Journal of Alzheimer's Disease - Volume 46, issue 4

Authors: Kärkkäinen, Elisa | Lahtinen, Hanna-Maija | Närväinen, Johanna | Gröhn, Olli | Tanila, Heikki

Article Type: Research Article

Abstract: Magnetic resonance imaging (MRI) volumetry is widely used in Alzheimer’s disease (AD) research and diagnostics alongside clinical assessment. Yet few MRI volumetry studies have been conducted in AD model mice with mixed results. We performed in vivo and ex vivo MRI and extensive postmortem histological analysis in transgenic mice derived from crossing amyloid plaque producing AβPP/PS1 mice with brain-derived neurotrophic factor (BDNF) +/− mice. This allowed us to compare developmental volumetric changes due to BDNF deficiency with progressive changes due to amyloid accumulation. We found decreased whole brain volume at 3 months and decreased cortical volume at both …3 and 8 months in vivo in BDNF +/− Tg mice but increased whole brain and cortical volumes at 8 months in AβPP/PS1 mice. Consistent with this, the postmortem histological analysis showed decreased brain parenchymal area in BDNF +/− mice but an increase in AβPP/PS1 mice. BDNF gene deficiency did not affect brain amyloid load or astrogliosis, but led to decreased dentate gyrus length, whereas AβPP/PS1 mice had significantly increased amyloid load, astrogliosis, and decreased neurogenesis. Distinct and layer-specific effects were found in the hippocampus of AβPP/PS1 and BDNF +/− mice. In contrast to human AD patients, brain atrophy in amyloid producing mice appears to be masked by volume increase due to amyloid accumulation and especially accompanying astrogliosis. Our results indicate that cortical MRI volumetry can be used to some extent as a proxy to progressive brain amyloidosis in preclinical studies. Show more

Keywords: Alzheimer’s disease, amyloid plaques, amyloid-β protein precursor, BDNF, magnetic resonance imaging, presenilin -1, volumetry

DOI: 10.3233/JAD-150059

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 929-946, 2015

Authors: Voyle, Nicola | Baker, David | Burnham, Samantha C. | Covin, Antonia | Zhang, Zhanpan | Sangurdekar, Dipen P. | Tan Hehir, Cristina A. | Bazenet, Chantal | Lovestone, Simon | Kiddle, Steven | Dobson, Richard J.B. | and the AIBL research group

Article Type: Research Article

Abstract: Background: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-β burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer’s disease (AD) therapeutics. Objective: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. Methods: Our …study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOE ɛ 4 carriage were used as covariates for all analysis. Results: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. Conclusions: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of replication, further studies are required. Show more

Keywords: Alzheimer’s disease, amyloid plaques, blood, positron emission tomography scan, proteomics

DOI: 10.3233/JAD-150020

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 947-961, 2015

Authors: Boccia, Maddalena | Acierno, Mauro | Piccardi, Laura

Article Type: Research Article

Abstract: Depression and cognitive impairment are both common disorders in elderly people and frequently occur together. Due to the presence of a common set of behavioral and cognitive symptoms, differential diagnosis may become arduous. Neuroimaging may offer a good tool during diagnosis. We performed a coordinate-based meta-analysis to compare gray matter changes in Alzheimer’s disease (AD) and late-life depression (LLD). AD and LLD led to brain atrophy in networks only partially overlapping. Both conditions are linked to a reduction of the bilateral hippocampal volume, but AD is correlated with great atrophy in the left anterior hippocampus and bilateral posterior cingulate cortex, …while LLD is correlated with great atrophy in the precuneus, superior frontal gyrus, and ventromedial frontal cortex. Present results shed some light on neural underpinnings of AD and LLD and provide new useful evidence for differential diagnosis. Show more

Keywords: Aging, Alzheimer’s disease, dementia, late-life depression, magnetic resonance imaging, neuroimaging, voxel-based morphometry

DOI: 10.3233/JAD-142955

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 963-970, 2015

Authors: Welt, Tobias | Kulic, Luka | Hoey, Sarah E. | McAfoose, Jordan | Späni, Claudia | Chadha, Antonella Santuccione | Fisher, Abraham | Nitsch, Roger M.

Article Type: Research Article

Abstract: Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer’s disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of …brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α -secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα , and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism. Show more

Keywords: AβPP processing, AβPP transgenic mice, Alzheimer’s disease, amyloid-β, microdialysis, muscarinic acetylcholine receptor

DOI: 10.3233/JAD-150152

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 971-982, 2015

Authors: Wurtman, Richard J.

Article Type: Research Article

Abstract: Drugs that block muscarinic cholinergic neurotransmission in the brain can, as a consequence, increase the formation of amyloid-β, and decrease brain levels of phosphatidylcholine (by slowing its synthesis and accelerating its turnover). Both of these effects might cause a decrease in brain synapses, as characterizes and probably underlies the memory disorder of early Alzheimer’s disease.

