Journal of Alzheimer's Disease - Volume 66, issue 2

Authors: Shukla, Deepika | Mandal, Pravat K. | Ersland, Lars | Grüner, Eli Renate | Tripathi, Manjari | Raghunathan, Partha | Sharma, Ankita | Chaithya, G.R. | Punjabi, Khushboo | Splaine, Christopher

Article Type: Research Article

Abstract: Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of closed and extended conformations. The present work in a multi-center research setting reports in-depth analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site National …Brain Research Center (NBRC) using in-house MRS processing toolbox (KALPANA) for consistency. We have found that both the closed and extended GSH conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. It is important to emphasize that in vivo experiments with different refocusing and inversion pulse positions, echo time, and voxel size, clearly evidence the presence of both the GSH conformations. The GSH conformer peak positions for the closed GSH (Cys-Hβ ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ ) peak at ∼2.95 ppm remain consistent irrespective of the selective refocusing OFF-pulse positions. This is the first in vivo study where both extended and closed GSH conformers are detected using the MEGA-PRESS sequence employing the parameters derived from the high resolution in vitro NMR studies on GSH. Show more

Keywords: Closed and extended conformation, glutathione, MEGA-PRESS MRS, multi-center

DOI: 10.3233/JAD-180648

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 517-532, 2018

Authors: Vipin, Ashwati | Foo, Heidi Jing Ling | Lim, Joseph Kai Wei | Chander, Russell Jude | Yong, Ting Ting | Ng, Adeline Su Lyn | Hameed, Shahul | Ting, Simon Kang Seng | Zhou, Juan | Kandiah, Nagaendran

Article Type: Research Article

Abstract: The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer’s disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total …WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognition, grey matter, white matter hyperintensity

DOI: 10.3233/JAD-180280

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 533-549, 2018

Authors: Abu-Rumeileh, Samir | Mometto, Nicola | Bartoletti-Stella, Anna | Polischi, Barbara | Oppi, Federico | Poda, Roberto | Stanzani-Maserati, Michelangelo | Cortelli, Pietro | Liguori, Rocco | Capellari, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer’s disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ)42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with …definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, behavioral variant, corticobasal syndrome, frontotemporal dementia, neurofilament light, parkinsonism, primary progressive aphasia, progressive supranuclear palsy, tau, TDP-43

DOI: 10.3233/JAD-180409

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 551-563, 2018

Authors: Manousakis, Jessica E. | Scovelle, Anna J. | Rajaratnam, Shantha M.W. | Naismith, Sharon L. | Anderson, Clare

Article Type: Research Article

Abstract: Background: Increased sleep fragmentation and advanced circadian timing are hallmark phenotypes associated with increased age-related cognitive decline. Subjective cognitive decline (SCD) is considered a prodromal stage of neurodegeneration and dementia; however, little is known about how sleep and circadian timing impact on memory complaints in SCD. Objective: To determine how sleep and circadian timing impact on memory complaint subtypes in older adults with SCD. Methods: Twenty-five older adults with SCD (mean age = 69.97, SD = 5.33) completed the Memory Functioning Questionnaire to characterize their memory complaints. They also underwent neuropsychological assessment, and completed 1 week …of at-home monitoring of sleep with actigraphy and sleep diaries. This was followed by a two-night laboratory visit with overnight polysomnography and a dim light melatonin onset assessment to measure circadian timing. Results: Advanced circadian timing was associated with greater memory complaints, specifically poorer memory of past events (r = –0.688, p = 0.002), greater perceived decline over time (r = –0.568, p = 0.022), and increased reliance on mnemonic tools (r = –0.657, p = 0.004). Increased sleep fragmentation was associated with reduced self-reported memory decline (r = 0.529, p = 0.014), and reduced concern about everyday forgetfulness (r = 0.435, p = 0.038). Conclusion: Advanced circadian timing was associated with a number of subjective memory complaints and symptoms. By contrast, sleep fragmentation was linked to lowered perceptions of cognitive decline, and less concern about memory failures. As circadian disruption is apparent in both MCI and Alzheimer’s disease, and plays a key role in cognitive function, our findings further support a circadian intervention as a potential therapeutic tool for cognitive decline. Show more

Keywords: Circadian rhythms, cognition, dementia risk, dim light melatonin onset, mild cognitive impairment, sleep disturbance, subjective memory impairment

