Pages 857-885
Review
Sanaz Nasoohi, Kehkashan Parveen, Tauheed Ishrat (Handling Associate Editor: Asgar Zaheer)
Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers
Abstract: Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer’s disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating “toxic metabolites” emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or “type 3 diabetes”. Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging, and AD as well underlying the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP function to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia.
Pages 887-899
Review
Lianying Jiang*, Jiafeng Wang*, Zhigang Wang, Wenhui Huang, Yixia Yang, Zhiyou Cai, Keshen Li *These authors contributed equally to this work.
Role of the Glyoxalase System in Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD.
Pages 901-925
Review
Hanane Ramzaoui, Sylvane Faure, Sara Spotorno (Handling Associate Editor: Kirk Daffner)
Alzheimer's Disease, Visual Search, and Instrumental Activities of Daily Living: A Review and a New Perspective on Attention and Eye Movements
Abstract: Many instrumental activities of daily living (IADLs), like cooking and managing finances and medications, involve finding efficiently and in a timely manner one or several objects within complex environments. They may thus be disrupted by visual search deficits. These deficits, present in Alzheimer’s disease (AD) from its early stages, arise from impairments in multiple attentional and memory mechanisms. A growing body of research on visual search in AD has examined several factors underlying search impairments in simple arrays. Little is known about how AD patients search in real-world scenes and in real settings, and about how such impairments affect patients’ functional autonomy. Here, we review studies on visuospatial attention and visual search in AD. We then consider why analysis of patients’ oculomotor behavior is promising to improve understanding of the specific search deficits in AD, and of their role in impairing IADL performance. We also highlight why paradigms developed in research on real-world scenes and real settings in healthy individuals are valuable to investigate visual search in AD. Finally, we indicate future research directions that may offer new insights to improve visual search abilities and autonomy in AD patients.
Pages 927-934
Short Communication
Andy Madrid, Kirk J. Hogan*, Ligia A. Papale, Lindsay R. Clark, Sanjay Asthana, Sterling C. Johnson, Reid S. Alisch *These authors contributed equally to this work.
DNA Hypomethylation in Blood Links B3GALT4 and ZADH2 to Alzheimer’s Disease
Abstract: Differentially methylated positions (DMPs) between persons with and without late-onset Alzheimer’s disease (LOAD) were observed at 477 of 769,190 loci in a plurality of genes. Of these, 17 were shared with DMPs identified using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) and phosphorylated tau 181 (p-tau181) levels, and t-tau/Aβ1–42 (Aβ42), p-tau181/Aβ42, and Aβ42/Aβ1–40 (Aβ40) ratios. In patients with LOAD, 12 of the shared 17 DMPs were hypomethylated in B3GALT4 (Beta-1,3-galatcosyltransferase 4) (EC 2.4.1.62), and 5 were hypomethylated in ZADH2 (Prostaglandin reductase 3) (EC 1.3.1.48).
Pages 935-938
Short Communication
Zimple Kurlawala, Jeffrey A. Roberts, Joseph D. McMillan, Robert P. Friedland
Diazepam Toxicity Presenting as a Dementia Disorder
Abstract: The toxicity associated with long-standing benzodiazepine use in older persons is a critical issue. Several epidemiological reports have studied correlation between benzodiazepine use and risk of dementia development. In this manuscript, we used a case report to demonstrate how chronic diazepam use can cause cognitive deficits that resemble Alzheimer's disease and related conditions. Benzodiazepine use is common in the geriatric population and is often taken for long periods of time in improper doses. In combination with age-related cortical atrophy on the MRI, our patient risked being misdiagnosed with Alzheimer's disease or another dementing disorder if not for the systematic investigation to resolve his symptoms. With elimination of the offending dispensable drug (diazepam), the patient's cognition improved greatly.
