Journal of Alzheimer's Disease - Volume 61, issue 4

Authors: Hall, James R. | Wiechmann, April | Johnson, Leigh A. | Edwards, Melissa | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders. Objective: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints. Methods: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, …neuropsychological functioning, and proteomic markers. Results: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers. Conclusion: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified. Show more

Keywords: Affective symptoms, biomarkers, Mexican-Americans, subjective cognitive complaints

DOI: 10.3233/JAD-170836

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1485-1492, 2018

Authors: Konishi, Kyoko | Joober, Ridha | Poirier, Judes | MacDonald, Kathleen | Chakravarty, Mallar | Patel, Raihaan | Breitner, John | Bohbot, Véronique D.

Article Type: Research Article

Abstract: Early detection of Alzheimer’s disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ 4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ 4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus …non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE ɛ 4 allele carriers. APOE ɛ 4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE ɛ 4 allele carriers who use spatial strategies. In contrast, APOE ɛ 4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE ɛ 4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy. Show more

Keywords: APOE, entorhinal cortex, hippocampus, spatial memory

DOI: 10.3233/JAD-170540

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1493-1507, 2018

Authors: Beach, Thomas G. | Maarouf, Chera L. | Intorcia, Anthony | Sue, Lucia I. | Serrano, Geidy E. | Lu, Ming | Joshi, Abhinay | Pontecorvo, Michael J. | Roher, Alex E.

Article Type: Research Article

Abstract: Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer’s disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment …while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18 F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42 . Spearman’s univariable correlations were significant for both Aβ40 and Aβ42 , but were much stronger for Aβ42 . Multiple linear regression showed significance only for Aβ42 . These results suggest that florbetapir binds only weakly, if at all, to Aβ40 . This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure. Show more

Keywords: Alzheimer’s disease, autopsy, diagnosis, diffuse plaque, neuritic plaque

DOI: 10.3233/JAD-170762

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1509-1516, 2018

Authors: Portacolone, Elena | Johnson, Julene K. | Covinsky, Kenneth E. | Halpern, Jodi | Rubinstein, Robert L.

Article Type: Research Article

Abstract: Background: One third of older adults with cognitive impairment live alone and are at high risk for poor health outcomes. Little is known about how older adults who live alone experience the process of receiving a diagnosis of mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: The aim of this study was to understand the effects and meanings of receiving a diagnosis of MCI or AD on the lived experience of older adults living alone. Methods: This is a qualitative study of adults age 65 and over living alone with cognitive impairment. Participants’ lived experiences …were elicited through ethnographic interviews and participant observation in their homes. Using a qualitative content analysis approach, interview transcripts and fieldnotes were analyzed to identify codes and themes. Results: Twenty-nine older adults and 6 members of their social circles completed 114 ethnographic interviews. Core themes included: relief, distress, ambiguous recollections, and not knowing what to do. Participants sometimes felt uplifted and relieved by the diagnostic process. Some participants did not mention having received a diagnosis or had only partial recollections about it. Participants reported that, as time passed, they did not know what to do with regard to the treatment of their condition. Sometimes they also did not know how to prepare for a likely worsening of their condition, which they would experience while living alone. Conclusion: Findings suggest the need for more tailored care and follow-up as soon as MCI or AD is diagnosed in persons living alone. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, diagnosis, health services, residence characteristics

DOI: 10.3233/JAD-170723

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1517-1529, 2018

Authors: Paley, Elena L. | Merkulova-Rainon, Tatiana | Faynboym, Aleksandr | Shestopalov, Valery I. | Aksenoff, Igor

Article Type: Research Article

Abstract: Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer’s disease (AD). Tryptophan is a product of the Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), …albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough. Show more

Keywords: Alzheimer’s disease, bacterial enzyme sequence, environmental stool samples, human gut microbiota, PCR testing

