Journal of Alzheimer's Disease - Volume 62, issue 1

Authors: Overk, Cassia | Masliah, Eliezer

Article Type: Review Article

Abstract:  It has been a year since we lost Dale Schenk on September 30, 2016. Dale’s visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-β (Aβ) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer’s disease (AD). Following Dale’s seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson’s disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary. The next steps in the …development of immunotherapies will require combinatorial approaches mixing antibodies against various targets (e.g., Aβ, α-syn, Tau, and TDP43) with small molecules that block toxicity, aggregation, inflammation, and promote cell survival. Show more

Keywords: Alzheimer’s disease, immunotherapy, Potamkin Prize, synucleinopthy, tauopathy

DOI: 10.3233/JAD-171071

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 1-13, 2018

Authors: Jha, Niraj Kumar | Jha, Saurabh Kumar | Sharma, Renu | Kumar, Dhiraj | Ambasta , Rashmi K. | Kumar, Pravir

Article Type: Review Article

Abstract: For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2 ) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2 . On the contrary, hypoxia to …the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration. Show more

Keywords: Angiogenesis, energy metabolism, hypoxia, neurodegeneration, neurogenesis, therapeutics

DOI: 10.3233/JAD-170589

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 15-38, 2018

Authors: Lang, Brittany | Kindy, Mark S. | Kozel, F. Andrew | Schultz, Susan K. | Taheri, Saeid

Article Type: Review Article

Abstract: Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from …different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory. Show more

Keywords: Biomarkers, cerebrovascular diseases, clustering, neuroimaging, vascular cognitive impairment, vascular dementia

DOI: 10.3233/JAD-170733

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 39-60, 2018

Authors: Ihara, Masafumi | Washida, Kazuo

Article Type: Review Article

Abstract: Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer’s disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In …addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients. Show more

Keywords: Alzheimer’s disease, anticoagulant, atrial fibrillation, catheter ablation, dementia, hypoperfusion, rhythm control

DOI: 10.3233/JAD-170970

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 61-72, 2018

Authors: Hashimoto, Makoto | Ho, Gilbert | Sugama, Shuei | Takamatsu, Yoshiki | Shimizu, Yuka | Takenouchi, Takato | Waragai, Masaaki | Masliah, Eliezer

Article Type: Research Article

Abstract:  Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of …APs in aging-associated neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin’s ‘gemmules’, imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis. Show more

Keywords: Alzheimer’s disease, amyloidogenic proteins, cancers, evolvability, neurodegenerative disease, stress, γ-synuclein, transmission, yeast prion

DOI: 10.3233/JAD-170894

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 73-83, 2018

Authors: Xie, Long | Das, Sandhitsu R. | Wisse, Laura E.M. | Ittyerah, Ranjit | Yushkevich, Paul A. | Wolk, David A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Short Communication

Abstract: Neurofibrillary tangle (NFT) pathology is linked to neurodegeneration in the medial temporal lobe (MTL). Using a tailored pipeline, we correlated atrophy rate, as measured from retrospective longitudinal MRI, with NFT burden, measured from 18 F-AV-1451 PET, within MTL regions of earliest NFT pathology. In amyloid-β positive but not amyloid-β negative individuals, we found significant correlation between 18 F-AV-1451 uptake and atrophy rate that was strongest in the transentorhinal cortex, the first region with NFT pathology. This supports the role of NFTs in driving neurodegeneration and the utility of 18 F-AV-1451 PET and structural measurement of transentorhinal cortex in tracking early …tau-mediated disease progression. Show more

Keywords: Alzheimer’s disease, amyloid, 18F-AV-1451 PET, medial temporal lobe, structural atrophy

DOI: 10.3233/JAD-170945

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 85-92, 2018

Authors: Berg, Jody-Lynn | Durant, January | Léger, Gabriel C. | Cummings, Jeffrey L. | Nasreddine, Ziad | Miller, Justin B.