DOI: 10.3233/JAD-180612

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 565-577, 2018

Authors: Larsson, Susanna C. | Wolk, Alicja

Article Type: Research Article

Abstract: Background: The role of lifestyle factors and sleep for dementia is uncertain. Objective: To examine the associations of major lifestyle factors and sleep duration with risk of late-onset dementia. Methods: We used data from a population-based cohort of 28,775 Swedish adults who were ≥65 years of age and completed a questionnaire about lifestyle and other modifiable factors in the autumn of 1997. Dementia cases were ascertained by linkage with the Swedish National Patient Register. Results: During a mean follow-up of 12.6 years, dementia was diagnosed among 3,755 participants (mean age at diagnosis 83.2±5.1 years). …There were no associations of an overall healthy diet (defined by a modified Dietary Approaches to Stop Hypertension Diet score or a Mediterranean diet score), alcohol and coffee consumption, or physical activity with dementia incidence. Compared with never smokers, dementia risk was increased in former and current smokers (hazard ratio [95% confidence interval] = 1.13 [1.04–1.23] and 1.10 [1.00–1.21], respectively). Extended time of sleep (>9 h per night) was associated with an increased risk of dementia. However, this association appeared to be related to a reverse causation effect since the association did not remain after exclusion of cases diagnosed within the first five or ten years of follow-up. Conclusions: This study found no evidence that major lifestyle factors, aside from smoking, or sleep duration influence the risk of dementia. Show more

Keywords: Cohort studies, dementia, diet, lifestyle, prospective studies, sleep

DOI: 10.3233/JAD-180529

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 579-586, 2018

Authors: Hadjichrysanthou, Christoforos | McRae-McKee, Kevin | Evans, Stephanie | de Wolf, Frank | Anderson, Roy M. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Despite the progressive nature of Alzheimer’s disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such ‘back-transitions’ are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer’s Coordinating Centre (NACC). The focus is on the observed improvement of individuals’ clinical condition recorded in …these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ 4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ 4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition. Show more

Keywords: Alzheimer’s disease, back-transitions, clinical states, dementia, longitudinal studies, mild cognitive impairment, misdiagnosis

DOI: 10.3233/JAD-180101

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 587-600, 2018

Authors: Cousins, Clara C. | Alosco, Michael L. | Cousins, Henry C. | Chua, Alicia | Steinberg, Eric G. | Chapman, Kimberly R. | Bing-Canar, Hanaan | Tripodis, Yorghos | Knepper, Paul A. | Stern, Robert A. | Pasquale, Louis R.

Article Type: Research Article

Abstract: Background: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer’s disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail’s cuticle and may help to describe further vascular contributions to AD. Objective: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC). Methods: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured …with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data. Results: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates. Conclusion: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral blood flow, cerebrovascular disease, dementia, mild cognitive impairment, nailfold capillaroscopy, tortuosity

DOI: 10.3233/JAD-180658

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 601-611, 2018

Authors: Zhang, Fanshuang | Wei, Jing | Li, Xundou | Ma, Chao | Gao, Youhe

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an incurable age-associated neurodegenerative disorder that is characterized by irreversible progressive cognitive deficits and extensive brain damage. The identification of candidate biomarkers before amyloid-β plaque deposition occurs is therefore of great importance for the early intervention of AD. Urine, which is not regulated by homeostatic mechanisms, theoretically accumulates changes associated with AD earlier than cerebrospinal fluid and blood. In this study, an APP (swe)/PSEN1dE9 transgenic mouse model was used to identify candidate biomarkers for early AD. Urine samples were collected from 4-, 6-, and 8-month-old transgenic mouse models, and the urinary proteomes were profiled using liquid …chromatography coupled with tandem mass spectrometry (LC-MS/MS). The levels of 29 proteins differed significantly between wild type and 4-month-old mice, which had not started to accumulate amyloid-β plaques. Among these proteins, 13 have been associated with the mechanisms of AD, while 9 have been suggested as AD biomarkers. Our results indicated that urine proteins enable detection of AD before amyloid-β plaque deposition, which may present an opportunity for intervention. Show more

Keywords: Alzheimer’s disease, APP (swe)/PSEN1dE9, early diagnosis, urine proteome

