Ankarcrona
Biochemical Studies of Poly-T Variants in the Alzheimer’s Disease Associated TOMM40 Gene
Abstract: The apolipoprotein E (APOE) gene, one in a growing field of risk factor candidates, remains the most strongly established risk factor for late onset Alzheimer’s disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length. Reported results are contradictory in regard to the very long poly-T variant that has been associated with both increased and decreased risk of LOAD. Our study aimed to elucidate the functional implication of rs10524523 in an in vitro model of human fibroblast cells obtained from cognitively healthy APOE ε3/ε4 carriers harboring very long or short poly-T variants coupled to their APOE ε3 allele. We have studied (i) expression levels of TOM40 protein and mRNA, (ii) TOM40 mRNA splicing, and (iii) mitochondrial function and morphology; and we have found no significant differences in regards to very long or short poly-T variant.

Pages 537-542
Chiara Villa, Laura Ghezzi, Chiara Fenoglio, Francesca Clerici, Alessandra Marcone, Luisa Benussi, Roberta Ghidoni, Salvatore Gallone, Maria Serpente, Claudia Cantoni, Elisa Ridolfi, Rossana Bonsi, Chiara Cerami, Stefano Cappa, Giuliano Binetti, Massimo Franceschi, Innocenzo Rainero, Claudio Mariani, Nereo Bresolin, Elio Scarpini*, Daniela Galimberti* (Handling Associate Editor: Emilio Di Maria) *These authors contributed equally to this work
Genetics and Expression Analysis of the Specificity Protein 4 Gene (SP4) in Patients with Alzheimer’s Disease and Frontotemporal Lobar Degeneration
Abstract: Transcription factor Sp4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer’s disease (AD), and Sp4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms (SNPs)—rs9639379, rs10272006, and rs6461569—has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three SNPs were found (p>0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132±1.301 versus 3.396±0.829, p<0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525±1.500 versus 3.396±0.829, p=0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases.

Supplementary Data for Villa et al. article (PDF)

Pages 543-553
Pablo Martínez-Martín, Emma Osa-Ruiz, Antonia Gómez-Conesa, Javier Olazarán, and the RSGE-CD Validation Group
A Rating Scale for Gait Evaluation in Cognitive Deterioration (RSGE-CD): Validation Study
Abstract: A relationship between decline in mobility and walking performance and cognitive impairment exists in the elderly. Therefore, clinical assessment of gait and mobility may be relevant for diagnostic and therapeutic purposes. However, the rating scales used for evaluation of gait disorder in the context of cognitive deterioration were not designed or validated for that setting. The present study was aimed at checking the clinimetric properties of the Rating Scale for Gait Evaluation in Cognitive Deterioration (RSGE-CD), specifically developed for assessment of gait dysfunction across all stages of cognitive decline. Two hundred fifty six subjects were included in the study and classified according to the Global Deterioration Scale (control, subjective/mild cognitive impairment, or dementia). Patients with dementia had a diagnosis of probable Alzheimer’s disease (73%) or dementia of combined etiology (27%). Cognitive and functional evaluations, the Tinetti scale, and timed tests were simultaneously applied with the tested scale, which is composed of two subscales: Functional ability and Examination. Exploratory factor analysis showed one factor (70% of the variance). Floor effect and skewness were observed in the control group, whereas internal consistency (Cronbach’s alpha=0.88-0.95), inter-observer and test-retest reliability (intraclass correlation coefficients ≥0.97) were satisfactory. Convergent validity with the other measures was ≥0.60 and the discriminant validity according to classification of subjects by cognitive state and other aspects was also satisfactory (p=0.0001). The RSGE-CD showed low standard errors of measurement. In this first validation study, the RSGE-CD showed satisfactory clinimetric attributes for assessing gait and mobility across the complete range of cognitive state.

Supplementary Data for Martinez-Martin et al. article (PDF)

Pages 555-567
Marco Matos, Elisabete Augusto, Nuno J. Machado, Alexandre dos Santos-Rodrigues, Rodrigo A. Cunha, Paula Agostinho
Astrocytic Adenosine A2A Receptors Control the Amyloid-β Peptide-Induced Decrease of Glutamate Uptake
Abstract: Alzheimer’s disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ1-42). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Aβ to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A2A receptors (A2AR) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A2AR also modulate astrocytic glutamate uptake, we now tested if A2AR blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, Aβ1-42 (1 µM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A2AR agonist, CGS 26180 (30 nM), and prevented by the A2AR antagonist, SCH 58261 (100 nM). Aβ1-42 also decreased D-aspartate uptake by 28±4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A2AR. In accordance with the long term control of glutamate transporter expression by A2AR, Aβ1-42 enhanced the expression and density of astrocytic A2AR and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A2AR knockout mice. This impact of Aβ1-42 on glutamate transporters and uptake, dependent on A2AR function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ1-42. These results provide the first demonstration for a direct key role of astrocytic A2AR in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.

