Pages 893-903
Review
Erica M. Weekman, Donna M. Wilcock (Handling Associate Editor: Jose Abisambra)
Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia
Abstract: The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer’s disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer’s disease.
Pages 905-915
Review
Udo Rüb, Katharina Stratmann, Helmut Heinsen, Domenico Del Turco, Estifanos Ghebremedhin, Kay Seidel, Wilfred den Dunnen*, Horst-Werner Korf* *Joint senior authors
Hierarchical Distribution of the Tau Cytoskeletal Pathology in the Thalamus of Alzheimer’s Disease Patients
Abstract: In spite of considerable progress in neuropathological research on Alzheimer’s disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 µm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns.
Pages 917-925
Hui-Dong Tang*, Yi Zhou*, Xiang Gao, Liang Liang, Miao-Miao Hou, Yuan Qiao, Jian-Fang Ma, Sheng-Di Chen *These authors contributed equally to this work.
Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study
Abstract: Background: China is facing a continuously rising numbers of people with cognitive impairment (CI). Objectives: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities. Methods: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n=4,429) and Wuliqiao (urban community, n=3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI. Results: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p=0.13). In the urban population, risk of having CI was associated with age (OR =1.04; 95% CI: 1.01-1.08), lack of physical activities (OR =2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR =1.79; 95% CI: 1.04-3.07), and having three or more children (OR =2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR =2.03; 95% CI: 1.08-3.82), age (OR =1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR =4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR =6.02; 95% CI: 1.92-18.85) and head trauma (OR =1.89; 95% CI: 1.10-3.24). Conclusions: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed.
Pages 927-943
Andrea F.N. Rosenberger, Riet Hilhorst, Elisabeth Coart, Leandro García Barrado, Faris Naji, Annemieke J.M. Rozemuller, Wiesje M. van der Flier, Philip Scheltens, Jeroen J.M. Hoozemans, Saskia M. van der Vies
Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer’s Disease Pathology
Abstract: Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20-30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value < 0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention.
Pages 945-959
Catharina Lange, Per Suppa, Lars Frings, Winfried Brenner, Lothar Spies, Ralph Buchert, for the Alzheimer’s Disease Neuroimaging Initiative
Optimization of Statistical Single Subject Analysis of Brain FDG PET for the Prognosis of Mild Cognitive Impairment-to-Alzheimer’s Disease Conversion
Abstract: Background: Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved. Objective: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI). Methods: The study included 108 ADNI MCI subjects grouped as ‘stable MCI’ (n=77) or ‘MCI-to-AD converter’ according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between ‘stable MCI’ and ‘MCI-to-AD converter’. The area (AUC) under the ROC curve was used as performance measure. Results: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p=0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p=0.048). Conclusion: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline.
Pages 961-969
Haiqun Xie*, Chengguo Zhang, Yukai Wang*, Xiping Xu, Shuyun Huang, Lisa Koski, Wei Cui, Wenbin Yang, Youbao Li, Meili Zheng, Mingli He, Jia Fu, Xiuli Shi, Kai Wang, Genfu Tang, Binyan Wang, Yong Huo *These authors contributed equally to the manuscript
Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination
Abstract: Background: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia. Objective: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations. Methods: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function. Results: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated. Conclusion: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered.
Pages 971-990
Guosong Liu, Jason G. Weinger, Zhong-Lin Lu, Feng Xue, Safa Sadeghpour
Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial
Abstract: Background: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents. Objective: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50-70) with cognitive impairment. Subjects were treated with MMFS-01 (n=23) or placebo (n=21) for 12 weeks and cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains. Results: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p=0.003; Cohen's d=0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined. Conclusions: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults.
Pages 991-1003
Sungeun Kim, Kwangsik Nho, Vijay K. Ramanan, Dongbing Lai, Tatiana M. Foroud, Katie Lane, Jill R. Murrell, Sujuan Gao, Kathleen S. Hall, Frederick W. Unverzagt, Olusegun Baiyewu, Adesola Ogunniyi, Oye Gureje, Mitchel A. Kling, P. Murali Doraiswamy, Rima Kaddurah-Daouk, Hugh C. Hendrie, Andrew J. Saykin
Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians
Abstract: Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer’s disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.