DOI: 10.3233/JAD-170764

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1531-1540, 2018

Authors: Wang, Hua | Stewart, Tessandra | Toledo, Jon B. | Ginghina, Carmen | Tang, Lu | Atik, Anzari | Aro, Patrick | Shaw, Leslie M. | Trojanowski, John Q. | Galasko, Douglas R. | Edland, Steven | Jensen, Poul H. | Shi, Min | Zhang, Jing | for The Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson’s disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42 ), tau, and phosphorylated tau (p-tau181 )] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer’s Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive …impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42 , tau, and p-tau181 . pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p  = 0.041, 95% CI [(0.0001)–(0.005)]). CSF α-synuclein predicted Alzheimer’s Disease Assessment Scale-Cognitive (β= –0.59, p  = 0.0015, 95% CI [(–0.96)–(–0.23)]), memory (β= 0.4, p  = 0.00025, 95% CI [(0.16)–(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)–(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p  = 0.0011, 95% CI [(0.002)–(0.20)]). pS129 was associated with executive function (β= –2.55, p  = 0.0085, 95% CI [(–4.45)–(–0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p  = 0.0012, 95% CI [(0.48)–(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181 -Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further. Show more

Keywords: α-synuclein, Alzheimer’s disease, biomarkers, cerebrospinal fluid, mild cognitive impairment, pS129-α-synuclein

DOI: 10.3233/JAD-171013

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1541-1553, 2018

Authors: Grassi, Massimiliano | Perna, Giampaolo | Caldirola, Daniela | Schruers, Koen | Duara, Ranjan | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Available therapies for Alzheimer’s disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information. Objective: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors. …Methods: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors. Results: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874). Conclusions: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials. Show more

Keywords: Alzheimer’s disease, clinical prediction rule, machine learning, mild cognitive impairment, personalized medicine

DOI: 10.3233/JAD-170547

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1555-1573, 2018

Authors: Tucholka, Alan | Grau-Rivera, Oriol | Falcon, Carles | Rami, Lorena | Sánchez-Valle, Raquel | Lladó, Albert | Gispert, Juan Domingo | Molinuevo, José Luis | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Gray matter changes associated with the progression of Alzheimer’s disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease. Objective: To identify the structural connectivity changes across the AD continuum. Methods: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n  = 68) and preclinical AD individuals (n  = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n  = 44), and AD patients (n  = 43). We compared the connectivity between groups, and …with CSF Aβ42 and tau biomarkers. Results: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy. Discussion: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage. Show more

Keywords: Alzheimer’s disease, biomarkers, connectivity, diffusion MRI, magnetic resonance imaging, mild cognitive impairment, preclinical stage, tractography

DOI: 10.3233/JAD-170553

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1575-1587, 2018

Authors: Fernando, W.M.A.D. Binosha | Rainey-Smith, Stephanie R. | Gardener, Samantha L. | Villemagne, Victor L. | Burnham, Samantha C. | Macaulay, S. Lance | Brown, Belinda M. | Gupta, Veer Bala | Sohrabi, Hamid R. | Weinborn, Michael | Taddei, Kevin | Laws, Simon M. | Goozee, Kathryn | Ames, David | Fowler, Christopher | Maruff, Paul | Masters, Colin L. | Salvado, Olivier | Rowe, Christopher C. | Martins, Ralph N. | For the AIBL Research Group

Article Type: Research Article

Abstract: Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer’s disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n  = 541, and n  = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of ‘high’ brain Aβ burden (PiB …PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p  = 0.008; p  = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of ‘high’ Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset. Show more

Keywords: Alzheimer’s disease, amyloid-β, dietary fiber, dietary protein, PiB PET

DOI: 10.3233/JAD-170742

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1589-1598, 2018

Authors: Pedrinolla, Anna | Venturelli, Massimo | Fonte, Cristina | Munari, Daniele | Benetti, Maria Vittoria | Rudi, Doriana | Tamburin, Stefano | Muti, Ettore | Zanolla, Luisa | Smania, Nicola | Schena, Federico

Article Type: Research Article

Abstract: Background: Although current literature has shown that patients with Alzheimer’s disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population. Objective: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT). Methods: In this study, we included a small portion of data belonging to a larger …study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli. Results: The 16 patients assigned to ET exhibited significant improvement of Cw (–0.9±0.1 J/kg·m- 1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (–0.2±0.5 J/kg·m-1 ). Conclusions: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient’s gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result. Show more

Keywords: Dementia, energy cost of walking, physical activity, spatio-temporal gait parameters

DOI: 10.3233/JAD-170625

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1599-1609, 2018