Pages 939-945
Commentary
Ning Tang, Kasper P. Kepp
Aβ42/Aβ40 Ratios of Presenilin 1 Mutations Correlate with Clinical Onset of Alzheimer’s Disease
Abstract: Missense mutations in presenilin 1 cause early onset familial Alzheimer’s disease in a way that is not understood. Increased Aβ42/Aβ40 ratios are the most consistent biochemical phenotype of such mutations in cultured cells and in vivo, and are thus considered central to the amyloid hypothesis. Previously, an inverse relation has been observed between the Aβ42/Aβ40 ratio of such mutants and the clinical age of symptom onset in patients carrying the mutation. However, a recent extensive study by Sun et al. of assayed presenilin 1 mutants concluded that such a relationship is not evident. To reconcile the disagreement, three different clinical datasets were compared directly with the data by Sun et al. After considering data noise and measurement uncertainty, we find a clear and highly significant inverse correlation between the Aβ42/Aβ40 ratio and the clinical age of onset in all three datasets even without removing noisy single- and double-patient data. With these data removed, the correlation coefficients increase further. The probability that these relationships are coincidental are approximately 0.1%.
Pages 947-970
Kim E. Innes, Terry Kit Selfe, Kathleen Brundage, Caitlin Montgomery, Sijin Wen, Sahiti Kandati, Hannah Bowles, Dharma Singh Khalsa, Zenzi Huysmans (Handling Associate Editor: J. Wesson Ashford)
Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer’s Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial
Abstract: Background: Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia. Objective: To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). Methods: Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months; cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. Results: Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction<0.006). Both groups improved in cognitive and psychosocial status (ps≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. Conclusion: Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.
Pages 971-981
Charisse N. Winston, Edward J. Goetzl, Laura D. Baker, Michael V. Vitiello, Robert A. Rissman
Growth Hormone-Releasing Hormone Administration in Mild Cognitive Impairment and Its Impact on Neuronal Exosome Biomarkers of Dementia
Abstract: Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ1-42 were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ1-42, NRGN, synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.
Pages 983-991
Francesco Di Lorenzo, Viviana Ponzo, Caterina Motta, Sonia Bonnì, Silvia Picazio, Carlo Caltagirone, Marco Bozzali, Alessandro Martorana, Giacomo Koch (Handling Associate Editor: Andrea Arighi)
Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer’s Disease Patients
Abstract: Background: Mechanisms of cortical plasticity have been recently investigated in Alzheimer’s disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. Objective: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). Methods: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS -5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. Results: In healthy subjects, ccPAS -5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS+5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. Conclusions: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.
Pages 993-999
Claudio Liguori, Nicola Biagio Mercuri, Marzia Nuccetelli, Francesca Izzi, Sergio Bernardini, Fabio Placidi (Handling Associate Editor: Luigi Ferini-Strambi)
Cerebrospinal Fluid Orexin Levels and Nocturnal Sleep Disruption in Alzheimer’s Disease Patients Showing Neuropsychiatric Symptoms
Abstract: Background: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by a progressive deterioration of cognition, frequently associated with neuropsychiatric symptoms (NPS). Among NPS, sleep disturbances often affect AD patients. Orexinergic system dysregulation has been associated with sleep impairment in AD patients. Objective: The present study investigated CSF orexin levels in AD patients and their relationship with both NPS, measured by the neuropsychiatric inventory (NPI), and sleep, measured via polysomnography. Methods: This is a secondary analysis of a previous study investigating CSF biomarkers, sleep impairment and cognitive decline in AD patients. AD patients completing the NPI were included in this analysis and distributed in two groups based on the presence (NPI score≥4, AD/NPS+) or absence (NPI score <4, AD/NPS-) of NPS. Results: Twenty-two AD patients constituted the AD/NPS+ group and 20 patients constituted the AD/NPS- group. We observed higher CSF orexin levels in AD/NPS+ than AD/NPS- patients. Moreover, AD/NPS+ showed a more fragmented and the reduction of REM sleep compared to AD/NPS- patients. Notably, higher NPI scores correlated with a more altered sleep structure, higher CSF orexin levels and lower MMSE scores. Conclusion: This study documented that AD patients showing NPS present a more fragmented sleep coupled with higher CSF orexin levels compared to AD patients not affected by NPS. This finding showing the increased orexinergic tone in AD patients affected by NPS suggests the possible influence of the orexinergic system dysregulation not only on sleep impairment but also on NPS in AD patients.
