Volume 51, Number 3, 2016

Pages 637-656

Pavlina Adam, Sona Krizkova, Zbynek Heger, Petr Babula, Vladimir Pekarik, Marketa Vaculovicova, Cláudio M. Gomez, Rene Kizek, Vojtech Adam
Metallothioneins and Prion- and Amyloid-Related Diseases
Abstract: Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and low molecular mass thiol-rich proteins, which in brain tissue is called metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with metal ions and regulation of their homeostasis. Moreover, the relationship between isoforms is discussed as well as in the perspective of their simultaneous analysis.

Pages 657-669

Katherine A. Southam*, Adele J. Vincent* and David H. Small *These authors contributed equally to this work.
Do Microglia Default on Network Maintenance in Alzheimer’s Disease?
Abstract: Although the cause of Alzheimer’s disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain’s immune cells. They play an important role in maintaining the brain’s extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.

Pages 671-675
Short Communication

Chul Hyoung Lyoo, Hanna Cho, Jae Yong Choi, Mi Song Hwang, Sang Kyoon Hong, Yun Joong Kim, Young Hoon Ryu, Myung Sik Lee (Handling Associate Editor: David Knopman)
Tau Accumulation in Primary Motor Cortex of Variant Alzheimer’s Disease with Spastic Paraparesis
Abstract: We studied topographic distribution of tau and amyloid-β in a patient with variant Alzheimer’s disease with spastic paraparesis (VarAD) by comparing AD patients. The proband developed progressive memory impairment, dysarthria, and spastic paraparesis at age 23. Heterozygous missense mutation (L166P) was found in exon 6 of presenilin-1 gene. The proband showed prominently increased amyloid binding in striatum and cerebellum and asymmetrical tau binding in the primary sensorimotor cortex contralateral to the side more affected by spasticity. We suspect that upper motor neuron dysfunctions may be attributed to excessive abnormal tau accumulation rather than amyloid-β in the primary motor cortex.

Pages 677-682
Short Communication

Annerieke S.R. Sierksma*, Laurence de Nijs*, Govert Hoogland, Tim Vanmierlo, Fred W. van Leeuwen, Bart P.F. Rutten, Harry W.M. Steinbusch, Jos Prickaerts, Daniel L.A. van den Hove *These authors contributed equally to this work
Fluoxetine Treatment Induces Seizure Behavior and Premature Death in APPswe/PS1dE9 Mice
Abstract: Treatment of Alzheimer’s disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.

Pages 683-687
Katharina Stoeck, Marios Nikos Psychogios, Andreas Ohlenbusch, Robert Steinfeld, Jens Schmidt
Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene
Abstract: A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto’s encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient’s neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.

Pages 689-699
Christian Peters, Denisse Bascuñán, Carlos Opazo, Luis G. Aguayo
Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms
Abstract: A major characteristic of Alzheimer’s disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ1-42; Aβ1-28 from the N-terminal region, Aβ25-35 from the central region, and Aβ17-42 from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ1-28 contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ25-35 is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ17-42 induced mitochondrial toxicity similar to the full length Aβ1-42, but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.

Pages 701-711
Vicent Bonet-Costa, Vicente Herranz-Pérez, MariCarmen Blanco-Gandía, Cristina Mas-Bargues, Marta Inglés, Patricia Garcia-Tarraga, Marta Rodriguez-Arias, Jose Miñarro, Consuelo Borras, Jose Manuel Garcia-Verdugo, Jose Viña
Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer’s disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. Treatment of an Alzheimer’s disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of Aβ levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPARγ-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer’s disease.

Pages 713-725
Nadine Külzow, A. Veronica Witte, Lucia Kerti, Ulrike Grittner, Jan Philipp Schuchardt, Andreas Hahn, Agnes Flöel (Handling Associate Editor: Kaarin Anstey)
Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults
Abstract: As the process of Alzheimer’s disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n=22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.

