Volume 22, Number 3, December 2010

Pages 699-714
Review
Adele J. Vincent, Robert Gasperini, Lisa Foa, David H. Small
Astrocytes in Alzheimer’s Disease: Emerging Roles in Calcium Dysregulation and Synaptic Plasticity
Abstract: Alzheimer’s disease (AD) is caused by the accumulation of amyloid-β (Aβ), which induces progressive decline in learning, memory, and other cognitive functions. Aβ is a neurotoxic protein that disrupts calcium signaling in neurons and alters synaptic plasticity. These effects lead to loss of synapses, neural network dysfunction, and inactivation of neuronal signaling. However, the precise mechanism by which Aβ causes neurodegeneration is still not clear, despite decades of intensive research. The role of astrocytes in early cognitive decline is a major component of disease pathology that has been poorly understood. Recent research suggests that astrocytes are not simply passive support cells for neurons, but are active participants in neural information processing in the brain. Aβ can disrupt astrocytic calcium signaling and gliotransmitter release, processes that are vital for astrocyte-neuron communication. Therefore, astrocyte dysfunction may contribute to the earliest neuronal deficits in AD. Here we discuss emerging concepts in glial biology and the implications of astrocyte dysfunction on neurodegeneration in AD.

Pages 715-740
Review
Vincenza Frisardi, Francesco Panza, Davide Seripa, Bruno P Imbimbo, Gianluigi Vendemiale, Alberto Pilotto, Vincenzo Solfrizzi
Nutraceutical Properties of Mediterranean Diet and Cognitive Decline: Possible Underlying Mechanisms
Abstract: Recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from mild cognitive impairment to Alzheimer’s disease (AD), reduced risk of AD, and decreased mortality in AD patients. Furthermore, the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. At present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA), and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for vascular dementia, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally support a protective role of these macronutrients against cognitive decline, dementia, and AD. We reviewed evidence on the possible mechanisms underlying the suggested protective role of MeDi against age-related changes in cognitive function, predementia syndromes, and dementia, examining the possible role of macronutrients and food nutrients of the MeDi and their nutraceutical properties in modulating the risk of cognitive decline. Although vascular variables are likely to be in the causal pathway between MeDi and dementia syndromes and should be considered as possible mediators, other nonvascular biological mechanisms (i.e., metabolic, oxidative, and inflammatory) may be invoked to explain the complex epidemiological association between MeDi and cognitive decline.

Pages 741-763
Review
Mordhwaj S. Parihar, Gregory J. Brewer
Amyloid-β as a Modulator of Synaptic Plasticity
Abstract: Alzheimer’s disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer’s disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate acid, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity.

Pages 765-769
Short Communication
Oriane Broustal*, Agnès Camuzat*, Lena Guillot-Noël, Nathalie Guy, Stéphanie Millecamps, Didier Deffond, Lucette Lacomblez, Véronique Golfier, Didier Hannequin, François Salachas, William Camu, Mira Didic, Bruno Dubois, Vincent Meininger, Isabelle Le Ber, Alexis Brice, and the French clinical and genetic research network on FTD/FTD-MND (Handling Associate Editor: Amalia Bruni) *These authors contributed equally to this work.
FUS Mutations in Frontotemporal Lobar Degeneration with Amyotrophic Lateral Sclerosis
Abstract: Rapid advances were made in the knowledge of amyotrophic lateral sclerosis (ALS) with the recent identification of TARDBP and FUS mutations in familial ALS. More recently, FUS-positive inclusions were found in a subset of TDP-43-negative frontotemporal lobar degeneration (FTLD) prompting us to analyze FUS in FTLD and FTLD-ALS patients. The p.Arg521His mutation was identified in a patient who initially had behavioral disorders and rapidly developed ALS. Although the frequency of mutations is low, our study enlarges the phenotypes associated with FUS mutations and shows that FUS could also play a direct pathogenic role in FTLD spectrum of diseases.