Pages 1001-1014
Yang Lei*, Zhi-Feng Zhang*, Rui-Xue Lei, Shu Wang, Yang Zhuang, An-Chun Liu, Yan Wu, Juan Chen, Jun-Chun Tang, Meng-Xian Pan, Rui Liu, Wei-Jing Liao, Yu-Gong Feng, Qi Wan, Mei Zheng (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury
Abstract: DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.
Pages 1015-1025
Tyler E. Owens, Mary M. Machulda, Joseph R. Duffy, Edythe A. Strand, Heather M. Clark, Sarah Boland, Peter R. Martin, Val J. Lowe, Clifford R, Jack, Jr, Jennifer L. Whitwell, Keith A. Josephs (Handling Associate Editor: Cristian Leyton)
Patterns of Neuropsychological Dysfunction and Cortical Volume Changes in Logopenic Aphasia
Abstract: Background: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). Objective: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. Methods: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. Results: We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. Conclusions: LvPPA patients without other cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.
Pages 1027-1040
Ron L.H. Handels, Anders Sköldunger, Anja Bieber, Rhiannon Tudor Edwards, Manuel Gonçalves-Pereira, Louise Hopper, Kate Irving, Hannah Jelley, Liselot Kerpershoek, Maria J. Marques, Gabriele Meyer, Mona Michelet, Elisa Portolani, Janne Røsvik, Geir Selbaek, Astrid Stephan, Marjolein de Vugt, Claire Wolfs, Bob Woods, Orazio Zanetti, Frans Verhey, Anders Wimo, Actifcare Consortium (Handling Associate Editor: Bernhard Michalowsky)
Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study
Abstract: Background: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. Objective: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. Methods: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver’s quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. Results: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers’ utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately €17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. Conclusion: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.
Pages 1041-1052
Keenan A. Walker, B. Gwen Windham, Charles H. Brown IV, David S. Knopman, Clifford R. Jack, Jr., Thomas H. Mosley, Jr., Elizabeth Selvin, Dean F. Wong, Timothy M. Hughes, Yun Zhou, Alden L. Gross, Rebecca F. Gottesman (Handling Associate Editor: Madhav Thambisetty)
The Association of Mid- and Late-Life Systemic Inflammation with Brain Amyloid Deposition: The ARIC-PET Study
Abstract: Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13-2.42), and among white (OR 1.33, 95% CI: 1.02-1.75), but not African American, participants (p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.
Pages 1053-1064
M. Mahafuzur Rahman, Gunilla T. Westermark, Henrik Zetterberg, Torleif Härd, Mats Sandgren
Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid
Abstract: Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer’s disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ42CC-binding partners. Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms.
Pages 1065-1082
Dana Mohammad, Courtney Ellis, Allison Rau, Paul B. Rosenberg, Jacobo Mintzer, Myuri Ruthirakuhan, Nathan Herrmann, Krista L. Lanctôt (Handling Associate Editor: Elizabeth Finger)
Psychometric Properties of Apathy Scales in Dementia: A Systematic Review
Abstract: Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer’s disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatry Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.