Article Type: Short Communication

Abstract: The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a …difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns. Show more

Keywords: Cognition, handheld computers, neuropsychological tests, reproducibility of results

DOI: 10.3233/JAD-170896

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 93-97, 2018

Authors: Backhouse, Tamara | Camino, Julieta | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: Behavioral crises in dementia are represented by a wide variety of symptoms, regularly require external intervention from professionals, and are reported as a risk factor for hospital admission. Little is known about the factors that are associated with them. Objective: To determine the factors associated with dementia-related behavioral crises. Methods: We searched MEDLINE, CINAHL, PsycINFO, EMBASE, and AMED databases. An additional lateral search including reference lists was conducted. Two researchers screened all records for potential eligibility. Narrative synthesis was used to bring together the findings. Results: Out of the 5,544 records identified, 24 …articles (18 distinct studies) met the eligibility criteria. Aggression and agitation were the most common behaviors present at crises. Delusions, wandering/absconding, and hallucinations were also key behaviors contributing to crises. Behavioral crises predominantly happened in the severe stages of dementia (according to MMSE scores), in people with dementia residing in their own homes and in long-term care, and were the catalyst for admissions to psychiatric inpatient settings, specialist-care units, long-term care settings, or for referrals to psychiatric community services. Lack of consistency in assessment of behavior, and management of agitation/aggression in dementia crises were evident. Conclusion: Interventions to reduce the likelihood of people with dementia-related behaviors reaching crisis point need to focus on both family and care home settings and incorporate aggression and agitation management. Future research should focus on determining the factors that could be addressed to prevent behavioral crises and the interventions and models of care that may help to prevent crises. Show more

Keywords: Behavior, behavioral symptoms, crisis intervention, dementia, hospitalization, institutionalization

DOI: 10.3233/JAD-170679

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 99-113, 2018

Authors: Mahady, Laura | Nadeem, Muhammad | Malek-Ahmadi, Michael | Chen, Kewei | Perez, Sylvia E. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer’s disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a …decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD. Show more

Keywords: Alzheimer’s disease, frontal cortex, histone deacetylase, epigenetics, mild cognitive impairment, neuropathology, sirtuins

DOI: 10.3233/JAD-171032

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 115-131, 2018

Authors: Marra, Angela | Naro, Antonino | Chillura, Antonino | Bramanti, Alessia | Maresca, Giuseppa | De Luca, Rosaria | Manuli, Alfredo | Bramanti, Placido | Calabrò, Rocco Salvatore

Article Type: Research Article

Abstract: Background: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose. Objective: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC. Methods: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer’s disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and …backward the face. Results: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up). Conclusions: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training. Show more

Keywords: Dementia, functional transcranial Doppler, mild cognitive impairment, MCI-to-dementia conversion, peripersonal space

DOI: 10.3233/JAD-170973

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 133-143, 2018

Authors: Schweda, Mark | Kögel, Anna | Bartels, Claudia | Wiltfang, Jens | Schneider, Anja | Schicktanz, Silke

Article Type: Research Article

Abstract: Background: Biomarker-supported testing for preclinical and prodromal Alzheimer’s disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries. Objectives: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns. Methods: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n  = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and …percentage distribution. Results: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a ‘right not to know’, 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73–75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested. Conclusions: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed. Show more

Keywords: Alzheimer’s disease, dementia, disclosure, ethics, Germany, questionnaires, surveys

DOI: 10.3233/JAD-170443

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 145-155, 2018

Authors: Corvol, Aline | Netter, Alix | Campeon, Arnaud | Somme, Dominique

Article Type: Research Article

Abstract: Background: The French National Alzheimer Plan 2008-2012 created specialized Alzheimer teams, which provide up to 15 sessions of cognitive rehabilitation in the patient’s home for 3 months. Sessions are conducted by an occupational therapist and a gerontological nursing assistant. Objectives: As the patient’s experience is one determinant of successful implementation, we explored the usefulness of these teams as viewed by the patient and his or her main caregiver. Methods: Thirteen patients and their caregiver, previously assisted by a specialized Alzheimer team, were individually given semi-structured interviews (n  = 26, duration 20 to 180 minutes). Results: …Our study showed that although patients and caregiver had no initial expectations, most of them appreciated the support provided by the specialized Alzheimer teams. Patients valued the “human” component, and favored interventions that improved quality of life over those intended to maintain functional capacities. Caregivers observed improved mood and behavior in patients. Those involved in sessions felt empowered by contact with a specialized Alzheimer team. We discuss how patients’ and caregivers’ feedback influenced the implementation process through comprehensive use of the five dimensions of the RE-AIM framework. Conclusion: Whereas intervention by specialized Alzheimer teams was largely accepted by health care professionals, patients, and caregivers, its effectiveness is questioned in view of its deviation from the evidence-based model. Interviews with patients and caregivers shed light on some reasons for this deviation, as what they value in the intervention differs from the functional focus of the model. Show more