Supplementary Data for Broustal et al. article (PDF)

Pages 771-775
Roberta Borghi, Alessandra Piccini, Erica Barini, Gabriella Cirmena, Michela Guglielmotto, Elena Tamagno, Michele Fornaro, George Perry, Mark A. Smith, Anna Garuti, Massimo Tabaton (Handling Editor: Jesus Avila)
Upregulation of Presenilin 1 in Brains of Sporadic, Late-Onset Alzheimer’s Disease
Abstract: The activity of the β-secretase involved in the cleavage of amyloid-β (Aβ) is increased in sporadic late-onset Alzheimer’s disease (AD). Whether the corresponding γ-secretase activity is altered is still uncertain. We evaluated mRNA expression and protein levels of presenilin 1 (PS1) and γ-secretase activity in the frontal cortex of 32 cases with late-onset sporadic AD and those of 29 control subjects. We found a significant increase in PS1 mRNA, protein levels and γ-secretase activity in AD cases. These findings suggest that upregulation of PS1 leads to Aβ overproduction and accumulation in sporadic AD.

Pages 777-794
Mária A. Deli, Szilvia Veszelka, Boglárka Csiszár, Andrea Tóth, Ágnes Kittel, Mária Csete, Áron Sipos, Anikó Szalai, Lívia Fülöp, Botond Penke , Csongor S. Ábrahám, Masami Niwa (Handling Associate Editor: William Banks)
Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity
Abstract: Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer’s disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer’s disease.

Pages 795-809
Pilar Monfort and Vicente Felipo
Amyloid-β Impairs and Ibuprofen Restores the cGMP Pathway, Synaptic Expression of AMPA Receptors and Long-Term Potentiation in Hippocampus
Abstract: Amyloid-β (Aβ) rapidly impairs hippocampal long-term potentiation (LTP) and cognitive function in rats. We hypothesized that: a) Aβ-induced impairment of LTP would be due to impairment of nitric oxide (NO)-cGMP pathway and AMPA receptors translocation; and b) treatment with the anti-inflammatory drug ibuprofen would restore the NO-cGMP pathway and LTP. The aims of this work were to assess whether ibuprofen prevents and/or rescues Aβ-induced LTP impairment in hippocampal slices and to analyze the role of altered NO-cGMP-protein kinase G pathway and AMPA receptors phosphorylation and synaptic expression in the mechanisms by which Aβ impairs and ibuprofen restores LTP. Aβ impairs tetanus-induced activation of guanylate cyclase and cGMP increase, preventing protein kinase G activation, phosphorylation of GluR1 in Ser845 and AMPA receptors translocation to synaptic membranes, which is responsible for LTP impairment by Aβ. Ibuprofen prevents LTP impairment by Aβ by restoring guanylate cyclase activation and increase in cGMP and, subsequently, activation of protein kinase G, phosphorylation of GluR1 in Ser845 and synaptic expression of AMPA receptors. Restoration of cGMP levels is enough to restore all this process as indicated by the fact that the cGMP analog 8-Br-cGMP also normalizes the function of this pathway and restores LTP in the presence of Aβ. These results indicate that Aβ impairs LTP by impairing the NO-cGMP pathway and that ibuprofen restores LTP by restoring this pathway. These data suggest that restoring cGMP levels may have therapeutic utility to improve cognitive function impaired by Aβ.

Pages 811-818
Edo Richard, Willem A. van Gool, Jeroen J.M. Hoozemans, Elise S. van Haastert, Piet Eikelenboom, Annemieke J.M. Rozemuller, Wilma D.J. van de Berg
Morphometric Changes in the Cortical Microvascular Network in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) pathology is accompanied by abnormalities of the microvasculature. Despite the potential importance of morphometric changes in the cortical capillary network on neuronal dysfunction and cognitive impairment, few autopsy studies have addressed this issue. In the present study, we investigated morphological microvascular changes and capillary length density (CLD) in ten well-characterized AD patients compared to ten age-matched controls using virtual isotropic hemispheres. The CLD in the temporal cortex was increased by 33% in AD patients compared to controls (p=0.04), whereas CLD in the occipital cortex was unchanged. An increase of CLD was correlated to a decrease of cortical diameter in the temporal cortex (Pearson’s r -0.62, p=0.003), suggesting that the increase in temporal CLD results from, or contributes to cortical atrophy. In the occipital cortex, more string vessels, probably remnants of degenerated capillaries, were observed in AD patients than in controls (p=0.004). An exploratory analysis suggests co-localization of Aβ and string vessels. Our data indicate that morphometric changes in the cortical capillary occur in AD in a region-specific manner and may be related to cortical atrophy in the affected regions.