Pages 1083-1094
Federica Lucchelli, Maria Cristina Saetti, Hans Spinnler (Handling Associate Editor: Andrea Arighi)
Degenerative Amnesia for Past Public Events: An Attempt to Measure Storage and Retrieval
Abstract: A still unsettled issue of amnesia concerns the differential contributions to recall impairment of the underlying retrieval and storage abilities. The aim of the present study was to disentangle and to measure such roles in the recall of past public events comparing patients with degenerative amnesia and healthy elderly. The experiment included 44 healthy elderly and two groups of participants with degenerative amnesia, namely 17 patients with amnestic mild cognitive impairment and 22 mild Alzheimer’s disease patients. Recall of famous past public events was assessed by means of a 52-item questionnaire standardized for the Italian population. A latent-variable approach was adopted in order to infer the contributions of retrieval and storage to the recall performances. A stochastic model was adopted, which in a previous study of recall of recent and remote past public events in healthy elderly succeeded to prove reduced retrieval efficiency for more recent events. The results of the present study suggest that retrieval is more fragile than storage in all three experimental groups. A storage impairment turned out only in the Alzheimer’s disease group, where it was limited to more recent memories. In view of the combined roles of the hippocampus and cortex in past memory processing, our results are consistent with the hypothesis that the degenerative process primarily impairs the strategic memory search. However, the sufficiency criterion of the adopted Markov model fell short of significance. Due to this statistical shortcoming, our conclusions, though consistent with the clinical predictions, are to be taken as provisional.
Pages 1095-1104
Omar M. Al-Janabi*, Christopher A. Brown*, Ahmed A. Bahrani, Erin L. Abner, Justin M. Barber, Brian T. Gold, Larry B. Goldstein, Ronan R. Murphy, Peter T. Nelson, Nathan F. Johnson, Leslie M. Shaw, Charles D. Smith, John Q. Trojanowski, Donna M. Wilcock, Gregory A. Jicha *These authors contributed equally to this work.
Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-β1-42 and Hypertension
Abstract: Background: Alzheimer’s disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. Objective: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. Methods: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer’s Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. Results: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN × CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42. Conclusion: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.
Pages 1105-1116
Lisa Florek*, Solveig Tiepolt*, Matthias L. Schroeter, Jörg Berrouschot, Dorothee Saur, Swen Hesse, Thies Jochimsen, Julia Luthardt, Bernhard Sattler, Marianne Patt, Karl-Titus Hoffmann, Arno Villringer, Joseph Classen, Hermann-Josef Gertz, Osama Sabri* Henryk Barthel* *These authors contributed equally to this work.
Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background: Current research diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates. Objective: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers. Methods: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed. Results: In the early images AD-typical patterns were present in 42%/27%/33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42%/29%/38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as “MCI due to AD-high likelihood”, 44% of the probable ADs as “probable AD with high evidence of AD pathophysiological process” and 28% of the possible ADs as “possible AD with evidence of AD pathophysiological process”. 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p=0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R=0.30 p=0.006). Conclusion: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.
Pages 1117-1129
Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Ramasamy Thangavel, Mohammad Ejaz Ahmed, Smita Zaheer, Keerthana Kuppamma Kumar, Anudeep Yelam, Harleen Kaur, Iuliia Dubova, Sudhanshu P. Raikwar, Shankar S. Iyer, Asgar Zaheer (Handling Associate Editor: P. Hemachandra Reddy)
Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation
Abstract: Parkinson’s disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators. Glia maturation factor (GMF), mast cells and proteinase activated receptor-2 (PAR-2) are implicated in neuroinflammation. Alpha-synuclein which induces neurodegeneration increases PAR-2 expression in the brain. However, the exact mechanisms are not yet understood. In this study, we quantified inflammatory mediators in the brains of MPTP-administered wild type (Wt), GMF-knockout (GMF-KO), and mast cell knockout (MC-KO) mice. Additionally, we analyzed the effect of MPP+, GMF, and mast cell proteases on PAR-2 expression in astrocytes and neurons in vitro. Results show that the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and the chemokine (C-C motif) ligand 2 (CCL2) were lesser in the brains of GMF-KO mice and MC-KO mice when compared to Wt mice brain after MPTP administration. Incubation of astrocytes and neurons with MPP+, GMF, and mouse mast cell protease-6 (MMCP-6) and MMCP-7 increased the expression of PAR-2. Our studies show that the absence of mast cells and GMF reduce the expression of neuroinflammatory mediators in the brain. We conclude that GMF along with mast cell interactions with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD and other neuroinflammatory disorders.
