Journal of Alzheimer's Disease - Volume 57, issue 3

Authors: Hatashita, Shizuo | Wakebe, Daichi

Article Type: Research Article

Abstract: The aim was to evaluate brain amyloid-β (Aβ) deposition in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using amyloid PET imaging and clarify the relationship between the annual change in Aβ deposition and disease progression. Forty-eight MCI patients underwent neuropsychological assessment and amyloid PET imaging using [11 C]-PIB over a follow-up of 5.7±1.5 years. Thirty-nine MCI patients who had an amyloid-positive scan were defined as MCI due to AD, and 9 MCI patients who had an amyloid-negative scan were included. Regions of interest were defined on co-registered MRI, and the PIB standardized uptake value ratio (SUVR) …on the same regions was used over follow-up. Annual change in PIB SUVR was calculated. Patients with MCI due to AD had higher baseline PIB SUVR (1.81±0.32, n  = 39, p  < 0.01) and a greater annual rate of change in PIB SUVR (0.044±0.027, n  = 39, p  < 0.01) compared to amyloid-negative MCI patients. Twenty-eight (71.8%) progressed to AD. In patients who progressed during a short duration of 1.7±0.8 years, the annual rate of increase in PIB SUVR was 0.101±0.094 (n  = 16, p  < 0.05), which was greater compared to patients with long conversion or stable patients. There was a negative correlation between the annual rate of increase in PIB SUVR and duration of progression to AD among individual MCI converters (r  = –0.47, n  = 28, p  < 0.05). The patients defined as MCI due to AD could progress to AD with a shorter period if they have a greater increased annual rate in brain Aβ deposition. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid PET imaging, mild cognitive impairment, progression

DOI: 10.3233/JAD-161074

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 765-773, 2017

Authors: Barocco, Federica | Spallazzi, Marco | Concari, Letizia | Gardini, Simona | Pelosi, Annalisa | Caffarra, Paolo

Article Type: Research Article

Abstract: Background: The rate of cognitive and functional decline in Alzheimer’s disease (AD) changes across individuals. Objectives: Our purpose was to assess whether the concept of “fast decline” really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD. Methods: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into “fast decliners” (n  = 62), defined by …a loss ≥5 points on the MMSE score within the first year from the baseline; “intermediate decliners” (n  = 37), by a loss ≥5 points after the first year and before the 18th month; or “slow decliners” (n  = 225), composed of the remaining patients. Results: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis. Conclusions: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called “fast decliners”. This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners. Show more

Keywords: Alzheimer’s disease, cognitive predictors, dementia progression, fast decliners, Mini-Mental State Examination

DOI: 10.3233/JAD-161264

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 775-786, 2017

Authors: Kramberger, Milica G. | Auestad, Bjørn | Garcia-Ptacek, Sara | Abdelnour, Carla | Olmo, Josep Garre | Walker, Zuzana | Lemstra, Afina W. | Londos, Elisabet | Blanc, Frederic | Bonanni, Laura | McKeith, Ian | Winblad, Bengt | de Jong, Frank Jan | Nobili, Flavio | Stefanova, Elka | Petrova, Maria | Falup-Pecurariu, Cristian | Rektorova, Irena | Bostantjopoulou, Sevasti | Biundo, Roberta | Weintraub, Daniel | Aarsland, Dag | on behalf of the E-DLB

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) patients. Methods: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and …DLB core features. Results: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p  = 0.07 compared to DLB) and 1.8 in PDD (p  = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. Conclusions: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB. Show more

Keywords: Dementia with Lewy bodies, international cohort, long-term cognitive decline, multicenter study

DOI: 10.3233/JAD-161109

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 787-795, 2017

Authors: Reed, Catherine | Happich, Michael | Argimon, Josep Maria | Haro, Josep Maria | Wimo, Anders | Bruno, Giuseppe | Dodel, Richard | Jones, Roy W. | Vellas, Bruno | Belger, Mark