Keywords: Acetylcholine, amyloid, choline, neurotransmission, synapses, synaptic membrane

DOI: 10.3233/JAD-150290

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 983-987, 2015

Authors: Yeo, Hyeon-Gu | Lee, Youngjeon | Jeon, Chang-Yeop | Jeong, Kang-Jin | Jin, Yeung Bae | Kang, Philyong | Kim, Sun-Uk | Kim, Ji-Su | Huh, Jae-Won | Kim, Young-Hyun | Sim, Bo-Woong | Song, Bong-Seok | Park, Young-Ho | Hong, Yonggeun | Lee, Sang-Rae | Chang, Kyu-Tae

Article Type: Research Article

Abstract: In line with recent findings showing Alzheimer’s disease (AD) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-STZ) administration has been proposed as a representative experimental model of AD. Although icv-STZ rodent models of AD have been increasingly researched, studies in non-human primate models are very limited. In this study, we aimed to characterize the cerebral damage caused by icv-STZ in non-human primates; to achieve this, three cynomolgus monkeys (Macaca fascicularis ) were administered four dosages of STZ (2 mg/kg) dissolved in artificial cerebrospinal fluid and another three controls were injected with only artificial cerebrospinal fluid at …the cerebellomedullary cistern. In vivo neuroimaging was performed with clinical 3.0 T MRI, followed by quantitative analysis with FSL for evaluation of structural changes of the brain. Immunohistochemistry was performed to evaluate cerebral histopathology. We showed that icv-STZ caused severe ventricular enlargement and parenchymal atrophy, accompanying amyloid-β deposition, hippocampal cell loss, tauopathy, ependymal cell loss, astrogliosis, and microglial activation, which are observed in human aged or AD brain. The findings suggest that the icv-STZ monkey model would be a valuable resource to study the mechanisms and consequences of a variety of cerebral pathologies including major pathological hallmarks of AD. Furthermore, the study of icv-STZ monkeys could contribute to the development of treatments for age- or AD-associated cerebral changes. Show more

Keywords: Alzheimer’s disease, animal model, brain, monkey, streptozotocin

DOI: 10.3233/JAD-143222

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 989-1005, 2015

Authors: Zhang, William I. | Antonios, Gregory | Rabano, Alberto | Bayer, Thomas A. | Schneider, Anja | Rizzoli, Silvio O.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is neuropathologically characterized by aggregates of amyloid-β peptides (Aβ) and tau proteins. The consensus in the AD field is that Aβ and tau should serve as diagnostic biomarkers for AD. However, their aggregates have been difficult to investigate by conventional fluorescence microscopy, since their size is below the diffraction limit (∼200 nm). To solve this, we turned to a super-resolution imaging technique, stimulated emission depletion (STED) microscopy, which has a high enough precision to allow the discrimination of low- and high-molecular weight aggregates prepared in vitro . We used STED to analyze the structural organization of Aβ and …tau in cerebrospinal fluid (CSF) from 36 AD patients, 11 patients with mild cognitive impairment (MCI), and 21 controls. We measured the numbers of aggregates in the CSF samples, and the aggregate sizes and intensities. These parameters enabled us to distinguish AD patients from controls with a specificity of ∼87% and a sensitivity of ∼79% . In addition, the aggregate parameters determined with STED microscopy correlated with the severity of cognitive impairment in AD patients. Finally, these parameters may be useful as predictive tools for MCI cases. The STED parameters of two MCI patients who developed AD during the course of the study, as well as of MCI patients whose Aβ ELISA values fall within the accepted range for AD, placed them close to the AD averages. We suggest that super-resolution imaging is a promising tool for AD diagnostics. Show more

Keywords: Alzheimer’s disease, amyloid-β, diagnostics, imaging, super-resolution, tau

DOI: 10.3233/JAD-150064

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1007-1020, 2015

Authors: Mehta, Pankaj D. | Patrick, Bruce A. | Barshatzky, Marc | Mehta, Sangita P. | Frackowiak, Janusz | Mazur-Kolecka, Bozena | Miller, David L.

Article Type: Research Article

Abstract: Secreted soluble amyloid-β (Aβ)38 is the second most prominent Aβ form next to Aβ40 , and is found in cerebrospinal fluid (CSF) and blood. Recent studies have shown the importance of quantitation of CSF Aβ38 levels in combination with those of Aβ40 and Aβ42 to support the diagnosis of Alzheimer’s disease (AD), and other neurodegenerative diseases, and to facilitate drug discovery studies. However, the availability of reliable and specific Aβ38 monoclonal antibody is limited. Our first aim was to generate and partially characterize rabbit monoclonal antibody (RabmAb) to Aβ38 . The antibody was specific to …Aβ38 , since it did not react with Aβ37 , Aβ39 , Aβ40 , or Aβ42 in ELISA or immunoblotting. The antibody was sensitive enough to measure Aβ38 levels in plasma. Our second aim was to quantitate Aβ38 levels in plasma from older Down syndrome (DS) persons and age-matched controls. Persons with DS (35 years and older) have neuropathological changes characteristic of AD. Studies have shown that plasma Aβ40 and Aβ42 levels are higher in older persons with DS than in controls. However, none examined Aβ38 levels in DS. Our quantitation data showed that, like Aβ40 and Aβ42 plasma levels, Aβ38 plasma levels were higher in DS than in controls. Longitudinal studies will determine whether plasma Aβ38 levels in combination with levels of Aβ40 and Aβ42 are useful to predict early signs of AD in DS. Show more