Pages 1131-1144
Monia Cabinio*, Marina Saresella*, Federica Piancone, Francesca LaRosa, Ivana Marventano, Franca Guerini, Raffaello Nemni, Francesca Baglio, Mario Clerici *These authors contributed equally to this work.
Association between Hippocampal Shape, Neuroinflammation, and Cognitive Decline in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition characterized by memory impairment and general decrease in cognitive functions and daily living competences, that leads to a complete loss of autonomy. The pathogenesis of AD is characterized by the deposition of amyloid-β plaques (Aβ plaques) and neurofibrillary tangles, initially involving cortical and hippocampal structures, and neuroinflammation. To date, no studies have investigated the topological association between neuroinflammation and hippocampal shape in AD. Objective: The aim of the present study is to assess the association between hippocampal shape, cognitive profile, and neuroinflammation in a group of AD patients in the mild stage of the disease. Methods: Thirty-one patients with typical onset AD (mild stage) underwent MRI examination (1.5T scanner); hippocampal structures were segmented using a vertex-wise analysis (FSL-FIRST). Immune parameters were evaluated on peripheral blood mononuclear cells by flow-cytometry. Correlation analyses were performed between hippocampal shape and both cognitive profile (ADAS-Cog and MMSE scores), and neuro-inflammatory variables (i.e., circulating monocytes, cytokines). Results: Statistically significant correlations (p<0.05FWE) between right hippocampal shape and cognitive measurements and between left hippocampal shape and inflammatory indices were detected. The hippocampal field mostly involved was the lateral portion of bilateral hippocampi, mainly overlapping with Cornu Ammonis, extending along the entire longitudinal axis. Conclusions: A topological relationship between hippocampal atrophy and both cognitive profile and neuroinflammation is found; the association with neuroinflammatory indices is in line with the pattern of AD-associated neuronal death, whereas the association with cognitive test might account for residual cognitive functions.
Pages 1145-1163
Pedro Cisternas*, Juan M. Zolezzi*, Carolina Lindsay, Daniela S. Rivera, Alexis Martinez, Francisco Bozinovic, Nibaldo C. Inestrosa *These authors contributed equally to this work.
New Insights into the Spontaneous Human Alzheimer’s Disease-Like Model Octodon degus: Unraveling Amyloid-β Peptide Aggregation and Age-Related Amyloid Pathology
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.
Pages 1165-1174
Niels Janssen, Ron L. Handels, Anders Sköldunger, Bob Woods, Hannah Jelley, Rhiannon Tudor Edwards, Martin Orrell, Geir Selbæk, Janne Røsvik, Manuel Gonçalves-Pereira, Maria J. Marques, Orazio Zanetti, Elisa Portolani, Kate Irving, Louise Hopper, Gabriele Meyer, Anja Bieber, Astrid Stephan, Liselot Kerpershoek, Claire A.G. Wolfs, Marjolein E. de Vugt, Frans R.J. Verhey, Anders Wimo, Actifcare Consortium
Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia
Abstract: Background: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. Objective: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. Methods: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. Results: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for “company” was significantly related to lower total costs. Conclusion: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.
Pages 1175-1191
Daniela Jara-Moreno*, Rubén D. Castro-Torres*, Miren Ettcheto, Carme Auladell, Marcelo J. Kogan, Jaume Folch, Ester Verdaguer, Amanda Cano, Oriol Busquets, Carla Delporte**, Antoni Camins** *These authors contributed equally to this work. **These authors contributed equally as senior authors.
The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer’s Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet
Abstract: The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology.
