Journal of Alzheimer's Disease - Volume 55, issue 3

Authors: Andreotti, Jennifer | Dierks, Thomas | Wahlund, Lars-Olof | Grieder, Matthias

Article Type: Research Article

Abstract: The progression of cognitive deficits in Alzheimer’s disease and semantic dementia is accompanied by grey matter atrophy and white matter deterioration. The impact of neuronal loss on the structural network connectivity in these dementia subtypes is, however, not well understood. In order to gain a more refined knowledge of the topological organization of white matter alterations in dementia, we used a network-based approach to analyze the brain’s structural connectivity network. Diffusion-weighted and anatomical MRI images of groups with eighteen Alzheimer’s disease and six semantic dementia patients, as well as twenty-one healthy controls were recorded to reconstruct individual connectivity networks. Additionally, …voxel-based morphometry, using grey and white matter volume, served to relate atrophy to altered structural connectivity. The analyses showed that Alzheimer’s disease is characterized by decreased connectivity strength in various cortical regions. An overlap with grey matter loss was found only in the inferior frontal and superior temporal areas. In semantic dementia, significantly reduced network strength was found in the temporal lobes, which converged with grey and white matter atrophy. Therefore, this study demonstrated that the structural disconnection in early Alzheimer’s disease goes beyond grey matter atrophy and is independent of white matter volume loss, an observation that was not found in semantic dementia. Show more

Keywords: Alzheimer’s disease, atrophy, diffusion magnetic resonance, frontotemporal dementia, structural connectivity

DOI: 10.3233/JAD-160571

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 981-993, 2017

Authors: Laiterä, Tiina | Paananen, Jussi | Helisalmi, Seppo | Sarajärvi, Timo | Huovinen, Joel | Laitinen, Marjo | Rauramaa, Tuomas | Alafuzoff, Irina | Remes, Anne M. | Soininen, Hilkka | Haapasalo, Annakaisa | Jääskeläinen, Juha E. | Leinonen, Ville | Hiltunen, Mikko

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer’s disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4 ), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing …the combined effects. Objective: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients. Methods: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition. Results: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition. Conclusion: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner. Show more

Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein E, genome wide association studies, idiopathic normal pressure hydrocephalus

DOI: 10.3233/JAD-160554

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 995-1003, 2017

Authors: Crispoltoni, Lucia | Stabile, Anna Maria | Pistilli, Alessandra | Venturelli, Massimo | Cerulli, Giuliano | Fonte, Cristina | Smania, Nicola | Schena, Federico | Rende, Mario

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, and by neuroinflammation. During the pathogenesis of AD, monocyte-macrophage lineage cells become increasingly ineffective in clearing Aβ deposits, less able to differentiate, and shift toward pro-inflammatory processes. Beta-nerve growth factor (β-NGF) and its receptors, TrKA and p75NTR, produce several biological responses, including cell apoptosis and survival, and inflammation. In the central nervous system, the involvement of these receptors in several critical hallmarks of AD is well known, but their role in circulating monocytes during the progression of …dementia is unclear. We investigated the relationship between plasma β-NGF concentration and TrkA/p75NTR receptor expression in monocytes of patients with mild cognitive impairment (MCI), mild AD, and severe AD. We observed that plasma β-NGF concentration was increased with a higher expression of TrKA, but not of p75NTR, in monocytes from patients with MCI and mild AD, whereas β-NGF concentration and TrKA expression were decreased and p75NTR expression was increased, associated with caspase 3-mediated apoptosis, in patients with severe AD. In our study, we show evidence of variation in plasmatic β-NGF and monocytic TrkA/p75NTR receptor expression during the progression of dementia. These novel findings add evidence to support the hypothesis for the involvement of β-NGF and its receptors on monocytes during AD progression. Show more

Keywords: Alzheimer’s disease, β-NGF, mild cognitive impairment, monocytes, p75NTR, TrKA

DOI: 10.3233/JAD-160625

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1005-1017, 2017

Authors: Krishnan, Kamini | Machulda, Mary M. | Whitwell, Jennifer L. | Butts, Alissa M. | Duffy, Joseph R. | Strand, Edythe A. | Senjem, Matthew L. | Spychalla, Anthony J. | Jack Jr., Clifford R. | Lowe, Val J. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: The logopenic variant of primary progressive aphasia (lvPPA) manifests due to a breakdown of the language network with prominent hypometabolism of the left temporoparietal region. LvPPA is strongly associated with amyloid deposition, yet there is question as to whether it is a homogeneous clinical entity. Objective: This study investigated whether differences in temporoparietal metabolic patterns on 18 F fludeoxyglucose positron emission tomography (FDG-PET) could elucidate brain regions preferentially affected in lvPPA. Method: We used differences in FDG-PET metabolic z-scores relative to controls for means of left lateral temporal, left inferior parietal, and left superior parietal regions …to classify 53 amyloid-positive lvPPA patients into temporal, parietal, or temporoparietal predominate groups. Clinical features and FDG-PET regions of hypometabolism outside of the temporoparietal region were then compared across the three groups; the latter using statistical parametric mapping. Results: Of the 53 lvPPA patients, 15 were classified as temporal, 14 as temporoparietal, and 22 as parietal predominate. There were no significant differences between the groups on demographic measures, language evaluation, or apolipoprotein E genotype. Compared to the other two groups, individuals with the parietal predominate pattern had extensive hypometabolism in left frontal lobe and the precuneus. Furthermore, this group had greater behavioral dyscontrol and deficits in executive function, visuospatial skills, visual memory retention, working memory, and cognitive flexibility (Bonferronip  < 0.05). Conclusions: This study demonstrates that there is clinical heterogeneity within amyloid-positive lvPPA. Patients with lvPPA with predominant parietal hypometabolism, unlike those with temporal or temporoparietal predominant hypometabolism, demonstrated widespread cognitive and behavioral changes. Show more