Pages 727-736
Christian LoBue, David Denney, Linda S. Hynan, Heidi C. Rossetti, Laura H. Lacritz, John Hart Jr., Kyle B. Womack, Fu L. Woon, C. Munro Cullum (Handling Associate Editor: Jose Abisambra)
Self-Reported Traumatic Brain Injury and Mild Cognitive Impairment: Increased Risk and Earlier Age of Diagnosis
Abstract: This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer’s Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ε4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI-) a history of TBI. TBI history was a significant predictor (p < 0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI =1.05–1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10–1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94–1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p < 0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.

Pages 737-745
Yeonsil Moon, Seol-Heui Han, Won-Jin Moon
Patterns of Brain Iron Accumulation in Vascular Dementia and Alzheimer’s Dementia Using Quantitative Susceptibility Mapping Imaging
Abstract: Background: Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer’s disease (AD) are rarely investigated. Objective: To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM). Materials and Methods: Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this institutional review-board approved study. Susceptibility maps were reconstructed from a three-dimensional multiecho spoiled gradient-echo sequence. Four regions of interest were drawn manually on QSM images, namely the globus pallidus, putamen, caudate nucleus, and pulvinar nucleus of the thalamus. Comparisons of patient demographics, and iron concentrations among the VaD, AD, and control subjects were assessed using analysis of variance and post-hoc analyses. The relationships of age and cognitive state with susceptibility values were assessed using partial correlation analysis. Results: In VaD and AD, overall susceptibility values were higher than those of control subjects. A significant difference in susceptibility values was found in the putamen and caudate nucleus (p < 0.001 and p = 0.002, respectively). However, susceptibility values did not differ between VaD and AD. Age and cognitive deficit severity were not related to susceptibility values in the VaD and AD groups. Conclusion: Increased iron deposition in the putamen and caudate nucleus in VaD and AD patients was not associated with age or the severity of cognitive deficits. Further evaluations are needed to determine the temporal changes in iron load and their diagnostic role in dementia pathology.

Pages 747-755
Miharu Nakanishi, Taeko Nakashima, Yumi Shindo, Junko Niimura, Atsushi Nishida
Japanese Care Location and Medical Procedures for People with Dementia in the Last Month of Life
Abstract: Background: Dementia-related societies worldwide have called for palliative end-of-life care for those suffering dementia; meanwhile, the Japanese dementia plan was revised on January 2015 to introduce into its objectives the support for end-of-life care via increased social and health care collaboration. Objective: The study focus was the use of medical procedures in the last month of life among dementia patients in different care locations in Japan. Methods: This study was conducted using a retrospective study design. Data from the Survey of Institutions and Establishments for Long-Term Care, which is a nationally representative cross-sectional survey of the public long-term care insurance services, were used. The 6,148 patients who received end-of-life care in their own home, nursing homes, or hospitals in September 2007, 2010, and 2013 were included for analysis. The primary disease of each patient was based on the ICD-10 code; a diagnosis of dementia included F00 (Alzheimer’s), F01 (vascular), F02 (other), and F03 (unspecified). Results: Of 6,148 patients, 886 (14.4%) had dementia as a primary disease; most received care in the last month of life in nursing homes (48.0%) or hospitals (44.8%) rather than in their own home (7.2%). Patients were less likely to undergo pain management when their primary disease was dementia (adjusted odds ratio, 0.44; 95% confidence interval, 0.21–0.91). Conclusion: Education and policy efforts are required to provide palliative end-of-life care to people with dementia at home. The national dementia plan should also explore possible approaches regarding pain management for dying people who have dementia.

Pages 757-773
Matthew W. Granger, Bettina Franko, Matthew W. Taylor, Claude Messier, Peter St. George-Hyslop, Steffany A.L. Bennett (Handling Associate Editor: Jack de la Torre)
A TgCRND8 Mouse Model of Alzheimer’s Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve
Abstract: Cognitive decline is sexually dimorphic in Alzheimer’s disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6 x C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

Pages 775-782
Samantha Schubert, Cristian E. Leyton, John R. Hodges, Olivier Piguet
Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation. Objective: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD. Methods: Consecutive cases diagnosed with probable bvFTD (n=22) and typical AD (n=31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts. Results: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group. Conclusions: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.