Pages 819-828
Manuel D. Gahete, Alicia Rubio, José Córdoba-Chacón, Francisco Gracia-Navarro, Rhonda D. Kineman, Jesús Avila, Raúl M. Luque, Justo P. Castaño (Handling Associate Editor: Garth Bissette)
Expression of the Ghrelin and Neurotensin Systems is Altered in the Temporal Lobe of Alzheimer’s Disease Patients
Abstract: Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer’s disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS-R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology.

Pages 829-838
Francisco J. Gil-Bea, Barbara Aisa, Alina Salomon, Maite Solas, Maria del Carmen Mugueta, Bengt Winblad, Miia Kivipelto, Angel Cedazo-Mínguez, María J. Ramírez (Handling Associate Editor: Gene Bowman)
HPA Axis Dysregulation Associated to Apolipoprotein E4 Genotype in Alzheimer’s Disease
Abstract: The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer’s disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.

Pages 839-848
Philip J. Ebenezer, Adam M. Weidner, Harry LeVine, III, William R. Markesbery, M. Paul Murphy, Le Zhang, Kalavathi Dasuri, Sun Ok Fernandez-Kim, Annadora J. Bruce-Keller, Elena Gavilán, Jeffrey N. Keller (Handling Associate Editor: Craig Atwood)
Neuron Specific Toxicity of Oligomeric Amyloid-β: Implications for JUN-Kinase and Oxidative Stress
Abstract: Recent studies have demonstrated a potential role for oligomeric forms of amyloid-β (Aβ) in the pathogenesis of Alzheimer’s disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD.

Pages 849-859
Pietra Candela, Fabien Gosselet, Julien Saint-pol, Emmanuel Sevin, Marie-Christine Boucau, Eric Boulanger, Roméo Cecchelli, Laurence Fenart
Apical-to-Basolateral Transport of Amyloid-β Peptides through Blood-Brain Barrier Cells is Mediated by the Receptor for Advanced Glycation End-Products and is Restricted by P-Glycoprotein
Abstract: Several studies have highlighted the close relationship between Alzheimer’s disease (AD) and alterations in the bidirectional transport of amyloid-β (Aβ) peptides across the blood-brain barrier (BBB). The brain capillary endothelial cells (BCECs) that compose the BBB express the receptors and transporters that enable this transport process. There is significant in vivo evidence to suggest that P-glycoprotein (P-gp) restricts Aβ peptides entry into the brain, whereas the receptor for advanced glycation end-products (RAGE) seems to mediate apical-to-basolateral passage across the BBB. However, deciphering the molecular mechanisms underlying these in vivo processes requires further in vitro characterization. Using an in vitro BBB model and specific competition experiments against RAGE, we have observed a significant decrease in apical-to-basolateral (but not basolateral-to-apical) transport of Aβ1-40 and Aβ1-42 peptides through BCECs. This transport is a caveolae-dependent process and fits with the apical location of RAGE observed in confocal microscopy experiments. Inhibition of P-gp and BCRP using different inhibitors increases transport of Aβ peptides suggesting that these efflux pumps are involved in Aβ peptide transport at the BCECs level. Taken as a whole, these results demonstrate the involvement of the caveolae-dependent transcytosis of Aβ peptides through the BBB in a RAGE-mediated transport process, reinforcing the hypothesis whereby this receptor is a potential drug target in AD.

Supplementary Data for Candela et al. article (PDF)

Pages 861-871
Mouhammad Motawaj, Katell Peoc’h, Jacques Callebert, Jean-Michel Arrang
CSF Levels of the Histamine Metabolite tele-Methylhistamineare only Slightly Decreased in Alzheimer’s Disease
Abstract: Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele-methylhistamine(t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non-significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 ± 0.13, 2.04 ± 0.12, and 2.76 ± 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 ± 0.10 vs 2.76 ± 0.13 pmol/ml, -22%, p<0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation-induced activation of microglia occurring in senescence and AD.