Keywords: Alzheimer’s disease, occupational therapy, patient acceptance of health care, public health systems research, qualitative research

DOI: 10.3233/JAD-170765

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 157-164, 2018

Authors: Haapalinna, Fanni | Kokki, Merja | Jääskeläinen, Olli | Hallikainen, Merja | Helisalmi, Seppo | Koivisto, Anne | Kokki, Hannu | Paajanen, Teemu | Penttinen, Janne | Pikkarainen, Maria | Rautiainen, Minna | Soininen, Hilkka | Solje, Eino | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Background: The neuropathology of Alzheimer’s disease (AD) has previously been shown to be rather common among the elderly. Objective: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOE ɛ 4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. Methods: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOE ɛ 4 status were analyzed. …Results: Of the studied subjects, 8.6% (n  = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. Conclusion: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E4, cerebrospinal fluid, cognition

DOI: 10.3233/JAD-170534

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 165-174, 2018

Authors: Wezyk, Michalina | Szybinska, Aleksandra | Wojsiat, Joanna | Szczerba, Marcelina | Day, Kelly | Ronnholm, Harriet | Kele, Malin | Berdynski, Mariusz | Peplonska, Beata | Fichna, Jakub Piotr | Ilkowski, Jan | Styczynska, Maria | Barczak, Anna | Zboch, Marzena | Filipek-Gliszczynska, Anna | Bojakowski, Krzysztof | Skrzypczak, Magdalena | Ginalski, Krzysztof | Kabza, Michal | Makalowska, Izabela | Barcikowska-Kotowicz, Maria | Wojda, Urszula | Falk, Anna | Zekanowski, Cezary

Article Type: Research Article

Abstract:  The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer’s disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content …of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD. Show more

Keywords: Alzheimer’s disease, BRCA1, DNA damage response, cell cycle re-entry, presenilin 1, ubiquitination

DOI: 10.3233/JAD-170830

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 175-202, 2018

Authors: Vogelgsang, Jonathan | Wedekind, Dirk | Bouter, Caroline | Klafki, Hans-W. | Wiltfang, Jens

Article Type: Research Article

Abstract: Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer’s disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42 ). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 … = 0.7129 (tTau, p  < 0.001), 0.7914 (pTau, p  < 0.001), 0.5078 (Aβ42 , p  < 0.001), 0.5739 (Aβ40 , p  < 0.001), and 0.4308 (Aβ42/40 , p  < 0.001). However, the diagnostic classifications of the Aβ42 , tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40 , instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, clinical diagnostics

DOI: 10.3233/JAD-170793

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 203-212, 2018

Authors: Watremez, William | Jackson, Joshua | Almari, Bushra | McLean, Samantha L. | Grayson, Ben | Neill, Joanna C. | Fischer, Nicolas | Allouche, Ahmad | Koziel, Violette | Pillot, Thierry | Harte, Michael K.

Article Type: Research Article

Abstract: Background: With current treatments for Alzheimer’s disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42 ) on cognitive, …inflammatory, synaptic, and neuronal markers in the rat. Methods: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μ L). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, cognition, parvalbumin interneurons

DOI: 10.3233/JAD-170489

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 213-226, 2018

Authors: Taragano, Fernando E. | Allegri, Ricardo F. | Heisecke, Silvina L. | Martelli, María I. | Feldman, Mónica L. | Sánchez, Viviana | García, Virginia A. | Tufro, Graciela | Castro, Diego M. | Leguizamón, Patricio Perez | Guelar, Verónica | Ruotolo, Eva | Zegarra, Cecilia | Dillon, Carol

Article Type: Research Article

Abstract: Background: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. Objective: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. Methods: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. …All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. Results: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p  < 0.001). MCI patients mostly converted to Alzheimer’s dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. Conclusion: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention. Show more