Pages 783-791
Kumar Krishna, Thomas Behnisch, Sreedharan Sajikumar (Handling Associate Editor: Ottavio Arancio)
Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons
Abstract: Neurodegenerative diseases such as Alzheimer’s disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzymes both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

Pages 793-800
Daniela Andruita, Véronique Moullart, Susanna Schraen, Agnes Devendeville, Marc-Etienne Meyer, Olivier Godefroy, for the Alzheimer’s Disease Neuroimaging Initiative
What are the Most Frequently Impaired Markers of Neurodegeneration in ADNI Subjects?
Abstract: The aim of this study was to examine the relationship between cerebrospinal fluid (CSF) levels of biomarkers for Alzheimer’s disease (AD) (Aβ1-42, t-tau, and p-tau) and 18Fluorodeoxyglucose positron emission tomography (FDG-PET) hypometabolism in subjects from the Alzheimer’s Disease Neuroimaging Initiative, and specifically to determine which index of neurodegeneration was most frequently affected. The secondary objective was to determine the most frequently hypometabolic region in patients with a CSF AD signature (abnormal Aβ1-42 and abnormal p-tau). We included the 372 subjects (85 normal subjects, 212 patients with mild cognitive impairment, and 75 patients with AD) with a CSF biomarker dosage (Aβ1-42, t-tau, and p-tau) and brain FDG-PET. The relationship between FDG-PET metabolism (in five regions of interest (ROI) known to be damaged in AD) and CSF t-tau and p-tau levels was studied as a function of CSF Aβ1-42 status. FDG-PET hypometabolism and CSF t-tau and p-tau levels were correlated only in patients with an abnormal CSF Aβ1-42 level (t-tau: R2=0.044, p=0.001; p-tau: R2=0.02, p=0.03). In the latter patients, CSF p-tau was the most frequently (p=0.0001) abnormal neurodegeneration marker (p-tau: 92.8%; FDG-PET: 56.5%; CSF t-tau: 59.1%). Within the five ROI of FDG PET, the angular gyrus metabolism (R2=0.149; p=0.0001) was selected as the most tightly associated with CSF AD signature. The relation between CSF markers of neurodegeneration (p-tau and t-tau) and brain hypometabolism (in FDG-PET) is conditioned by presence of amyloid abnormality. This finding supports current physiopathological model of AD. P-tau is the most frequently impaired biomarker. Using FDG PET angular gyrus hypometabolism is the most sensitive to CSF-biomarker-defined AD.

Pages 801-813
Dominika Dingova, Tomas Fazekas, Petra Okuliarova, Jaroslava Strbova, Matej Kucera, Anna Hrabovska
Low Plasma Cholinesterase Activities are associated with Deficits in Spatial Orientation, Reduced Ability to Perform Basic Activities of Daily Living, and Low Body Mass Index in Patients with Progressed Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by a central cholinergic deficit. Non-neuronal cholinergic changes are, however, described as well. Here we focused on possible changes in the activity of the plasma cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hospitalized AD patients. We analyzed plasma AChE and BChE activities with regards to age, gender, body mass index (BMI), cognitive functions, and ability to perform activities of daily living in AD patients in comparison to healthy subjects. We observed lower AChE activity and trend toward lower BChE activity in AD patients, which both correlated with low BMI. AD patients unable to perform basic activities of daily living (feeding, bathing, dressing, and grooming) showed reduced plasma AChE activities, while worse spatial orientation was linked to lower BChE activities. Three out of four AD patients with the lowest BChE activities died within one year. In conclusion, progressed AD was accompanied by lower plasma AChE activity and trend toward lower BChE activity, which correlated with BMI and deficits in different components of the AD.