Pages 873-887
Amar Jyoti, Andrea Plano, Gernot Riedel and Bettina Platt (Handling Associate Editor: Othman Ghribi)
EEG, Activity, and Sleep Architecture in a Transgenic AβPPSWE/PSEN1A246E Alzheimer’s Disease Mouse
Abstract: Since sleep and electroencephalogram (EEG) disturbances are endophenotypes of Alzheimer’s disease (AD) patients alongside cognitive dysfunction, we here characterized these parameters in transgenic mice carrying transgenes for amyloid-β protein precursor (AβPPSWE) and presenilin 1 (PSEN1A246E) at 5 (pre-plaque) and 20 months, relative to PSEN1 and wild-type (WT) mice, using a novel wireless microchip device. While circadian rhythms were not affected, we obtained significantly higher overall activity at 5 months in the AβPP/PSEN1 strain (p<0.001) compared to both PSEN1 and WT animals. Vigilance staging revealed that AβPP/PSEN1 animals present with an age-independent increase in wakefulness (p<0.001) and a decrease in non rapid-eye movement (NREM) sleep (p<0.01). These changes were age- and genotype-dependent only during the light phase, while dark phase activity pattern were equally affected at both ages. In all genotypes, the amount of REM sleep was lower at 20 months indicating a general age-related profile. Spectral power of qEEG changed in APP/PSEN1 mice at 5 months during wakefulness and REM sleep, during wakefulness hippocampal delta (0.5-5Hz) was reduced and theta (5-9Hz) power enhanced. By contrast, NREM EEG spectra were affected by age and genotype. Interestingly, PSEN1 animals also showed spectral EEG changes, these differed from both WT and AβPP/PSEN1 animals. Our results indicate that AβPP/PSEN1 mice exhibit abnormalities in activity and sleep architecture preceding amyloid plaque deposition as well as age-related changes in cortical EEG power. Though not fully recapitulating the profile of AD patients, this suggests activity and EEG recordings as sensitive and translational biomarkers in murine models.

Supplementary Data for Jyoti et al. article (PDF)

Pages 889-896
Jesús Cacho, Julián Benito-León, Ricardo García-García, Bernardino Fernández-Calvo, José Luis Vicente-Villardón, Alex J. Mitchell
Does the Combination of the MMSE and Clock Drawing Test (Mini-Clock) Improve the Detection of Mild Alzheimer’s Disease and Mild Cognitive Impairment?
Abstract: There is currently a need to develop tools to identify patients with mild AD and mild cognitive impairment (MCI). We determined the validity and reliability of a brief, easily administered cognitive screening battery consisting of fusion of two well-known brief tests (Mini-Mental Status Examination [MMSE] and Clock Drawing Test [CDT]) (Mini-clock) to differentiate between patients with mild AD, MCI, and healthy control subjects. 66 consecutive patients with mild AD, 21 with MCI, and 66 healthy controls seen in a memory clinic setting were compared. Receiver operating characteristic (ROC) curve analysis was used to calculate the cut-off value permitting discrimination between mild AD, MCI, and healthy control subjects. Interrater and test-retest reliability (correlation coefficients) were also assessed. Mean cognitive scores for patients with AD, MCI, and control subjects on all two individual tests were significantly different (for each, p < 0.001). The mean area under the ROC curve for Mini-clock was higher than that obtained with MMSE or CDT in differentiating mild AD from controls (0.973 vs. 0.952 and 0.881, respectively) and MCI from controls (0.855 vs. 0.821 and 0.779, respectively). Test-retest reliability for the Mini-clock was 0.99, meanwhile interrater reliability was 0.87. The mean time to complete the test for all subjects was 8 min and 50 s. The Mini-clock is highly sensitive and specific in the detection of mild AD and reasonably accurate when attempting to separate MCI from health controls. It has a high interrater and test-retest reliability, can be quickly administered, and does not require major training.