Keywords: Amyloid-β, executive function, 18F fludeoxyglucose, positron emission tomography, primary progressiveaphasia, visuospatial deficit, working memory

DOI: 10.3233/JAD-160614

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1019-1029, 2017

Authors: Tong, Zhiqian | Wang, Weishan | Luo, Wenhong | Lv, Jihui | Li, Hui | Luo, Hongjun | Jia, Jianping | He, Rongqiao

Article Type: Research Article

Abstract: Although Alzheimer’s disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n  = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants …were selected from the four groups (n  = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia. Show more

Keywords: Alzheimer’s disease, formaldehyde, Mini-Mental State Examination, norepinephrine, post-stroke dementia, semicarbazide-sensitive amine oxidase

DOI: 10.3233/JAD-160357

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1031-1038, 2017

Authors: Cebers, Gvido | Alexander, Robert C. | Haeberlein, Samantha Budd | Han, David | Goldwater, Ronald | Ereshefsky, Larry | Olsson, Tina | Ye, Naidong | Rosen, Laura | Russell, Muir | Maltby, Justine | Eketjäll, Susanna | Kugler, Alan R.

Article Type: Research Article

Abstract: AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer’s disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1–750 mg with a food-effect component (n  = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n  = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer’s disease (Part 2, n  = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food …effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing. Show more

Keywords: Amyloid-beta peptides, AZD3293, BACE1 protein-human, cerebrospinal fluid proteins, early onset Alzheimer’s disease, pharmacodynamics, pharmacokinetics, Phase I clinical trials

DOI: 10.3233/JAD-160701

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1039-1053, 2017

Authors: Pekkala, Timo | Hall, Anette | Lötjönen, Jyrki | Mattila, Jussi | Soininen, Hilkka | Ngandu, Tiia | Laatikainen, Tiina | Kivipelto, Miia | Solomon, Alina

Article Type: Research Article

Abstract: Background and objective: This study aimed to develop a late-life dementia prediction model using a novel validated supervised machine learning method, the Disease State Index (DSI), in the Finnish population-based CAIDE study. Methods: The CAIDE study was based on previous population-based midlife surveys. CAIDE participants were re-examined twice in late-life, and the first late-life re-examination was used as baseline for the present study. The main study population included 709 cognitively normal subjects at first re-examination who returned to the second re-examination up to 10 years later (incident dementia n  = 39). An extended population (n  = 1009, incident dementia …151) included non-participants/non-survivors (national registers data). DSI was used to develop a dementia index based on first re-examination assessments. Performance in predicting dementia was assessed as area under the ROC curve (AUC). Results: AUCs for DSI were 0.79 and 0.75 for main and extended populations. Included predictors were cognition, vascular factors, age, subjective memory complaints, and APOE genotype. Conclusion: The supervised machine learning method performed well in identifying comprehensive profiles for predicting dementia development up to 10 years later. DSI could thus be useful for identifying individuals who are most at risk and may benefit from dementia prevention interventions. Show more

Keywords: Computer-assisted decision making, dementia, prediction, prevention, supervised machine learning

DOI: 10.3233/JAD-160560

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1055-1067, 2017

Authors: Vemuri, Prashanthi | Knopman, David S. | Jack Jr, Clifford R. | Lundt, Emily S. | Weigand, Stephen D. | Zuk, Samantha M. | Thostenson, Kaely B. | Reid, Robert I. | Kantarci, Kejal | Slinin, Yelena | Lakshminarayan, Kamakshi | Davey, Cynthia S. | Murray, Anne

Article Type: Research Article

Abstract: Background: Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD. Objective: To measure the association between kidney function biomarkers and brain MRI findings in CKD. Methods: In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and …joint models that included both predictors, adjusted for vascular risk factors. Results: We obtained 240 baseline MRI scans (150 CKD with eGFR <45 in ml/min/1.73 m2 ; 16 mild CKD: eGFR 45–59; 74 controls: eGFR≥60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity. Conclusions: Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was a greater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD. Show more

Keywords: Cerebrovascular disease, chronic kidney disease, infarctions, magnetic resonance imaging

DOI: 10.3233/JAD-160834

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1069-1082, 2017

Authors: Nilson, Ashley N. | English, Kelsey C. | Gerson, Julia E. | Barton Whittle, T. | Nicolas Crain, C. | Xue, Judy | Sengupta, Urmi | Castillo-Carranza, Diana L. | Zhang, Wenbo | Gupta, Praveena | Kayed, Rakez

Article Type: Research Article

Abstract: It is well-established that inflammation plays an important role in Alzheimer’s disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be …a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies. Show more

Keywords: Alzheimer’s disease, frontotemporal lobar dementia, neuroinflammation, oligomer, retinal degeneration, tau protein, tauopathy

DOI: 10.3233/JAD-160912

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1083-1099, 2017

Authors: Zhuang, Xianbo | Chen, Yanxiu | Zhuang, Xianpeng | Xing, Tao | Chen, Tuanzhi | Jiang, Guisheng | Yang, Xiafeng

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression— a hallmark property in the visual system— are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. …There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway. Show more

Keywords: Aging, Alzheimer’s disease, center-surround suppression, cortical inhibition, motion perception

DOI: 10.3233/JAD-160603

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1101-1108, 2017