Keywords: Alzheimer’s disease, amyloid-β (Aβ) peptide, Down syndrome, ELISA, immunoblotting, plasma, rabbit monoclonal antibodies to Aβ peptides

DOI: 10.3233/JAD-142592

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1021-1032, 2015

Authors: Cagnin, Annachiara | Simioni, Mariachiara | Tagliapietra, Matteo | Citton, Valentina | Pompanin, Sara | Della Puppa, Alessandro | Ermani, Mario | Manara, Renzo

Article Type: Research Article

Abstract: Background: Idiopathic normal-pressure hydrocephalus (iNPH) can resemble or occur in combination with other brain disorders frequently present in the elderly such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: To study the accuracy of a simplified callosal angle measure in differentiating iNPH from DLB and AD using conventional brain MRI. Methods: 76 patients (24 iNPH, 30 DLB, 22 AD) and 40 healthy controls served as discovering cohort. The callosal angle measure was obtained on standard coronal brain MRI images crossing the corpus callosum midpoint. 41 patients (21 iNPH and 20 DLB/AD) were …used as independent validation cohort. A set of other conventional MRI markers of iNPH was also evaluated. Results: iNPH showed a significantly decreased mean callosal angle value compared to both disease groups and controls (iNPH = 109±9; DLB = 136.9±8.2; AD = 135.4±11.3; Controls = 138.5±5.2; p  <  0.00001). Using a cut off angle of 123, derived by the mean -3SD of the control group, an accuracy of 96% (sensitivity 100% , specificity 95.4% ) was obtained. By ROC analysis, the area under the curve was 0.99 (95% CI: 0.97–1). The measure was consistent (intra-rater: r  = 0.94) and reproducible (inter-rater: r  = 0.89). In the validation cohort, this cut off angle value discriminated iNPH from DLB/AD with 97.5% accuracy. None of the conventional MRI signs reached the same accuracy. Conclusions: This simplified callosal angle measure represents an accurate, reproducible, and easy marker of iNPH. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, idiopathic normal-pressure hydrocephalus, MRI marker

DOI: 10.3233/JAD-150107

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1033-1038, 2015

Authors: Dregan, Alex | Chowienczyk, Phil | Gulliford, Martin C.

Article Type: Research Article

Abstract: Background: There is limited primary-care based evidence for an association between chronic inflammation and related therapy with all-cause dementia. Objective: To estimate the association between several chronic inflammatory disorders and related drug therapy and all-cause dementia. Methods: The study population included a cohort of patients diagnosed with inflammatory conditions and matching controls (ratio 1:2) from the Clinical Practice Research Datalink, a database or primary care records in the UK. Inflammation patients and controls were matched on age, gender, and family practice. The study outcome measure was all-cause dementia. Chronic inflammation diagnosis and anti-inflammatory drugs represented …the exposure variables of interest. Competing risks analyses were used to estimate the risk of dementia associated with exposure variables. Results: There were 1,378 (1% ) and 2,805 (1% ) dementia events recorded for chronic inflammation patients and their matched controls, respectively. Systemic vasculitis was associated with increased hazard ratios of dementia (1.75, 95% confidence interval (CI) 1.35–2.27, p  <  0.001). The analyses revealed increased risk of dementia for systemic vasculitis (1.64, 95% CI 1.24–2.18), Crohn’s diseases (2.08, 95% CI 1.16–3.74), bullous skin diseases (1.55, 95% CI 1.11–2.18), and inflammatory arthritis (1.33, 95% CI1.06–1.63) among treated patients. Combined glucocorticoids and NSAID therapy suggested reduced risk of dementia across most conditions, particularly systemic autoimmune disorders (0.41, 95% CI 0.18–0.95). Conclusion: The association between chronic inflammation and dementia varied across inflammatory disorders, being stronger for systemic vasculitis. There was evidence that combined therapy was associated with lower risk of dementia across most disorders. These data highlight potential avenues for future mechanistic and intervention investigations. Show more

Keywords: Chronic inflammation, dementia, glucocorticoids, NSAIDs, primary care

DOI: 10.3233/JAD-150171

Citation: Journal of Alzheimer's Disease, vol. 46, no. 4, pp. 1039-1047, 2015