Pages 897-907
Fabienne Collette, Martial Van der Linden, Eric Salmon (Handling Associate Editor: Anna Rita Giovagnoli)
Dissociation between Controlled and Automatic Processes in the Behavioral Variant of Fronto-Temporal Dementia
Abstract: A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby [1]. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal dementia (bv-FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD.

Pages 909-922
Juan Fortea, Roser Sala-Llonch, David Bartrés-Faz, Beatriz Bosch, Albert Lladó, Nuria Bargalló, José Luis Molinuevo, Raquel Sánchez-Valle
Increased Cortical Thickness and Caudate Volume Precede Atrophy in PSEN1 Mutation Carriers
Abstract: Neuroimaging studies of familial Alzheimer’s disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n=6) or symptomatic (n=5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images were reanalyzed with voxel-based morphometry methodology. Cereprospinal fluid amyloid-β1-42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p<0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p<0.01), increased caudate volumes (p<0.01), and decreased MD (p<0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC.

Pages 923-931
Alessandro Padovani, Maura Cosseddu, Enrico Premi, Silvana Archetti, Alice Papetti, Chiara Agosti, Barbara Bigni, Carlo Cerini, Barbara Paghera, Giuseppe Bellelli, Barbara Borroni (Handling Associate Editor: Marco Bozzali)
The Speech and Language FOXP2 Gene Modulates the Phenotype of Frontotemporal Lobar Degeneration
Abstract: The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging study. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping (SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p<0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.

Pages 933-938
Walter Maetzler, Velichka Stoycheva, Benjamin Schmid, Claudia Schulte, Ann-Kathrin Hauser, Kathrin Brockmann, Arthur Melms, Thomas Gasser, Daniela Berg
Neprilysin Activity in Cerebrospinal Fluid is Associated with Dementia and Amyloid-β42 Levels in Lewy Body Disease
Abstract: Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer’s disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ42 levels. Not surprisingly, within affected Lewy body disease patients, there is a strong association between dementia and Aβ pathology. Neprilysin (NEP) is an Aβ-degrading protein detectable at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP activity levels may also be associated with dementia and lowered CSF Aβ42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2-81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2-87.2; p=0.004) and controls (21.5 pmol/ml*min, 0.15-413.4; p=0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ42 levels (Rho = 0.28, p=0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway.

Pages 939-948
Jyri J. Virta, Tarja Järvenpää, Kauko Heikkilä, Markus Perola, Markku Koskenvuo, Ismo Räihä, Juha O. Rinne, Jaakko Kaprio (Handling Associate Editor: Israel Ampuero)
Midlife Alcohol Consumption and Later Risk of Cognitive Impairment: A Twin Follow-up Study
Abstract: In this prospective follow-up study, we monitored the effects of midlife alcohol consumption and drinking patterns on cognitive impairment risks in late life. 1,486 subjects recruited from the Finnish Twin Cohort were included in the analyses. Alcohol consumption data was obtained with structured questionnaires in 1975 and 1981, and subjects were contacted between 1999 and 2007 to conduct a telephone interview evaluating cognitive function. The mean follow-up period was 22.8 years (standard deviation 2.1 years). Both abstainers and heavy drinkers were found to have an increased risk of cognitive impairment in comparison to light drinkers (relative risk ratios 1.44; 95% confidence interval: 1.02, 2.10, and 1.94; 1.10, 3.44, respectively). Also, binge drinking at least monthly in 1975 and 1981, as well as more than two pass-outs due to excess drinking in 1981 were associated with an increased risk of cognitive impairment (1.98, 1.08-3.64 and 3.85, 1.51-9.83, respectively), even when excluding abstainers and controlling for total alcohol consumption. Subgroup analyses based on apolipoprotein E ε4 status suggest that the increased risk of cognitive impairment associated with being an abstainer is limited to subjects without an ε4 allele. Our results add to the evidence that light to moderate alcohol use is associated with a lower risk of cognitive impairment compared with higher levels of consumptionIn addition, binge drinking was found to be an independent risk factor for cognitive impairment.