DOI: 10.3233/JAD-180412

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 613-637, 2018

Authors: Ramos de Matos, Mafalda | Ferreira, Catarina | Herukka, Sanna-Kaisa | Soininen, Hilkka | Janeiro, André | Santana, Isabel | Baldeiras, Inês | Almeida, Maria Rosário | Lleó, Alberto | Dols-Icardo, Oriol | Alcolea, Daniel | Benussi, Luisa | Binetti, Giuliano | Paterlini, Anna | Ghidoni, Roberta | Nacmias, Benedetta | Meulenbroek, Olga | van Waalwijk van Doorn, Linda J.C. | Kuiperi, H. Bea j | Hausner, Lucrezia | Waldemar, Gunhild | Simonsen, Anja Hviid | Tsolaki, Magda | Gkatzima, Olymbia | Resende de Oliveira, Catarina | Verbeek, Marcel M. | Clarimon, Jordi | Hiltunen, Mikko | de Mendonça, Alexandre | Martins, Madalena

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer’s disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1–42 ), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1–42 is decreased due to the accumulation of Aβ1–42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To …better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42 , t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers. Our results highlighted five genes, APOE , LOC100129500 , PVRL2 , SNAR-I , and TOMM40 , previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D , CD2AP , and CASS4 , showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, endophenotypes, European multicenter study, quantitative trait loci

DOI: 10.3233/JAD-180512

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 639-652, 2018

Authors: Stephan, Blossom C.M. | Birdi, Ratika | Tang, Eugene Yee Hing | Cosco, Theodore D. | Donini, Lorenzo M. | Licher, Silvan | Ikram, M. Arfan | Siervo, Mario | Robinson, Louise

Article Type: Research Article

Abstract: Background: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline. Objective: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time. Methods: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained. Results: Overall, prevalence rates are largely increasing …(evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria. Conclusions: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies. Show more

Keywords: Dementia, incidence, prevalence, secular trends, systematic review

DOI: 10.3233/JAD-180375

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 653-680, 2018

Authors: Kim, Si Eun | Woo, Sookyoung | Kim, Seon Woo | Chin, Juhee | Kim, Hee Jin | Lee, Byung In | Park, Jinse | Park, Kyung Won | Kang, Do-Young | Noh, Young | Ye, Byoung Seok | Yoo, Han Soo | Lee, Jin San | Kim, Yeshin | Kim, Seung Joo | Cho, Soo Hyun | Na, Duk L. | Lockhart, Samuel N. | Jang, Hyemin | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker. Objective: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE ) genotype between Aβ+ aMCI and Aβ–aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram. Methods: We recruited 523 aMCI patients who underwent Aβ PET …imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model. Results: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOE ɛ 4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. Conclusions: The nomogram consisting of NP profiles, especially memory domain, and APOE ɛ 4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI. Show more

Keywords: Amnestic mild cognitive impairment, amyloid PET positivity, neuropsychological tests, nomogram, prediction

DOI: 10.3233/JAD-180048

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 681-691, 2018

Authors: Baird, Amee | Brancatisano, Olivia | Gelding, Rebecca | Thompson, William Forde

Article Type: Research Article

Abstract: Background: Music evoked autobiographical memories (MEAMs) have been documented in people with Alzheimer’s disease (AD), but it is unclear whether music is more effective than other familiar stimuli at evoking memories. Objective: To explore the frequency and specificity of memories in response to famous songs compared with photographs of famous events (photograph evoked autobiographical memories, PEAMs), and whether stimuli from the period of the reminiscence bump (10–30 years of age) were more likely to elicit memories. Methods: 10 participants with AD and 10 aged-matched healthy elderly people reported memories following exposure to 2 songs (longest time …at number one in Australian music charts) and 2 photographs (of prominent famous events) from each decade from 1930 to 2010. Results: PEAMs were more frequent than MEAMs in healthy elderly (p < 0.05), but no such differences were observed among people with AD. There was no difference in the frequency of MEAMs between groups, but people with AD showed a significant decline in the frequency of PEAMs. In both groups, MEAMs were typically less specific than PEAMs and comprised semantic knowledge or repeated/extended events. Stimuli from when participants were aged 10–30 years triggered more frequent memories compared with stimuli from later decades, but this was only statistically significant for MEAMs. Conclusion: Our findings indicate a preserved mnemonic effect of music relative to pictures in this patient population, corroborating suggestions that MEAMs represent an island of preservation during the progression of AD. Show more