Pages 569-580
Gemma S. Morgan, John Gallacher, Antony Bayer, Mark Fish, Shah Ebrahim, Yoav Ben-Shlomo
Physical Activity in Middle-Age and Dementia in Later Life: Findings from a Prospective Cohort of Men in Caerphilly, South Wales and a Meta-Analysis
Abstract: Previous studies suggest that physical activity may be protective for dementia and cognitive impairment. We report findings comparing leisure-time and work-related physical activity from the Caerphilly Prospective study (CaPS) with dementia and cognitive impairment not dementia (CIND) after around 16 years of follow-up. We synthesized our results with a meta-analysis specifically testing if length of follow-up was associated with the size of any association. Age-adjusted models found no real association with dementia, and if anything increased risk for CIND (odds ratio (OR) highest versus lowest tertile 2.61, 95% CI 1.58 to 4.31), though this was attenuated after adjustment for other confounders (OR highest versus lowest tertile 1.38, 95% CI 0.78 to 2.44). There was no evidence that this differed by type (vascular versus non-vascular) of cognitive disease. Meta-analysis of other published effect estimates showed a protective effect of physical activity on cognitive impairment (OR 0.66, 95% CI 0.52 to 0.85) but with significant heterogeneity which was partially explained by length of follow up (p=0.03). A protective association was also seen for dementia (OR 0.78, 95% CI 0.65, 0.94), which did not appear to be related to follow-up length but there was evidence of small study bias (p=0.002) suggesting an absence of small null studies. The apparent protective effects of physical activity on cognitive health may partially reflect reverse causation and current estimates may be overly optimistic in terms of cognitive benefits.

Supplementary Data for Morgan et al. article (PDF)

Pages 581-591
Anna Antonell, Silvia Gil, Raquel Sánchez-Valle, Mircea Balasa, Beatriz Bosch, Mª Carmen Prat, Anne-Cécile Chiollaz, Manel Fernández, Jordi Yagüe, José Luis Molinuevo, Albert Lladó (Handling Associate Editor: Christine van Broeckhoven)
Serum Progranulin Levels in Patients with Frontotemporal Lobar Degeneration and Alzheimer’s Disease: Detection of GRN Mutations in a Spanish Cohort
Abstract: Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer’s disease (AD), or Parkinson’s disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers,and 18 control individuals. We detected 5 patients with PGRN levels below <94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean=145.5 ng/mL, SD=28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean=50.5 ng/mL, SD=21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139P (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels.

Pages 593-599
Giacomo Koch, Francesco Di Lorenzo, Sonia Bonnì, Viviana Ponzo, Carlo Caltagirone, Alessandro Martorana
Impaired LTP- but not LTD-like Cortical Plasticity in Alzheimer’s Disease Patients
Abstract: In animal models of Alzheimer’s disease (AD), amyloid-β fragments interfere with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). In the current study, we applied repetitive transcranial magnetic stimulation over the primary motor cortex (M1) in AD patients and in age-matched healthy controls, using protocols of theta burst stimulation (TBS) that are known to induce plastic changes resembling the LTP and LTD mechanisms described in animal models. AD patients showed consistent LTD-like effects that were comparable to those obtained in healthy controls when submitted to 40 seconds of continuous TBS. Conversely, AD patients did not show any LTP-like after effect when submitted to other two different TBS protocols that induced an LTP-like effect in healthy controls such as intermittent TBS and 20 seconds of continuous TBS followed by one minute of muscular contraction. These results demonstrate the impairment of LTP-like together with normal LTD-like cortical plasticity in AD patients.