Pages 949-958
Félix Bermejo-Pareja, Julián Benito-León, Elan D. Louis, Rocío Trincado, Eva Carro, Alberto Villarejo, Agustín Gómez de la Cámara
Risk of Incident Dementia in Drug-Untreated Arterial Hypertension: A Population-Based Study
Abstract: Arterial hypertension in midlife may increase the risk of late-life dementia. Notably, there is conflicting data as to whether hypertension in the elderly (age 65 years and older) is a risk factor for dementia and Alzheimer’s disease (AD). We determined whether drug-untreated hypertension was associated with a higher risk of incident dementia and AD. In a population-based study of older people in central Spain (NEDICES), non-demented participants were followed prospectively. Dementia at follow-up was diagnosed using DSM-IV criteria. Using Cox proportional hazards models, the risk of dementia was estimated in participants with drug-untreated hypertension and in participants with drug-treated hypertension versus controls. The 3,824 participants had a mean duration of follow-up of 3.2 years. Sixty-two (3.3%) of 1,870 participants without baseline hypertension developed incident dementia versus 78 (4.7%) of 1,657 with drug-treated, baseline hypertension and 19 (12.0%) with drug-untreated, baseline hypertension. In an unadjusted Cox model, risk of dementia was increased in participants with drug-untreated hypertension (relative risk [RR] = 1.93, 95% confidence interval [CI] = 1.15-3.23, p = 0.01) and in participants with drug-treated hypertension (RR = 1.43, 95% CI = 1.02-2.0, p = 0.035) versus participants without hypertension (reference group). In a fully adjusted Cox model, the risk of dementia remained increased in participants with drug-untreated hypertension (RR = 2.38, 95% CI = 1.32-4.29, p = 0.004). Results were similar for risk of AD. Our results suggest that drug-untreated hypertension may be an independent risk factor for dementia and AD in the elderly.

Pages 959-970
Haim Belinson, Zehavit Kariv-Inbal, Rakez Kayed, Eliezer Masliah, Daniel M. Michaelson (Handling Associate Editor: Thomas Bayer)
Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-beta resulting in neurodegeneration
Abstract: According to the amyloid hypothesis, the accumulation of oligomerized amyloid-β (Aβ) is a primary event in the pathogenesis of Alzheimer’s disease (AD). The trigger of the amyloid cascade and of Aβ oligomerization in sporadic AD, the most prevalent form of the disease, remains elusive. Here, we examined the hypothesis that apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for AD, triggers the accumulation of intraneuronal oligomerized Aβ following activation of the amyloid cascade. We investigated the intracellular organelles that are targeted by these processes and govern their pathological consequences. This revealed that activation of the amyloid cascade in vivo by inhibition of the Aβ degrading enzyme neprilysin specifically results in accumulation of Aβ and oligomerized Aβ and of ApoE4 in CA1 neurons of ApoE4 mice. This was accompanied by lysosomal and mitochondrial pathology and the co-localization of Aβ, oligomerized Aβ, and ApoE4 with enlarged lysosomes and of Aβ and oligomerized Aβ with mitochondria. The time course of the lysosomal effects paralleled that of the loss of CA1 neurons, whereas the mitochondrial effects reached a plateau earlier. These findings suggest that ApoE4 potentiates the pathological effects of Aβ and the amyloid cascade by triggering the oligomerization of Aβ, which in turn, impairs intraneuronal mitochondria and lysosomes and drives neurodegeneration.

Supplementary Data for Belinson et al. article (PDF)