Keywords: Alzheimer’s disease, autobiographical memory, music, reminiscence bump

DOI: 10.3233/JAD-180627

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 693-706, 2018

Authors: Kustra, Rafal | Awh, Carl C. | Rojas-Fernandez, Carlos | Zanke, Brent

Article Type: Research Article

Abstract: Background: An interaction between genetic variants in complement factor H (CFH ) and age-related maculopathy susceptibility 2 (ARMS2 ) and high-dose zinc supplementation on progression to advanced age-related macular degeneration (AMD) exists. Because cognitive impairment (CI) is associated with AMD, we used data from the Women’s Health Initiative (WHI) to search for a zinc/genetics interaction. Objective: To study the interaction of chronic zinc supplementation with genetic variants in CFH and ARMS2 on the development of CI. Background: Zinc dietary supplements, CFH and ARMS2 genotypes, and serial mental status was analyzed in …participants with available genetic data (n = 7,483). Cognition was assessed using the Modified Mini-Mental State Examination. The development of CI over 5 years was analyzed by genotype and zinc intake using a repeated measures logistic regression model. Results: Zinc supplementation of approximately 15 mg/day was associated with decreased development of CI in women with 1 or 2 CFH and no ARMS2 risk alleles (OR = 0.46: 1 CFH risk allele; 0.20: 2 CFH risk alleles; p = 0.002). Conclusion: Low-dose zinc (approximately 15 mg) is associated with reduced CI in women with 2 CFH and 0 ARMS2 AMD risk alleles. This interaction is opposite in direction to that observed in AMD, where patients with 2 CFH and 0 ARMS2 risk alleles had increased progression to neovascular AMD if treated with 80 mg/day of zinc. This may be due to a zinc dose-response or to a fundamental difference in the role of zinc in the progression of early CI versus advanced AMD. Show more

Keywords: Cognitive dysfunction, complement factor H, gene-environment interaction, genotype, macular degeneration, zinc

DOI: 10.3233/JAD-180673

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 707-715, 2018

Authors: Nguyen, Trung P. | Schaffert, Jeff | LoBue, Christian | Womack, Kyle B. | Hart, John | Cullum, C. Munro

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson’s disease, and Alzheimer’s disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). Objective: The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. Method: Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer’s Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history …of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer’s Disease Center visit) was associated with earlier DLB symptom onset. Results: Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. Conclusions: Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted. Show more

Keywords: Age of onset, dementia, dementia with Lewy bodies, traumatic brain injury

DOI: 10.3233/JAD-180586

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 717-723, 2018

Authors: Bohlken, Jens | Jacob, Louis | Kostev, Karel

Article Type: Research Article

Abstract: Background: There is a conflicting literature on the association between the use of antihyperglycemic drugs and dementia risk. Objective: The goal of this case-control study was to analyze the association between the use of antihyperglycemic drugs and dementia risk in patients followed in general practices in Germany. Methods: This study included patients with type 2 diabetes mellitus who had received a first dementia diagnosis in 972 general practices in Germany between January 2013 and December 2017 (index date). Controls without dementia were matched (1:1) to cases by age, gender, index year, and physician. …Two multivariate regression models were used to study the association between the use of antihyperglycemic drugs and dementia risk. Model 1 included all antihyperglycemic drugs prescribed to patients regardless of the prescription duration, whereas Model 2 only included the longest therapy prescribed to each patient. Results: There were 8,276 diabetes patients with dementia and 8,276 diabetes patients without dementia included in this study. In Model 1, glitazones were associated with a decreased dementia risk (odds ratio [OR] = 0.80), whereas insulin was associated with an increased risk of developing the condition (OR = 1.34). In Model 2, metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with a decrease in the likelihood of subsequently being diagnosed with dementia. By contrast, the combination of basal insulin and bolus insulin (OR = 1.47) and premix insulin (OR = 1.33) were risk factors for dementia. Conclusion: Metformin and glitazones were negatively associated with dementia, while insulin was positively associated with dementia. Show more

Keywords: Antihyperglycemic drugs, case-control study, dementia, Germany

DOI: 10.3233/JAD-180808

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 725-732, 2018

Authors: Elias, Alby | Cummins, Tia | Tyrrell, Regan | Lamb, Fiona | Dore, Vincent | Williams, Robert | Rosenfeld, J.V. | Hopwood, Malcolm | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: An association between obstructive sleep apnea (OSA) and Alzheimer’s disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome. Objective: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. Methods: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) …of 18 F-florbetaben and 18 F-AV1451, to quantify amyloid and tau burden. Results: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18 F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p  = 0.04). There were more apolipoprotein E ɛ 4 allele (APOE ɛ 4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18 F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ 4 was adjusted. The reported use of CPAP (n  = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18 F-AV1451 uptake between the two groups. Conclusions: Obstructive sleep apnea is associated with Alzheimer’s disease pathology, but this relationship is moderated by APOE ɛ 4 and BMI. Show more

Keywords: Alzheimer’s disease, amyloid PET, dementia, obstructive sleep apnea, tau PET

DOI: 10.3233/JAD-180640

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 733-741, 2018

Authors: Katisko, Kasper | Kokkonen, Nina | Krüger, Johanna | Hartikainen, Päivi | Koivisto, Anne M. | Helisalmi, Seppo | Korhonen, Ville E. | Kokki, Merja | Tuusa, Jussi | Herukka, Sanna-Kaisa | Solje, Eino | Haapasalo, Annakaisa | Tasanen, Kaisa | Remes, Anne M.