Keywords: Alzheimer’s disease, conversion to dementia, follow-up, frontotemporal disease, Lewy body disease, mild behavioral impairment, mild cognitive impairment, pre-dementia

DOI: 10.3233/JAD-170632

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 227-238, 2018

Authors: Shoda, Chiho | Kitagawa, Yorihisa | Shimada, Hiroyuki | Yuzawa, Mitsuko | Tateno, Amane | Okubo, Yoshiro

Article Type: Research Article

Abstract: Background: Histopathological studies have confirmed that soft drusen contains amyloid-β (Aβ). Objective: To examine the relationship between the area of soft drusen in the macular area and cerebral Aβ accumulation or plasma Aβ level in elderly persons without dementia. Methods: Fourteen consecutive patients (18 eyes) aged ≥50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 μm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral …cortical-to-cerebellar Aβ accumulation. Ratio of plasma Aβ1-42 to Aβ1-40 level was calculated. Results: Mean age was 73.3±7.6 years. The soft drusen area was 4.32±2.42 mm2 . The SUVR was 1.08±0.15. Plasma Aβ1-42 /Aβ1-40 ratio was 0.17±0.08. When SUVR ≥1.10 was defined as positive and <1.10 as negative, the soft drusen area in SUVR-positive patients (6.19±1.14 mm2 ) was significantly (p  = 0.0043) larger than that in SUVR-negative patients (3.13±2.27 mm2 ). Multivariate regression analysis showed that SUVR positivity correlated with soft drusen area (p  = 0.0484) and with Voxel-based Specific Regional Analysis System for Alzheimer’s Disease score (p  = 0.0360). However, there was no correlation with gender (p  = 0.1921), age (p  = 0.2361), Alzheimer’s Disease Assessment Scale score (p  = 0.6310), Mini-Mental State Examination score (p  = 0.4246), or plasma Aβ1-42 /Aβ1-40 ratio (p  = 0.8398). Conclusion: Among elderly persons without dementia, the area of soft drusen was larger in those with more extensive cerebral Aβ accumulation. The area of soft drusen may be a biomarker of cerebral Aβ accumulation. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, florbetapir, macular degeneration, positron-emission tomography

DOI: 10.3233/JAD-170956

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 239-245, 2018

Authors: Babiloni, Claudio | Del Percio, Claudio | Lizio, Roberta | Noce, Giuseppe | Lopez, Susanna | Soricelli, Andrea | Ferri, Raffaele | Pascarelli, Maria Teresa | Catania, Valentina | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Aarsland, Dag | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Onofrj, Marco | Stocchi, Fabrizio | Vacca, Laura | Stirpe, Paola | Fuhr, Peter | Gschwandtner, Ute | Ransmayr, Gerhard | Garn, Heinrich | Fraioli, Lucia | Pievani, Michela | Frisoni, Giovanni B. | D’Antonio, Fabrizia | De Lena, Carlo | Güntekin, Bahar | Hanoğlu, Lutfu | Başar, Erol | Yener, Görsev | Emek-Savaş, Derya Durusu | Triggiani, Antonio Ivano | Franciotti, Raffaella | Taylor, John Paul | De Pandis, Maria Francesca | Bonanni, Laura

Article Type: Research Article

Abstract: The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was …used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers. Show more

Keywords: Exact low resolution brain electromagnetic source tomography (eLORETA), mild cognitive impairment due to Alzheimer’s disease, mild cognitive impairment due to dementia with Lewy bodies, receiver operating characteristic curve, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-170703

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 247-268, 2018

Authors: Leskelä, Stina | Takalo, Mari | Marttinen, Mikael | Huber, Nadine | Paananen, Jussi | Mitra, Vikram | Rauramaa, Tuomas | Mäkinen, Petra | Leinonen, Ville | Soininen, Hilkka | Pike, Ian | Remes, Anne M. | Hiltunen, Mikko | Haapasalo, Annakaisa

Article Type: Research Article

Abstract: A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 …levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, C9orf72, frontotemporal dementia

DOI: 10.3233/JAD-170362

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 269-278, 2018

Authors: Jęśko, Henryk | Lukiw, Walter J. | Wilkaniec, Anna | Cieślik, Magdalena | Gąssowska-Dobrowolska, Magdalena | Murawska, Emilia | Hilgier, Wojciech | Adamczyk, Agata