Pages 815-825
Olivier Godefroy, Serge Bakchine, Marc Verny, Jean-Philippe Delabrousse-Mayoux, Martine Roussel, Jean-Jacques Pere; on the behalf of the REFLEX study group
Characteristics of Alzheimer’s Disease Patients with Severe Executive Disorders
Abstract: Background: Executive dysfunctions in Alzheimer’s disease (AD) have been assessed using variable batteries and/or in selected populations. Objective: The primary objective of this observational study was to determine the prevalence and severity of executive dysfunction in AD patients using a previously validated battery. The secondary objective was to determine the characteristics including treatment outcomes of AD patients with severe executive dysfunction. Methods: The study included AD patients with mild-to-moderate dementia aged 60 or over, consulting in various clinical settings including memory clinics and requiring the introduction of an antidementia drug. Executive dysfunction was examined using a validated, shortened executive battery. Results: 381 patients were included. Executive dysfunctions were observed in 88.2% of the patients (95%CI: 84.9 -91.4) and were severe (defined as ≥2/3 impaired scores) in 80.4% (95%CI: 76.9- 84.8). Global hypoactivity with apathy was more frequent (p=0.0001) than impairment in executive function tests. The 308 patients with severe executive dysfunction were older (p=0.003) and had more severe dementia (p=0.0001). Similarly, in the subset of 257 patients with mild dementia, individuals with severe executive dysfunction were older (p=0.003) and had more severe dementia. Global hypoactivity was independently associated with difficulties in IADL and a higher caregiver burden (p=0.0001 for both). The severity of executive dysfunction did not significantly influence the patients’ outcomes at 6 months. Conclusions: Executive dysfunction is a very common disorder in a representative population of patients with mild-to-moderate AD. It was independently correlated with impaired autonomy and increased caregiver burden but did not significantly influence treatment outcomes.

Pages 827-835
Raquel Sánchez-Valle, Gemma C. Monté, Roser Sala-Llonch, Beatriz Bosch, Juan Fortea, Albert Lladó, Anna Antonell, Mircea Balasa, Nuria Bargalló, José Luis Molinuevo
White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer’s Disease
Abstract: PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer’s disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p < 0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p < 0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease and that DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

Pages 837-846
Sarah A. Chau, Jonathan Chung, Nathan Herrmann, Moshe Eizenman, Krista L. Lanctôt
Apathy and Attentional Biases in Alzheimer’s Disease
Abstract: Background: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer’s disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation. Objective: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients. Methods: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE>10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured. Results: Of the 36 AD patients (14 females, age=78.2±7.8, sMMSE=22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F1,32 = 4.31, p = 0.046) and fixation frequency (F1,32 = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F3,32 = 3.65, p = 0.023). Conclusion: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.

Pages 847-855
Tilly Eichler*, Jochen René Thyrian*, Johannes Hertel, Steffen Richter, Diana Wucherer, Bernhard Michalowsky, Stefan Teipel, Ingo Kilimann, Adina Dreier, Wolfgang Hoffmann (Handling Associate Editor: Alexandra König) *These authors contributed equally to this work.
Unmet Needs of Community-Dwelling Primary Care Patients with Dementia in Germany: Prevalence and Correlates
Abstract: Background: To provide an optimal care for persons with dementia (PWD), their individual unmet needs have to be identified and comprehensively addressed. Objectives: Present analyses aim to describe the number and types of unmet needs of German primary care patients screened positive for dementia and factors associated with the number of unmet needs. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner-based, cluster-randomized controlled intervention trial. Analyses are based on the baseline data of 227 PWD (≥70 years, living at home) of the intervention group who had screened positive for dementia (DemTect<9) and received a standardized computer-assisted needs assessment. Results: PWD had on average 8.77±5.04 unmet needs (Range=0-31). More than 90% of the PWD had three or more unmet needs. Unmet needs were identified across all predefined 26 subcategories. The majority of unmet needs occurred in the domains “nursing treatment and care” (38%), “social counseling and legal support” (20%), and “pharmacological treatment and care” (15%). More impairment in the activities of daily living was the only factor that was significantly associated with a higher number of unmet needs, independent of age, gender, living situation, presence of an informal caregiver, cognitive impairment, and depression. Conclusions: Present results demonstrate that community-dwelling PWD had a broad range of varying unmet needs. These findings emphasize the importance of a comprehensive needs assessment that allows the identification of individual needs as the basis for a tailored intervention—such as Dementia Care Management—that can address these needs. ClinicalTrials.gov Identifier: NCT01401582

Pages 857-866
Junko Nishihira, Takashi Tokashiki, Yasushi Higashiuesato, Donald Craig Willcox, Nora Mattek, LynneLynne Shinto, Yusuke Ohya, Hiroko H. Dodge
Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study
Abstract: Background: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known. Objective: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old. Methods: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1 ± 3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating < 1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letters). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia. Results: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders. Conclusions: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.