Article Type: Research Article

Abstract: Recent studies have shown an epidemiological and immunological association between bullous pemphigoid (BP) and several neurological or psychiatric diseases. Here, our aim was for the first time to specify whether an association exists between BP and frontotemporal lobar degeneration (FTLD). Medical histories of FTLD patients (N = 196) were screened for clinical comorbidity, and BP180 and BP230 autoantibodies were analyzed in the sera of FTLD patients (N = 70, including 24 C9orf72 repeat expansion carriers) by BP180-NC16A-ELISA and BP230-ELISA. One FTLD patient (C9orf72 repeat expansion carrier) had a comorbid diagnosis of BP. Increased levels of serum BP180 autoantibodies …(cutoff value >9 U/ml) were detected more often in FTLD patients (10.0%) than in controls (4.9%). Moreover, elevated levels of both BP180 and BP230 autoantibodies were found more often in C9orf72 repeat expansion-carrying FTLD than non-carrying patients or controls. However, none of these differences reached a statistical significance likely due to our limited cohort size. In conclusion, our findings suggest that subset of FTLD patients especially with the C9orf72 repeat expansion may have an immunological association with BP. Show more

Keywords: Autoantibody, bullous pemphigoid, C9orf72 , comorbidity, dementia, frontotemporal dementia, immunology

DOI: 10.3233/JAD-180624

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 743-750, 2018

Authors: Chen, Mei | Song, Hailong | Cui, Jiankun | Johnson, Catherine E. | Hubler, Graham K. | DePalma, Ralph G. | Gu, Zezong | Xia, Weiming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ )-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using …Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development. Show more

DOI: 10.3233/JAD-180726

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 751-773, 2018

Authors: Weng, Yi-Ching | Hsiao, Ing-Tsung | Huang, Chu-Yun | Huang, Kuo-Lun | Liu, Chi-Hung | Chang, Ting-Yu | Yen, Tzu-Chen | Lin, Kun-Ju | Huang, Chin-Chang

Article Type: Research Article

Abstract: Background: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer’s disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown. Objective: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis. Methods: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18 F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in …serial brain 18 F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients. Results: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from –2.62% to –16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively. Conclusions: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage. Show more

Keywords: Amyloid, angiopathy, annual change rate, brain AV-45 PET, familial Alzheimer’s disease, Taiwan D678H APP mutation

DOI: 10.3233/JAD-180824

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 775-787, 2018

Authors: Zuo, Li-jun | Guo, Peng | Liu, Li | Yu, Shu-yang | Lian, Teng-hong | Yu, Qiu-jin | Hu, Yang | Jin, Zhao | Wang, Rui-dan | Piao, Ying-shan | Li, Li-xia | Wang, Ya-jie | Wang, Xiao-min | Zhang, Wei

Article Type: Research Article

Abstract: Background: OD is common in patients with Alzheimer’s disease (AD). However, the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients are still unknown. Objective: To explore the relationship between OD and clinical symptoms and the potential mechanisms of OD in AD patients. Methods: We evaluated OD using the Hyposmia Rating Scale (HRS), classified patients into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups, and detected the levels of free radicals and inflammatory factors, including hydroxyl radical (•OH), hydrogen peroxide (H2 O2 ), nitric oxide, interleukin-1β , …interleukin-6, tumor necrosis factor-α , and prostaglandin E2 in serum from AD patients. Results: It was shown that the scores of the Mini-Mental State Examination, Animal Fluency Test, Boston Naming Test (BNT), and Auditory Verbal Learning Test-delayed recall were all significantly lower and the score of overall activity of daily living (ADL) and instrumental ADL were significantly higher in AD-OD group than those in AD-NOD group. Compared with AD-NOD group, •OH level in serum was prominently elevated, and H2 O2 level was dramatically declined in AD-OD group. In the correlation analysis, HRS score was significantly and positively correlated with the score of BNT, and negatively correlated with •OH level in serum. Conclusions: AD-OD patients suffered from severe cognitive impairment in the domain of language. Oxidative stress might be correlated with AD-OD featured by the drastically increased •OH level in serum. Show more

