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