Pages 1193-1211
Tenielle Porter, Samantha C. Burnham, Lidija Milicic, Greg Savage, Paul Maruff, Yen Ying Lim, Qiao-Xin Li, David Ames, Colin L. Masters, Stephanie Rainey-Smith, Christopher C. Rowe, Olivier Salvado, David Groth, Giuseppe Verdile, Victor L. Villemagne, Simon M. Laws, for the AIBL Research Group
Utility of an Alzheimer’s Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer’s Disease: A Prospective Longitudinal Study
Abstract: Background: With the exception of APOE, genetic variants associated with increased Alzheimer’s disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. Objective: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. Methods: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer’s Cognitive Composite (PACC). Results: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Αβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Αβhigh CN older adults is due to a saturating effect of APOE genotype. Conclusions: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.
Pages 1213-1221
Ganesh M. Babulal, Suzie Chen, Monique M. Williams, Jean-Francois Trani, Parul Bakhshi, Grace L. Chao, Sarah H. Stout, Anne M. Fagan, Tammie L.S. Benzinger, David M. Holtzman, John C. Morris, Catherine M. Roe
Depression and Alzheimer’s Disease Biomarkers Predict Driving Decline
Abstract: Background: Symptomatic Alzheimer’s disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD. Objective: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults. Methods: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models. Results: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD=1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p=0.024, HR=2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p≤0.05, HR=2.51-3.15). In the CSF ptau181 model, depression diagnosis (p=0.031, HR=2.51) and antidepressant use (p=0.037, HR=2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance. Conclusions: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults.
Pages 1223-1234
Sarah J. Banks, Xiaowei Zhuang, Ece Bayram, Chris Bird, Dietmar Cordes, Jessica Z.K. Caldwell, Jeffrey L. Cummings for the Alzheimer’s Disease Neuroimaging Initiative
Default Mode Network Lateralization and Memory in Healthy Aging and Alzheimer’s Disease
Abstract: Lateralization of default mode network (DMN) functioning has been shown to change with age. Similarly, lateralization of frontal lobe function has been shown to decline in age. The impact of amyloid pathology and the progression of Alzheimer’s disease (AD) on resting state lateralization has not been investigated. Due to the preferential involvement of the left hemisphere in verbal tasks, there may be a benefit to higher levels of left-lateralization in the performance of verbal memory tasks. Here we compared functional lateralization of the anterior and posterior DMN between four groups of participants: amyloid negative (Aβ-) and amyloid positive (Aβ+) groups with normal cognition (NC), and Aβ+ groups with mild cognitive impairment (Aβ+MCI) or dementia (Aβ+AD). Differences were evident between groups in posterior DMN; the Aβ-NC group was more left-lateralized than both cognitively impaired Aβ+ groups. There was no difference in anterior DMN. No differences in overall network connectivity between groups were observed, suggesting that the functional lateralization finding is not secondary to general changes in connectivity. Left-lateralization of both networks was associated with better verbal recall performance. Older subjects, overall, had less left functional lateralization of the anterior DMN.
Pages 1235-1244
Ibtisam Bagallab, Jorge Mauricio Reyes-Ruiz, Khalid Abulnaja, Etimad Huwait, Charles Glabe (Handling Associate Editor: Elizabeth Head)
Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8
Abstract: The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer’s disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.
Pages 1245-1254
Hanlin Zhang*, Kang Chen*, Naili Wang, Di Zhang, Qian Yang, Qing Zhang, Pan Liu, Mengyao Wan, Changlin Gong, Xinyu Hong, Wenying Qiu, Xiaojing Qian, Yongmei Chen, Chao Ma *These authors contributed equally to this work.
Analysis of Brain Donors’ Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China
Abstract: The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p<0.001) and at an older age when registration (p<0.001) and donation (p<0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China.