Pages 1005-1019
Geon-Hwi Lee*, Byungki Jang*, Hong-Seok Choi*, Hee-Jun Kim, Jeong-Ho Park, Yong-Chul Jeon, Richard I. Carp, Yong-Sun Kim, Eun-Kyoung Choi *These authors contributed equally to this work.
Upregulation of Connexin 43 Expression via c-Jun N-Terminal Kinase Signaling in Prion Disease
Abstract: Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx)-assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion-affected brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell-cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases.
Pages 1021-1029
Eva Mª Arroyo-Anlló, Adèle Turpin Bouston, Marie-Noëlle Fargeau, Begoña Orgaz Baz, Roger Gil
Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia
Abstract: Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning.
Pages 1031-1042
Martha Dlugaj, Angela Winkler, Christian Weimar, Jan Dürig, Martina Broecker-Preuss, Nico Dragano, Susanne Moebus, Karl-Heinz Jöckel, Raimund Erbel, Lewin Eisele on behalf of the Heinz Nixdorf Recall Study Investigative Group
Anemia and Mild Cognitive Impairment in the German General Population
Abstract: There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin
Pages 1043-1050
Elisabeth Stogmann, Doris Moser, Stefanie Klug, Andreas Gleiss, Eduard Auff, Peter Dal-Bianco, Gisela Pusswald, Johann Lehrner
Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer’s Disease
Abstract: Background: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest. Objectives: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: We included 752 consecutive patients suffering from (SCD), non-amnestic (naMCI) or amnestic MCI (aMCI), Alzheimer’s disease (AD), and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed. Results: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls−SCD−naMCI−aMCI−AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7). Conclusions: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease.
Pages 1051-1064
Jieqiong Liu, Xinqing Zhang, ChunshuiYu, Yunyun Duan, Junjie Zhuo, Yue Cui, Bing Liu, Kuncheng Li, Tianzi Jiang, Yong Liu (Handling Associate Editor: Jin-Tai Yu)
Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases. Objective: To investigate if disease severity associated altered PHG connectivity in Alzheimer’s disease (AD) exists. Methods: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson’s correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability. Results: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe. Conclusions: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.
Pages 1065-1074
Maxime Bertoux, Leonardo Cruz de Souza LC, Claire O’Callaghan, Andrea Greve, Marie Sarazin, Bruno Dubois, Michael Hornberger
Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease Regardless of Amnesia?
Abstract: Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer’s disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7%) with ~50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9%). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1%) for amnestic bvFTD versus AD and increased to very high (93.9%) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD.
Pagges 1075-1083
Raphael Le Bouc*, Cecilia Marelli*, Emilie Beaufils*, Claudine Berr, Caroline Hommet, Jacques Touchon, Florence Pasquier, Vincent Deramecourt *These authors contributed equally to this work.
Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics
Abstract: Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families’ negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians’ rate of making requests and the public’s awareness about the importance of brain donation.
Pages 1085-1093
Giuseppe Tosto, Sarah E. Monsell, Stephen E. Hawes, Bruno Giuseppe, Richard Mayeux
Progression of Extrapyramidal Signs in Alzheimer’s Disease: Clinical and Neuropathological Correlates
Abstract: Background. Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson’s disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions. Objective: To identify clusters of EPS progression over time and their clinical and neuropathological correlates. Methods: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings. Results: Three clusters of EPS progression were identified: no/low (n=1,583), medium (n=1,259), and high (n=660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies. Conclusions: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.
Pages 1095-1103
Bernadette McGuinness, Marc Fuchs, Suzanne Barrett, A. Peter Passmore and Janet A. Johnston
Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study
Abstract: A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer’s disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.
Pages 1105-1114
Martina Sattlecker, Mizanur Khondoker, Petroula Proitsi, Stephen Williams, Hilkka Soininen, Iwona Kłoszewska, Patrizia Mecocci, Magda Tsolaki, Bruno Vellas, Simon Lovestone on behalf of the AddNeuroMed Consortium, Richard JB Dobson
Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer’s Disease
Abstract: Biomarkers of Alzheimer’s disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.