Article Type: Research Article

Abstract: Urea cycle enzymes may play important yet poorly characterized roles in Alzheimer’s disease (AD). Our previous results showed that amyloid-β (Aβ) affects urea cycle enzymes in rat pheochromocytoma (PC12) cells. The aim of the present study was to investigate the changes in arginases, other urea cycle enzymes, and nitric oxide synthases (NOS s) in PC12 cells transfected with AβPP bearing the double ‘Swedish’ mutation (APPsw , K670M/N671L) and in postmortem sporadic AD brain hippocampus; the mutation intensifies Aβ production and strongly associates with AD neuropathology. mRNA expression was analyzed using real-time PCR in cell cultures and DNA microarrays in …hippocampal CA1 area of human AD brains. Arginase activity was measured spectrophotometrically, and arginine, ornithine, and citrulline levels by high-performance liquid chromatography. Our data demonstrated that the expression and activity of arginases (Arg1 and Arg2 ), as well as the expression of argininosuccinate synthase (Ass ) were significantly reduced in APPsw cells compared to control. However, argininosuccinate lyase (Asl ) was upregulated in APPsw cells. Real-time PCR analysis revealed significant elevation of neuronal nitric oxide synthase (Nnos ) mRNA in APPsw cells, without changes in the endothelial Enos , whereas inducible Inos was undetectable. The changes were found to follow closely those observed in the human hippocampal CA1 region of sporadic AD brains. The changes in enzyme expression were accompanied in APPsw cells by significantly elevated citrulline, ornithine, and arginine. Our findings demonstrate that AβPP/Aβ alters arginine metabolism and induces a shift of cellular homeostasis that may support the oxidative/nitrosative stress observed in AD. Show more

Keywords: Alzheimer’s disease, amyloid β, amyloid-β protein precursor, arginase, arginine, argininosuccinate lyase, argininosuccinate synthase, citrulline, nitric oxide synthase, ornithine

DOI: 10.3233/JAD-170427

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 279-291, 2018

Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). …Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12). Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p  < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p  = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p  = 0.006). MBT TIP remained a significant predictor of dementia (p  = 0.0002) when adjusting for FCSRT-FR or CR-L1. Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, longitudinal studies, memory, survival analysis

DOI: 10.3233/JAD-170714

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 293-304, 2018

Authors: Mullan, Kathryn | Cardwell, Chris R. | McGuinness, Bernadette | Woodside, Jayne V. | McKay, Gareth J.

Article Type: Research Article

Abstract: Serum antioxidants may afford neuroprotection against Alzheimer’s disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and …vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance. Show more

Keywords: Alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, uric acid, vitamin A, vitamin C, vitamin E, zeaxanthin

DOI: 10.3233/JAD-170758

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 305-317, 2018

Authors: Huang, Haiqing | Tanner, Jared | Parvataneni, Hari | Rice, Mark | Horgas, Ann | Ding, Mingzhou | Price, Catherine

Article Type: Research Article

Abstract:  Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n  = 48) and non-surgery peers with osteoarthritis (n  = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative …memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p  < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change. Show more

Keywords: Anesthesia, cognitive dysfunction, cognitive reserve, dementia, efficiency, magnetic resonance imaging, orthopedics

DOI: 10.3233/JAD-170496

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 319-333, 2018

Authors: Angulo Sevilla, David | Carreras Rodríguez, María Teresa | Heredia Rodríguez, Patricia | Fernández Sánchez, Marisa | Vivancos Mora, José Aurelio | Gago-Veiga, Ana Beatriz

Article Type: Research Article

Abstract: Background: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia. Objective: To identify the differential clinical profile of patients with dementia who present SS. Methods: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and …conducted a logistic regression analysis to establish a predictive nomogram. Results: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p  = 0.0001), dependence (p  < 0.0001), institutionalization (p  < 0.0001), caregiver burden (p  < 0.0001), anxiety (p  < 0.0001), delirium (p  < 0.0001), hallucinations (p  < 0.0001), wandering (p  < 0.0001), Lewy body dementia (p  = 0.05), higher Global Deterioration Scale score (GDS; p  < 0.0001), and sleep disorders (p  < 0.0001). The multivariate analysis revealed that age (p  = 0.048), GDS score (p  = 0.01), and the presence of insomnia or hypersomnia (p  < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%. Conclusion: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia. Show more

Keywords: Behavioral disorder, clinical profile, dementia, sundown syndrome

DOI: 10.3233/JAD-170488

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 335-346, 2018

Authors: Lanzillotta, Chiara | Tramutola, Antonella | Meier, Shelby | Schmitt, Frederick | Barone, Eugenio | Perluigi, Marzia | Di Domenico, Fabio | Abisambra, Jose F.