Article Type: Research Article

Abstract: Background: Country differences in resource use and costs of Alzheimer’s disease (AD) may be driven by differences in health care systems and resource availability. Objective: To compare country resource utilization drivers of societal costs for AD dementia over 18 months. Methods: GERAS is an observational study in France (n  = 419), Germany (n  = 550), and the UK (n  = 526). Resource use of AD patients and caregivers contributing to >1% of total societal costs (year 2010) was assessed for country differences, adjusting for participant characteristics. Results: Mean 18-month societal costs per patient were France €33,339, …Germany €38,197, and UK €37,899 (£32,501). Caregiver time spent on basic and instrumental activities of daily living (ADL) contributed the most to societal costs (54% France, 64% Germany, 65% UK). Caregivers in France spent less time on ADL than UK caregivers and missed fewer work days than in other countries. Compared with other countries, patients in France used more community care services overall and were more likely to use home aid. Patients in Germany were least likely to use temporary accommodation or to be institutionalized at 18 months. UK caregivers spent the most time on instrumental ADL, UK patients used fewest outpatient resources, and UK patients/caregivers were most likely to receive financial support. Conclusion: Caregiver time on ADL contributed the most to societal costs and differed across countries, possibly due to use of community care services and institutionalization. Other resources had different patterns of use across countries, reflecting country-specific health and social care systems. Show more

Keywords: Activities of daily living, Alzheimer’s disease, caregivers, costs, health resources

DOI: 10.3233/JAD-160449

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 797-812, 2017

Authors: Beydoun, May A. | Gamaldo, Alyssa A. | Beydoun, Hind A. | Shaked, Danielle | Zonderman, Alan B. | Eid, Shaker M.

Article Type: Research Article

Abstract: We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer’s disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002–2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N = 92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3–7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation (“CVD/Blood”) as well as neurophysiological and …psychological evaluation and treatment (“Neuro”) procedures increased by 5–8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of “Brain” procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk. Show more

Keywords: Alzheimer’s disease, healthcare resource utilization, hospital inpatients, hospitalization outcomes, hospital procedures

DOI: 10.3233/JAD-161225

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 813-824, 2017

Authors: Pievani, Michela | Pini, Lorenzo | Ferrari, Clarissa | Pizzini, Francesca B. | Boscolo Galazzo, Ilaria | Cobelli, Chiara | Cotelli, Maria | Manenti, Rosa | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Background: The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design. Objective: Based on the observation that Alzheimer’s disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits. Methods: A systematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based …meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method. Results: DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area – BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex. Conclusions: NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, default mode network, meta-analysis, non-invasive brain stimulation, salience network

DOI: 10.3233/JAD-161105

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 825-843, 2017

Authors: Chirles, Theresa J. | Reiter, Katherine | Weiss, Lauren R. | Alfini, Alfonso J. | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was …used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated. Show more

Keywords: Aging, Alzheimer’s disease, cognitive disorders, connectivity, default mode network, exercise intervention, neural plasticity, posterior cingulate, precuneus, resting state functional MRI

DOI: 10.3233/JAD-161151

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 845-856, 2017

Authors: Romeo, Margherita | Stravalaci, Matteo | Beeg, Marten | Rossi, Alessandro | Fiordaliso, Fabio | Corbelli, Alessandro | Salmona, Mario | Gobbi, Marco | Cagnotto, Alfredo | Diomede, Luisa

Article Type: Research Article

Abstract: The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42 , and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in …vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action. Show more

Keywords: Alzheimer’s disease, amyloid-β, Caenorhabditis elegans, humanin, inclusion body myositis, oligomers

DOI: 10.3233/JAD-160951

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 857-871, 2017

Authors: Ravona-Springer, Ramit | Schnaider-Beeri, Michal | Goldbourt, Uri

Article Type: Research Article

Abstract: Background: The relationship of obesity with risk for dementia is complex and may change with age. Objective: To analyze the relationship between measures of obesity at age 40–65 and dementia prevalence in survivors 36 years later. Methods: Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n  = 9,760 men aged 40–65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n  = 1,643 participants of the original cohort who survived until 1999/2000 (age ≥76 years) and had anthropometric measures in 1963. Results: …Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p  = 0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70–0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p  = 0.6 in trend test). Conclusions: Lower triceps skinfold at age 40–65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health. Show more

Keywords: Dementia prevalence, obesity, skinfold, triceps

DOI: 10.3233/JAD-160786

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 873-883, 2017

Authors: Huang, Yan | Shen, Wei | Su, Jie | Cheng, Bin | Li, Dong | Liu, Gang | Zhou, Wen-Xia | Zhang, Yong-Xiang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator …of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy. Show more

Keywords: Alzheimer’s disease, amyloid-β, balance, GluN2A, GluN2B

DOI: 10.3233/JAD-161186

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 885-897, 2017