Pages 971-980
Andreas Haldenwanger, Paul Eling, Andreas Kastrup, Helmut Hildebrandt
Correlation between Cognitive Impairment and CSF Biomarkers in Amnesic MCI, non-Amnesic MCI, and Alzheimer’s Disease
Abstract: Decreased delayed recall, decreased amyloid-β peptides (Aβ1-42), and increased tau protein concentration in cerebrospinal fluid (CSF) are generally regarded to be valid neuropsychological and biological markers for Alzheimer’s disease (AD). Previous studies failed to demonstrate clear-cut correlations between neuropsychological impairment and CSF markers. In this study we test recent models of disease progression, that propose that changes in CSF biomarkers already reach a plateau in a preclinical phase, before cognitive decline begins, that is, even before MCI can be diagnosed. We recruited 73 patients with probable AD (n=36) and mild cognitive impairment (MCI) (amnesic MCI = 25; non-amnesic MCI = 12). We used the CERAD-NP, a widely used neuropsychological battery with norms for different age and education groups, and additional neuropsychological tests for assessing the cognitive profile of these patient groups. We found a significant correlation between Aβ1-42 in the CSF and memory performance for amnesic MCI patients, but not for non-amnesic MCI and AD patients. All other correlations between cognitive tasks and Aβ1-42 were not significant. Tau protein concentration in the CSF was not correlated with any neuropsychological marker in none of the patients groups. We conclude that the decrease of Aβ1-42 in the CSF mirrors disease progression during the early stages up into AD and therefore is not restricted to the preclinical phase. The decrease of Aβ1-42 reaches a plateau only in the full blown demented syndrome and further functional disease progression is then related to neurodegeneration without further reduction of Aβ1-42 in the CSF.

Pages 981-984
Emma C. Schofield, Glenda M. Halliday, John Kwok, Clement Loy, Kay L. Double, John R. Hodges
Low Serum Progranulin Predicts the Presence of Mutations: A Prospective Study
Abstract: Serum progranulin is decreased in frontotemporal dementia (FTD) patients with progranulin gene (PGRN) mutations. We investigate the utility of prospective serum screening as a surrogate diagnostic marker for progranulin mutations. A commercial ELISA was used to measure progranulin protein concentration in serum from 63 FTD patients and 32 normal controls, and DNA screening then performed. Four patients (2/17 behavioral variant, 2/8 corticobasal syndrome) had abnormally low progranulin levels with PGRN mutations confirmed on DNA testing. Surprisingly, elevated levels were found in 6/16 patients with progressive non-fluent aphasia, the significance of which is unclear. Serum testing is an accurate and cost effective means of predicting PGRN mutations.

Pages 985-991
Roberta Ghidoni, Luisa Benussi, Michela Glionna, Silvia Desenzani, Valentina Albertini, Efrat Levy, Enzo Emanuele, Giuliano Binetti (Handling Associate Editor: Daniela Galimberti)
Plasma Cystatin C and Risk of Developing Alzheimer’s Disease in Subjects with Mild Cognitive Impairment
Abstract: Recent years have witnessed an increasing interest in mild cognitive impairment (MCI), particularly as a possible prodromal stage of Alzheimer’s disease (AD). Experimental and clinical data have suggested that cystatin C (CysC) is protective against the development of AD. In this study, we sought to cross-sectionally and longitudinally investigate the changes in plasma CysC levels in patients with MCI and whether the levels of this molecule might serve as a biochemical predictor of cognitive decline in this patient group. Cross-sectional analysis of baseline data showed a borderline significant difference in plasma CysC levels among the three study groups (Controls, n=63; AD, n=63; MCI, n=59) (p = 0.032) that disappeared after post hoc analysis. Plasma CysC levels did not differ at baseline (t1) and at follow-up (t2) both in MCI patients that converted to AD (n=32) and those that did not convert (n=27). However, a significant independent association between CysC at t1 and CysC at t2 was found in non-converters but not in converters MCI subjects. Moreover, when disease onset was evaluated in patients groups stratified on the basis of their CysC plasma levels, a significant anticipation of the conversion to dementia in MCI subjects with CysC levels below the median (CysC < 1067 ng/ml) (p = 0.0011) was observed. Altogether, this work adds to the growing body of literature suggesting that CysC modulates the clinical expression of cognitive decline, and opens a new area of investigation of CysC as a therapeutic target for neurodegenerative disorders.