Article Type: Research Article

Abstract: Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. DS individuals have an increased risk of developing Alzheimer’s disease (AD)-like pathology and dementia by the age of 40 due to the triplication of several genes involved in the formation of amyloid plaques and tau tangles. Further, DS and AD are characterized by the aberrant accumulation of unfolded/misfolded proteins resulting from over-burdened protein quality control systems. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the …unfolded protein response (UPR). Long-term activation of the UPR mediates neuronal dysfunction in AD. We hypothesized that the UPR is impacted in a mouse model of DS. To test this, we performed gene and protein expression analysis of ER stress markers in the Ts65Dn mouse model of DS at 3, 9, and 18 months. We identified activation of the PERK pathway in Ts65Dn DS mice at 3 months of age compared to euploid controls. We also determined that the early and overt UPR activation decreased with age, the UPR signal was significantly reduced by 18 months. Our data suggest that UPR activation in DS mouse models occurs early before consistent brain neurodegeneration and might be an essential contributor to dys-proteostasis. Show more

Keywords: Down syndrome, eif2 alpha, PERK, Ts65Dn, unfolded protein response

DOI: 10.3233/JAD-170617

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 347-359, 2018

Authors: Xu, Lin | Zhang, Wenchao | Liu, Xianchen | Zhang, Cuili | Wang, Pin | Zhao, Xiulan

Article Type: Research Article

Abstract: Background: Environmental exposure to toxic metals has been postulated to play a role in the pathophysiological processes of Alzheimer’s disease (AD). However, the circulatory levels of toxic metals in AD patients are not consistent in previous studies. Objective: To systematically assess levels of toxic metals (aluminum, mercury, cadmium, lead) in the circulation (blood, serum/plasma) of AD patients and controls. Methods: PubMed, Web of Science, Science Direct, Cochrane Library, and the China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies published up to January 1, 2017. Meta-analyses were performed using random-effects models and the pooled …standardized mean difference (SMD) were reported with 95% confidence intervals (CI). Results: We identified 17, 7, 8, and 10 studies for aluminum, mercury, cadmium, and lead, respectively. Meta-analyses showed significantly elevated circulatory levels of aluminum (SMD = 1.08, 95% CI: 0.66, 1.50), mercury (SMD = 0.55, 95% CI, 0.15, 0.95), and cadmium (SMD = 0.62, 95% CI: 0.12, 1.11), whereas lower levels of lead (SMD = –0.23, 95% CI: –0.38, –0.07) in AD patients than in controls. Publication bias was only observed for aluminum studies, but the “trim and fill” analysis showed that the publication bias did not alter the direction of the effect. Sensitivity analyses showed no studies from the pooled analysis changed the results. Conclusion: Compared to controls, circulatory levels of aluminum, mercury, and cadmium are significantly higher but the levels of lead were reduced in AD patients. These findings suggest that elevated aluminum, mercury, and cadmium in the circulation, especially in serum may play a role in the progression of AD. Show more

Keywords: Alzheimer’s disease, circulation, meta-analyses, systematic review, toxic metals

DOI: 10.3233/JAD-170811

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 361-372, 2018

Authors: Pons, Anke | LaMonica, Haley M. | Mowszowski, Loren | Köhler, Sebastian | Deckers, Kay | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife. Objective: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning …in a clinical, health-seeking sample of community-based older adults. Methods: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self-report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors. Results: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI. Conclusion: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI. Show more

Keywords: Dementia, mild cognitive impairment, modifiable risk factors, prevention

DOI: 10.3233/JAD-170731

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 373-384, 2018

Authors: Bettcher, Brianne M. | Johnson, Sterling C. | Fitch, Ryan | Casaletto, Kaitlin B. | Heffernan, Kate S. | Asthana, Sanjay | Zetterberg, Henrik | Blennow, Kaj | Carlsson, Cynthia M. | Neuhaus, John | Bendlin, Barbara B. | Kramer, Joel H.