Pages 867-873
Per Suppa, Harald Hampel, Timo Kepp, Catharina Lange, Lothar Spies, Jochen B. Fiebach, Bruno Dubois*, Ralph Buchert* and Alzheimer’s Disease Neuroimaging Initiative *The authors contributed equally to this work as senior authors.
Performance of Hippocampus Volumetry with FSL-FIRST for Prediction of Alzheimer's Disease Dementia in at Risk Subjects with Amnestic Mild Cognitive Impairment
Abstract: MRI-based hippocampus volume, a core feasible biomarker of Alzheimer’s disease (AD), is not yet widely used in clinical patient care, partly due to lack of validation of software tools for hippocampal volumetry that are compatible with routine workflow. Here, we evaluate fully-automated and computationally efficient hippocampal volumetry with FSL-FIRST for prediction of AD dementia (ADD) in subjects with amnestic mild cognitive impairment (aMCI) from phase 1 of the Alzheimer’s Disease Neuroimaging Initiative. Receiver operating characteristic analysis of FSL-FIRST hippocampal volume (corrected for head size and age) revealed an area under the curve of 0.79, 0.70, and 0.70 for prediction of aMCI-to-ADD conversion within 12, 24, or 36 months, respectively. Thus, FSL-FIRST provides about the same power for prediction of progression to ADD in aMCI as other volumetry methods.

Pages 875-887
Elena Vallino Costassa, Michele Fiorini, Gianluigi Zanusso, Simone Peletto, Pierluigi Acutis, Elisa Baioni, Cristiana Maurella, Fabrizio Tagliavini, Marcella Catania, Marina Gallo, Monica Lo Faro, Maria Novella Chieppa, Daniela Meloni, Antonio D’Angelo, Orlando Paciello, Roberta Ghidoni, Elisa Tonoli, Cristina Casalone, Cristiano Corona
Characterization of Amyloid-β Deposits in Bovine Brains
Abstract: Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer’s disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation.

Pages 889-903
Stephanie Wong, Maxime Bertoux, Greg Savage, John R Hodges, Olivier Piguet, Michael Hornberger (Handling Associate Editor: Sharon Naismith)
Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer’s Disease and Behavioral-Variant Frontotemporal Dementia
Abstract: Alzheimer’s disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. This aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n=12) and AD patients with relatively impaired executive functioning (IEF-AD; n=23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n=22), who typically exhibit significant executive deficits, and age-matched healthy controls (n=38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD.

Pages 905-0913
Lou Grangeon, Claire Paquet, Stephanie Bombois, Muriel Quillard-Muraine, Olivier Martinaud, Bertrand Bourre, Romain Lefaucheur, Gaël Nicolas, Julien Dumurgier, Emmanuel Gerardin, Mary Jan, Jean-Louis Laplanche, Katell Peoc’h, Jacques Hugon, Florence Pasquier, David Maltête, Didier Hannequin, David Wallon and the collaborators of the ePLM.fr group
Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein
Abstract: Background: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process and mainly in Alzheimer’s disease (AD). A particularly high Tau level may indicate AD but may also be associated Creutzfeldt Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses. Objective: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD. Methods: Patients (n=202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria. Results: Patients were diagnosed with AD (n=148, 73.2%), mixed dementia (n=38, 18.8%), CJD, vascular dementia (n=4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n=3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (< 0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p <0.0001). Conclusion: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

Pages 915-927
Shira Simonovitch*, Eran Schmukler*, Alina Bespalkoa Tal Iram, Dan Frenkel, David M. Holtzman, Eliezer Masliah, Danny M. Michaelson, Ronit Pinkas-Kramarski *These authors contributed equally to this work.
Impaired Autophagy in APOE4 Astrocytes
Abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins organelles and proteins aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer rapamycin enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor chloroquine blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.