Pages 1255-1264
Thomas Gilbert, Sylvain Roche, Emilie Blond, Jean-Yves Bar, Jocelyne Drai, Charlotte Cuerq, Marine Haution-Bitker, René Ecochard, Marc Bonnefoy (Handling Associate Editor: Lilian Calderon-Garciduenas)
Association between Peripheral Leptin and Adiponectin Levels and Cognitive Decline in Patients with Neurocognitive Disorders ≥65 Years
Abstract: Background: There is evidence that adipokines have roles in brain functioning and cognitive decline. Objective: Assess the role of leptin and adiponectin levels in predicting changes in neuro-cognitive disorders (NCD). Methods: The study included 205 patients over 65 years of age presenting for a one-day hospitalization for current assessment of cognitive function. Peripheral blood leptin and adiponectin levels were measured at admission. Demographic variables, body mass index (BMI), and history of hypertension were also recorded. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) at admission and at later scheduled visits over a median follow-up period of 14.5 months. Conventional univariate comparisons were made between diagnosis groups (Alzheimer’s disease (AD), mild NCD, vascular/mixed dementia). Changes in MMSE scores over time were examined with regard to the above variables using a linear mixed model. Results: The mean BMI was significantly lower (by 2 kg/m², p=0.01) in patients with AD than in patients with either mild-NCD or vascular/mixed dementia. Leptin levels were significantly higher (p=0.043) and adiponectin levels significantly lower (p=0.045) in patients with mild-NCD than in patients with major-NCD (AD or vascular/mixed dementia). However, the mixed model suggested no influence of the baseline levels of these two biomarkers on the course of cognitive decline. Conclusion: The present study confirms the associations between leptin and adiponectin and AD or AD-related disorders but did not confirm that these peptides may be used as predictive biomarkers of cognitive decline.
Pages 1265-1273
Gamze Tuna, Görsev G. Yener, Gülgün Oktay, G. Hüray İşlekel, F. Güldal Kırkalı
Evaluation of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9) and Their Tissue Inhibitors (TIMP-1 and TIMP-2) in Plasma from Patients with Neurodegenerative Dementia
Abstract: Matrix metalloproteinases (MMPs) are substantial regulators of learning and memory and might be involved in neurodegeneration. It is known that MMPs are involved in pathogenesis of Alzheimer’s disease (AD) and are particularly involved in the amyloid-β processing pathway. However, information on circulating levels of these proteins and their tissue inhibitors (TIMPs) in AD and other neurodegenerative dementia (ND) diseases such as dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) is not clear. Therefore, this study was directed toward finding out how plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 vary in AD, DLB, and FTD; and investigating the correlation of the levels of MMPs and their inhibitors with clinical parameters of the patients. MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Plasma MMP-2 levels were significantly lower in all the patient groups than in the age-matched healthy controls (HCs) (p < 0.05). MMP-9 levels were significantly lower in the FTD patients than in the HCs (p < 0.05). Also, TIMP-1 levels were lower in the AD and FTD patients than in the HCs (p < 0.05). TIMP-2 levels were similar in all the groups. These findings highlight the importance of circulating MMPs in ND and suggest that MMPs and their inhibitors might play a role in impaired amyloid-β peptide metabolism which is responsible for the genesis and progression of ND. Furthermore, measurement of MMP-2 and MMP-9 and their inhibitors may be of great importance for large scale basic research and clinical studies of ND.
Pages 1275-1282
Gina M. Peloso, Alexa S. Beiser, Anita L. Destefano, Sudha Seshadri
Genetic Interaction with Plasma Lipids on Alzheimer’s Disease in the Framingham Heart Study
Abstract: Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer’s disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p=0.006), but no interaction of the GRS with HDL-C (p=0.458) or LDL-C (p=0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOE ε4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.
Pages 1283-1294
Sanneke van Rooden, Annette A. van den Berg-Huysmans, Pauline H. Croll, Gerda Labadie, Jessica M. Hayes, Raymond Viviano, Jeroen van der Grond, Serge A.R.B. Rombouts, Jessica S. Damoiseaux (Handling Associate Editor: Juan Zhou)
Subjective Cognitive Decline Is Associated with Greater White Matter Hyperintensity Volume
Abstract: Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer’s disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. Objective: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). Methods: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. Results: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. Conclusion: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.
Pages 1295-1308
Catherine A. S. Deane, Ian R. Brown (Handling Associate Editor: Karen Mearow)
Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress
Abstract: HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized to the periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.