Article Type: Research Article

Abstract: Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer’s disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n  = 173). CSF samples were analyzed for markers of AD pathology (Aβ42 , phosphorylated tau [p-tau], sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n  = 147). …Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42 . Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage. Show more

Keywords: Aging, Alzheimer’s disease, biomarkers, neuroinflammation, preclinical AD, systemic inflammation

DOI: 10.3233/JAD-170602

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 385-397, 2018

Authors: Ben Bouallègue, Fayçal | Mariano-Goulart, Denis | Payoux, Pierre | for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) subjects was performed using baseline 18 F-florbetapir and 18 F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase …was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid PET, FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-170833

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 399-408, 2018

Authors: Phua, April Ka Sin | Hiu, Shaun Kuan Wei | Goh, Win King | Ikram, Mohammad Kamran | Venketasubramanian, Narayanaswamy | Tan, Boon Yeow | Chen, Christopher Li-Hsian | Xu, Xin

Article Type: Research Article

Abstract: Background: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. Objective: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. Methods: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 …standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. Results: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64–0.78] & 0.73 [0.66–0.80] for overall decline; 0.78 [0.70–0.85] & 0.80 [0.73–0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). Conclusion: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change. Show more

Keywords: Cognitive decline, cognitive impairments, dementia, geriatric assessment, longitudinal studies, neuropsychological test, outpatient clinic

DOI: 10.3233/JAD-170831

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 409-416, 2018

Authors: Malpas, Charles B. | Saling, Michael M. | Velakoulis, Dennis | Desmond, Patricia | Hicks, Rodney J. | Zetterberg, Henrik | Blennow, Kaj | O’Brien, Terence J.

Article Type: Research Article

Abstract: The two cardinal pathologies of Alzheimer’s disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer’s type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18 F]-FDG-PET. Amyloid-related pathology was …preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebral glucose uptake, cerebrospinal fluid, cortical thickness, P-tau

DOI: 10.3233/JAD-170250

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 417-427, 2018

Authors: Xu, Qing-qing | Shan, Chun-shuo | Wang, Yong | Shi, Yi-hua | Zhang, Qi-hao | Zheng, Guo-qing

Article Type: Research Article

Abstract: Background: Vascular dementia (VaD) is the second common form of dementia and Chinese herbal medicine (CHM) has been used for aging-related disorders for thousands of years. However, there is still a lack of scientific evidence using CHM for VaD. Objective: To conduct a systematic review to assess the current evidence available for the effectiveness and safety of CHM for VaD. Methods: Six databases were searched for high-quality randomized-controlled clinical trials that met the requirements of at least 4 of the 7 domains of the Cochrane risk of bias tool from their inception to February 2017. RevMan …5.3 was applied for data analysis. Results: Forty studies with 42 comparisons and 3,572 individuals were included. The studies investigated the CHM versus placebo (n  = 4), CHM versus western conventional treatment (WCT) (n  = 36), and CHM plus WCT versus WCT (n  = 2). Meta-analysis showed that CHM for VaD could improve Mini-Mental State Examination (MMSE), the Activities of Daily Living, Hasegawa’s dementia scale, and clinical effective rate but had statistically similar effect based on Blessed Behavior Scale (BBS) outcome when compared with WCTs. When compared with placebo, CHMs were more beneficial in improving MMSE but showed no significant difference in BBS scores. CHM as adjuvant therapy exerted an additive anti-VaD benefit on MMSE scores. The participants of CHM group had fewer adverse events than that of the placebo group or WCT group. Conclusion: The findings of the present study support, at least to an extent, that CHM can be recommended for routine use for treatment of VaD. Show more

Keywords: Chinese herbal, meta-analysis, systematic review, traditional Chinese medicine, vascular dementia

DOI: 10.3233/JAD-170856

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 429-456, 2018

Authors: Ritchie, Craig W. | Black, Christopher M. | Khandker, Rezaul K. | Wood, Robert | Jones, Eddie | Hu, Xiaohan | Ambegaonkar, Baishali M.