Pages 1115-1122
Marissa D. Zwan Victor L. Villemagne, Vincent Doré, Rachel Buckley, Pierrick Bourgeat, Robyn Veljanoski, Olivier Salvado, Rob Williams, Laura Margison, Alan Rembach, S. Lance Macaulay, Ralph Martins, David Ames, Wiesje M. van der Flier, Kathryn A. Ellis, Philip Scheltens, Colin L. Masters, Christopher C. Rowe for the AIBL study (Handling Associate Editor: Barbara Caracciolo)
Subjective Memory Complaints in APOE ε4 Carriers are Associated with High Amyloid-β Burden
Abstract: Background: APOE ε4 genotype and aging have been identified as risk factors for Alzheimer’s disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. Objective: To assess whether APOE ε4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly. Methods: 307 cognitively normal participants (72.7±6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOE ε4 genotype, age, SMC, and episodic memory with Aβ pathology. Results: Odds of high Aβ burden were greater at an older age (OR=3.21; 95% CI=1.68-6.14), when SMC were present (OR=1.90; 95% CI=1.03-3.48), and for APOE ε4 carriers (OR=7.49; 95% CI=3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOE ε4 carriers (OR=4.58, 95% CI=1.83-11.49) and younger participants (OR=3.73, 95% CI=1.39-10.01). Conclusion: Aging, APOE ε4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOE ε4 carriers. These findings suggest that selection based on the presence of SMC, APOE ε4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.
Pages 1123-1134
Gerald Novak, Nick Fox, Shona Clegg, Casper Nielsen, Steven Einstein, Yuan Lu, Iulia Cristina Tudor, Keith Gregg, Jianing Di, Peter Collins, Bradley T. Wyman, Eric Yuen, Michael Grundman, H. Robert Brashear, Enchi Liu (Handling Associate Editor: Philip Scheltens)
Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer’s Disease
Abstract: Background: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ε4 carriers and noncarriers, respectively, with Alzheimer’s disease. Objectives: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. Methods: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. Results: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. Conclusions: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.
Pages 1135-1141
Audrey Gabelle, Laure-Anne Gutierrez, Jean-François Dartigues, Karen Ritchie, Jacques Touchon, Claudine Berr
Palmomental Reflex a Relevant Sign in Early Alzheimer’s Disease Diagnosis?
Abstract: Background: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer’s disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe. Objective: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis. Methods: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before. Results: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD=5.9); median MMSE at diagnosis=23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0%, p=0.03) and at time of diagnosis (30.3 versus 12.3%, p=0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80. Conclusion: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.
Pages 1143-1159
Juergen Dukart, Fabio Sambataro, Alessandro Bertolino, for the Alzheimer’s Disease Neuroimaging Initiative
Accurate Prediction of Conversion to Alzheimer’s Disease using Imaging, Genetic, and Neuropsychological Biomarkers
Abstract: A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer’s disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer’s Disease Neuroimaging Initiative data of AD (n=144), controls (n=112), stable (n=265) and converter (n=177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naïve Bayes classifiers were built on AD and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD.
Pages 1161-1168
Junhua Geng*, Lu Xia*, Wanjie Li, Changqi Zhao, Fei Dou *These authors contributed equally to this work.
Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells
Abstract: Neurofibrillary tangles are the main pathological feature of Alzheimer’s disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions.
Pages 1169-1177
Nagaendran Kandiah, Russell Jude Chander, Xuling Lin, Aloysius Ng, Yen Yeong Poh, Chin Yee Cheong, Alvin Rae Cenina, Pryseley Nkouibert Assam
Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score
Abstract: Background: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3–6 months after mild stroke will be useful for clinicians. Objective: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI. Methods: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients. Results: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months. Conclusion: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.
Pages 1179-1187
James Bennett, Jr., Jeffrey Burns, Paul Welch, Rebecca Bothwell
Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is an aging-related, degenerative brain disease of adults. Most (~95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300 mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n=1), improved (n=2), declined 1-3 points (n= 5), or declined 4-13 points (n=8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r=0.97, p<0.0001). CSF [PPX] was not related to CSF [Aβ(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.