Pages 993-1003
Flavio Nobili, Debora Mazzei, Barbara Dessi, Silvia Morbelli, Andrea Brugnolo, Paola Barbieri, Nicola Girtler, Gianmario Sambuceti, Guido Rodriguez, Marco Pagani
Unawareness of Memory Deficit in Amnestic MCI: FDG-PET Findings
Abstract: To unveil the brain metabolic correlates of (un)awareness of memory deficit in subjects with amnestic mild cognitive impairment (aMCI), forty-two outpatients underwent brain 18F-FDG-PET. Awareness of memory deficit was assessed with the Memory Complaint Questionnaire (MAC-Q), identifying two groups: low (MCI/unaware; 17 patients) and good (MCI/aware; 25 patients) aMCI awareness. Twenty-nine age-matched healthy subjects represented the control group. SPM2 was used to assess the correlation between brain metabolism and MAC-Q score, for comparisons between each patient group and controls, and between aMCI/unaware and aMCI/aware groups. The two aMCI groups were comparable in terms of age, gender, education, depression, and neuropsychological tests scores. In the whole 42-patient group, a positive correlation was found between MAC-Q score and metabolism in posterior cingulate cortex in both hemispheres and in inferior parietal lobule, middle cingulate cortex, precuneus and angular gyrus in the left hemisphere. Compared to controls, hypometabolism was found in aMCI/unaware in three large clusters, including precuneus, inferior parietal lobule and superior occipital gyrus, in the left hemisphere, and in inferior parietal lobule, angular gyrus and middle temporal gyrus in the right hemisphere. Smaller clusters of hypometabolism were found in bilateral temporal lobe in aMCI/aware. Hypometabolism in inferior parietal lobule, angular gyrus and superior temporal gyrus in the left hemisphere was highlighted in aMCI/unaware versus aMCI/aware. The significant correlation in all 42 aMCI patients points to posteromedial cortex as a key node of the network being involved in awareness of memory deficit. Patients with low awareness show a more severe hypometabolic pattern, typical of Alzheimer’s disease and therefore could be more at risk of developing dementia.

Pages 1005-1013
Simon D. Israeli-Korn*, Magda Massarwa*, Edna Schechtman, Rosa Strugatsky, Shiri Avni, Lindsay A. Farrer, Robert P. Friedland, Rivka Inzelberg *The first two authors contributed equally
Mild Cognitive Impairment is Associated with Mild Parkinsonian Signs in a Door-to-Door Study of an Elderly Arab Population
Abstract: Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥ 65 years (n = 687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n = 111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p < 0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR = 1.19, 95% CI, 1.05 to 1.35, p = 0.006) and higher limb bradykinesia scores (OR = 1.75, 95% CI, 1.2 to 2.56, p = 0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.

Pages 1015-1021
Marwan N. Sabbagh, Michael Malek-Ahmadi, Rahul Kataria, Christine M. Belden, Donald J. Connor, Caleb Pearson, Sandra Jacobson, Kathryn Davis, Roy Yaari, Upinder Singh
The Alzheimer’s Questionnaire: A Proof of Concept Study for a New Informant-Based Dementia Assessment
Abstract: The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer’s disease (AD) that can be administered in a primary care setting. The Alzheimer’s Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.

Pages 1023-1031
Isobel J. Whitehouse, Carolyn Jackson, Anthony J. Turner and Nigel M. Hooper
Prion Protein is Reduced in Aging and in Sporadic but not in Familial Alzheimer’s Disease
Abstract: The cellular form of the prion protein (PrPC) has been shown to inhibit the production of amyloid-β which is critically involved in the pathogenesis of Alzheimer’s disease (AD). We examined the expression of PrPC by immunoblot analysis in the hippocampus and temporal cortex in sporadic AD, familial AD, and appropriate age-matched controls, and in an aging series (age 20 to 88 years) of brains. PrPC was reduced by 53% (p = 0.032) in the hippocampus in sporadic AD as compared to the age-matched controls. No such reduction in PrPC was seen in familial AD. PrPC was reduced in the hippocampus with aging (rs = 0.03). The reduction in PrPC in sporadic but not familial AD suggests that reduced PrPC expression reflects a primary mechanism of disease and is not merely a secondary consequence of other AD-associated changes. The reduction of PrPC in the brain with aging suggests that age-related decreases in PrPC may contribute to the increased incidence of AD in older people.

Pages 1033-1037
Meeting Report from the Alzheimer Research Forum
Trial News: Woes, New Approaches

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