Pages 601-612
Wei Zhang, Janna Arteaga, Daniel K. Cashion, Gang Chen, Umesh Gangadharmath, Luis F. Gomez, Dhanalakshmi Kasi, Chung Lam, Qianwa Liang, Changhui Liu, Vani P. Mocharla, Fanrong Mu, Anjana Sinha, A. Katrin Szardenings, Eric Wang, Joseph C. Walsh, Chunfang Xia, Chul Yu, Tieming Zhao, Hartmuth C. Kolb
A Highly Selective and Specific PET Tracer for Imaging of Tau Pathologies
Abstract: Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer’s disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-β positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process. A competitive autoradiography assay was set up to test compounds for binding to native tau tangles and amyloid-β plaques on human brain tissue sections. In our in vitro assays, the 18F labeled compound [18F]-T808 displayed a high level of binding affinity and good selectivity for tau aggregates over amyloid-β plaques. [18F]-T808 showed rapid uptake and washout in rodent brains. Our in vitro and preclinical in vivo studies suggest that [18F]-T808 possesses suitable properties and characteristics to be a specific and selective PET probe for imaging of paired helical filament tau in human brains.

Pages 613-621
Carla Velarde, Elizabeth Perelstein, Wendy Ressmann, Charles J. Duffy (Handling Associate Editor: Alan Lerner)
Independent Deficits of Visual Word and Motion Processing in Aging and Early Alzheimer’s Disease
Abstract: We tested whether visual processing impairments in aging and Alzheimer’s disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits.

Pages 623-633
Enrica Cavedo,Samantha Galluzzi, Michela Pievani, Marina Boccardi, Giovanni B. Frisoni (Handling Associate Editor: Laura Petrosini)
Norms for Imaging Markers of Brain Reserve
Abstract: Brain reserve allows some people to be more resilient to neurodegeneration processes and brain diseases. Structural markers of brain reserve are hippocampus, lateral ventricles, and white matter lesions volume (HV, LVV, WMLV). Subjects in the low end of the distribution of these markers are at higher risk to develop brain diseases such as Alzheimer’s disease. We described the distribution of the above markers in a large group of cognitively-intact persons. A sample of 158 people aged between 40 to 90 years (mean±SD: 60±12 years, education 9±4 years, MMSE score 28±2) belonging to the Italian Brain Normative Archive was selected. HV, LVV, and WMLV were measured with validated procedures. The HV and LVV were measured by manual segmentation and the Freesurfer software, respectively, and normalized by head size; WMLV was measured with semi-automated thresholding. Test-retest reliability was >0.83 for all measures. No relationship was found between HV and age, whereas a significant relationship was found for LVV and WMLV (ventricle left: B 0.02, 95% CI 0.22 to 0.34; ventricle right: B 0.02 95% CI 0.23 to 0.34 p<0.001; WML: B 0.04; 95% CI 0.03 to 0.06 p<0.005). The 5th percentile threshold indicating lower brain reserve were: (i) HV below 2,260 mm3 at 40 and 2,000 mm3 at 90; (ii) LVV above 17,000 mm3 at 40 and 60,000 mm3 at 90; and (iii) WMLV above 1,200 mm3 at 40 and 8,700 mm3 at 90. Normative data of brain reserve markers can be used to estimate the brain resilience to neurodegeneration.

Pages 635-649
Xiaqin Sun, Xiaolu Meng, Jie Zhang, Yonghui Li, Liping Wang, Xiaoyan Qin, Nan Sui, Yan Zhang
GABA Attenuates Amyloid Toxicity by Downregulating its Endocytosis and Improves Cognitive Impairment
Abstract: GABA (gamma-aminobutyric acid) receptor modulators have been investigated as a potential treatment strategy in Alzheimer’s disease (AD). In the present study, we found that GABA levels were different in wild type (WT) and AβPP/PS1 mouse brains. GABA downregulated amyloid-β (Aβ) uptake in neurons through the receptor for advanced glycation end-products. Therefore, relative high levels of GABA decreased cytotoxicity induced by Aβ in WT mice. GABA treatment decreased basal levels of cell death and the cell death induced by hydrogen peroxide in WT and AβPP/PS1 neurons. Application of GABA during early life before 2 months of age can improve cognitive function significantly in AβPP/PS1 mice. However, GABA treatment at 6 and 8 months of age cannot improve water maze performance. Activating or suppressing GABAA receptors by optogenetic methods also confirmed that GABA activation before 2 months of age increased water maze performance in AβPP/PS1 mice. Our data suggest that GABA administration during early life can be a potential treatment for AD.