Article Type: Research Article

Abstract: To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients’ cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3–7 months of initial consultation. However, only 20% of patients received a diagnosis …before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained—indeed where possible invigorated. Show more

Keywords: Caregivers, cognitive impairment, consultation, diagnosis, earlier and intervention, early diagnosis, prodromal, real-world, referral

DOI: 10.3233/JAD-170864

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 457-466, 2018

Authors: Reale, Marcella | D’Angelo, Chiara | Costantini, Erica | Di Nicola, Marta | Yarla, Nagnedra Sastry | Kamal, Mohammad Amjad | Salvador, Nieves | Perry, George

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), a neurodegenerative disease, is associated with dysfunction of the olfactory and the entorhinal cortex of the brain that control memory and cognitive functions and other daily activities. Pro-inflammatory cytokines, amyloid-β (Aβ), and the cholinergic system play vital roles in the pathophysiology of AD. However, the role of changes in cholinergic system components, Aβ accumulation, and cytokines in both the olfactory and entorhinal cortex is not known clearly. Objective: The present study is aimed to evaluate the changes of cholinergic system components, Aβ accumulation, and cytokines in both the olfactory bulb (OB) and entorhinal cortex …(EC) of young and aged APPSWE /PS1dE9 transgenic (Tg) mice. Methods: We have explored the changes of cholinergic system components, Aβ accumulation, and expression profiling of cytokines in the OB and EC of aged APPswe transgenic mice and age-matched wild type mice using quantitative Real-Time PCR assays and immunohistochemistry techniques. Results: In aged Tg mice, a significant increase of expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and chemokine MCP1 (p  < 0.001, p  < 0.001, and p  = 0.001, respectively) and a significant reduction of nAChRα4 (p  = 0.048) and AChE (p  = 0.023) was observed when compared with age-matched wild type mice. Higher levels of AChE and BuChE are expressed in OB and EC of the APPSWE /PS1dE9 of Tg mice. Aβ accumulation was observed in OB and EC of the APPSWE /PS1dE9 of Tg mice. Conclusion: The study demonstrates the expression profiling of pro-inflammatory cytokines and cholinergic markers as well as Aβ accumulation in OB and EC of the APPSWE /PS1dE9 Tg mice. Moreover, the study also demonstrated that the APPSWE /PS1dE9 Tg mice can be useful as a mouse model to understand the role of pro-inflammatory cytokines and cholinergic markers in pathophysiology of AD. Show more

Keywords: Aβ accumulation, Alzheimer’s disease, APPswe transgenic mice, cholinergic markers, pro-inflammatory cytokines

DOI: 10.3233/JAD-170999

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 467-476, 2018

Authors: Zhou, Futao | Chen, Shuangrong

Article Type: Research Article

Abstract: Leptin, as a link between fat mass and the brain, has been reported to be associated with gender. The gender differences in leptin levels between Alzheimer’s disease (AD) and healthy elderly controls are inconclusive so far. To quantitatively summarize the leptin data available from female and male patients with AD, we searched PubMed and EMBASE for articles published from inception to July 20, 2017. Data were extracted from 27 studies, consisting of 3,014 participants. The pooled results showed that the overall leptin levels were lower in AD (Hedges’ g  = –0.481; p  = 0.002) than in controls, and the leptin levels in …whole blood and serum were decreased with moderate and large effect sizes (g  = –0.677, –0.839; respectively; both of p -values <0.001) in AD compared with controls. In blood, there were significantly lower concentrations of leptin in female AD than in female controls (g  = –0.590; p  = 0.014), but not in male case-control group (g  = –0.666; p  = 0.067). Meta-regression analysis demonstrated that the decreased extent of leptin levels in AD paralleled the degree of the severity of dementia symptoms, as well as the alterations of body mass index (p -values ≤0.002). The findings provide strong evidence that 1) the blood concentrations of leptin are lower in female AD patients than in female controls; and 2) the greater the severity of dementia symptoms, the greater the decreases in the blood leptin levels. But more future investigations on the blood leptin levels in male AD patients is warranted. Show more

Keywords: Alzheimer’s disease, female, leptin, male, meta-analysis

DOI: 10.3233/JAD-170983

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 477-486, 2018