Keywords: Alzheimer’s disease, language, •OH , olfactory dysfunction, oxidative stress

DOI: 10.3233/JAD-180425

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 789-799, 2018

Authors: Salas, Isabel H. | Callaerts-Vegh, Zsuzsanna | D’Hooge, Rudi | Saido, Takaomi C. | Dotti, Carlos G. | De Strooper, Bart

Article Type: Research Article

Abstract: Commonly used Alzheimer’s disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL ), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL /NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.

Keywords: Aging, Alzheimer’s disease, amyloid plaques, behavior, cognition, knock-in

DOI: 10.3233/JAD-180410

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 801-809, 2018

Authors: Müller-Ehrenberg, Lisa | Riphagen, Joost M. | Verhey, Frans R.J. | Sack, Alexander T. | Jacobs, Heidi I.L. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer’s disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1–4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the …validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, hippocampus, polynomial, subfields, tau

DOI: 10.3233/JAD-180676

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 811-823, 2018

Authors: Zotcheva, Ekaterina | Bergh, Sverre | Selbæk, Geir | Krokstad, Steinar | Håberg, Asta Kristine | Strand, Bjørn Heine | Ernstsen, Linda

Article Type: Research Article

Abstract: Background: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk. Objective: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia. Methods: Our study comprised 28,916 participants aged 30–60 years from the Nord-Trøndelag Health Study (HUNT1, 1984–1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trøndelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios …(HRs) and 95% confidence intervals (95% CI). Results: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62–1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99–1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54–0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22–1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44–0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk. Conclusion: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals. Show more

Keywords: Anxiety, cognition, dementia, depression, exercise, psychological stress

DOI: 10.3233/JAD-180768

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 825-833, 2018

Authors: Ryan, Margaret M. | Guévremont, Diane | Mockett, Bruce G. | Abraham, Wickliffe C. | Williams, Joanna M.

Article Type: Research Article

Abstract: Pathological changes underlying Alzheimer’s disease (AD) begin decades before the classical symptoms of memory loss become evident. As microRNAs are released from neurons and enter the bloodstream, circulating microRNAs may be reflective of AD progression and are ideal candidates as biomarkers for early-stage disease detection. Here, we provide a novel, in-depth analysis of how plasma microRNAs alter with aging, the most prominent risk factor for AD, and with development of amyloid-β (Aβ) plaque deposition. We assessed the circulating microRNAs in APPswe/PSEN1dE9 transgenic mice and wild-type controls at 4, 8 and 15 m (n = 8–10) using custom designed Taqman …arrays representing 185 neuropathology-related microRNAs. We performed a linear mixed-effects model to investigate the effects of age and genotype on plasma microRNAs expression. Following this analysis, we found 8 microRNAs were significantly affected by age alone in wild-type animals and 12 microRNAs altered in APPswe/PSEN1dE9 mice, either prior to Aβ plaque deposition (4 m) or during the development of AD-like pathogenesis (8 m or 15 m). Importantly, we found that differing sets of microRNAs were identified at each time point. Functional analysis of these data revealed that while common biological pathways, such as Inflammatory Response , were enriched throughout the disease process, Free Radical Scavenging, Immunological Disease , and Apoptosis Signaling were specifically enriched later in the disease process. Overall, this study reinforces that distinct biological processes underpin the early versus late stages of AD-like pathogenesis and highlights potential pre-symptomatic microRNAs biomarkers of neurodegeneration. Show more

Keywords: Aging, Alzheimer’s disease, circulating microRNAs, real-time polymerase chain reaction, transgenic mice

DOI: 10.3233/JAD-180385

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 835-852, 2018

Authors: Bamji-Mirza, Michelle | Li, Yan | Najem, Dema | Liu, Qing Yan | Walker, Douglas | Lue, Lih-Fen | Stupak, Jacek | Chan, Kenneth | Li, Jianjun | Ghani, Mahdi | Yang, Ze | Rogaeva, Ekaterina | Zhang, Wandong

Article Type: Correction

DOI: 10.3233/JAD-189009

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 853-854, 2018

Authors: Sigurdsson, Einar M.

Article Type: Correction

DOI: 10.3233/JAD-189010

Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 855-856, 2018