Pages 651-657
Sandra Schütze (née Ebert), Tobias Loleit, Moritz Zeretzke, Stephanie Bunkowski, Wolfgang Brück, Sandra Ribes, Roland Nau
Additive Microglia-Mediated Neuronal Injury Caused by Amyloid-β and Bacterial TLR Agonists in Murine Neuron-Microglia Co-Cultures Quantified by an Automated Image Analysis using Cognition Network Technology
Abstract: Activated microglia is considered to be involved in the progression of Alzheimer’s disease (AD). We investigated the effect of amyloid-β40 (Aβ40) and exogenous agonists of toll-like receptor (TLR) 1/2 (Pam3CSK4) and TLR4 (LPS) on neurons in primary murine neuron-microglia co-cultures. Neuronal viability, assessed by quantifying the number of intact neuronal extensions and their crossings using a newly developed Definiens Cognition Network Technology-based method, was significantly decreased after treatment with Pam3CSK4, LPS, and Aβ40. Combined treatment with Aβ40 and Pam3CSK4 or LPS had an additive effect. Hence, in patients with AD, synergistic microglial activation by Aβ and bacterial products during infections might contribute to disease progression.

Pages 659-668
Robyn A. Honea, Eric D. Vidoni, Russell H. Swerdlow, Jeffrey M. Burns, for the Alzheimer’s Disease Neuroimaging Initiative
Maternal Family History is Associated with Alzheimer’s Disease Biomarkers
Abstract: A family history of Alzheimer’s disease (AD) increases one’s risk of developing late-onset AD (LOAD), and a maternal family history of LOAD influences risk more than a paternal family history. Accumulating evidence suggests that a family history of dementia associates with AD-typical biomarker changes. We analyzed cross-sectional data from non-demented, mild cognitive impairment (MCI), and LOAD participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n=99) and cerebrospinal fluid (CSF) analysis (n=403) for amyloid-β peptide (Aβ) and total tau. We assessed the relationship of CSF and PiB biomarkers and family history of dementia, as well as parent gender effects. In the larger analysis of CSF biomarkers, we assessed diagnosis groups individually. In the overall sample, CSF Aβ, tau/Aβ ratio, and global PiB uptake were significantly different between family history positive and negative groups, with markers of increased AD burden associated with a positive maternal family history of dementia. Moreover, a maternal family history of dementia was associated with significantly greater PiB Aβ load in the brain in the parietal cortex, precuneus, and sensorimotor cortex. Individuals with MCI positive for a maternal family history of dementia had significantly more markers of AD pathophysiology than individuals with no family history of dementia. A family history of dementia is associated with AD-typical biomarker changes. These biomarker associations are most robust in individuals with a maternal family history, suggesting that a maternally inherited factor influences AD risk.

Pages 669-676
Karin Wallin, Alina Solomon, Ingemar Kåreholt, Jaakko Tuomilehto, Hilkka Soininen, Miia Kivipelto (Handling Associate Editor: Sandrine Andrieu)
Midlife Rheumatoid Arthritis Increases the Risk of Cognitive Impairment Two Decades Later: A Population-Based Study
Abstract: Inflammation has been associated with Alzheimer’s disease (AD) and dementia. The association between rheumatoid arthritis (RA) or arthritis and dementia/AD has been investigated in several case-control or hospital- and register-based studies with mixed results. This long-term population-based study investigates the association between presence of joint disorders (RA and other joint disorders) in midlife and cognitive status later in life. 1,449 participants were first evaluated in 1972, 1977, 1982, and 1987 and follow-up was performed after 21 years. A self-administered questionnaire including questions on joint disorders was used at both evaluations. Cognitive status (control, mild cognitive impairment, dementia/AD) was assessed at follow-up. The presence of any joint disorder in midlife was significantly associated with a worse cognitive status later in life: OR (95% CI) in an ordinal logistic regression analysis adjusted for age, gender, follow-up time, education, APOEε4, body mass index, smoking, drug treatment, and diabetes was 1.96 (1.17-3.28). For RA only, OR (95% CI) was 2.77 (1.26-6.10). The correlation remained significant for RA when AD was considered instead of dementia OR (95% CI) 2.49 (1.09-5.67). The presence of joint disorders, especially RA, at midlife seems to be associated with a worse cognitive status later in life. Given the chronic inflammatory component of RA, this study suggests that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD.

Pages 677-678
   Maheen M. Adamson
   Commentary on “Abnormalities of the Fornix in Mild Cognitive Impairment are Related to Episodic Memory Loss”