Journal of Alzheimer's Disease - Volume 47, issue 3

Authors: Floris, Gianluca | Di Stefano, Francesca | Cherchi, Maria Valeria | Costa, Gianna | Marrosu, Francesco | Marrosu, Maria Giovanna

Article Type: Short Communication

Abstract: Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimer’s disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful …to monitoring side effects. Show more

Keywords: Alzheimer’s disease, amyloid angiopathy, ARIA, cerebral microbleeds, PSEN1 mutation

DOI: 10.3233/JAD-150165

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 535-538, 2015

Authors: Tiepolt, Solveig | Patt, Marianne | Hoffmann, Karl-Titus | Schroeter, Matthias L. | Sabri, Osama | Barthel, Henryk

Article Type: Short Communication

Abstract: The revised NIA-AA diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD make use of amyloid pathology and neurodegeneration biomarkers which increase the diagnostic confidence in the majority of patients. However, in daily praxis, cases with conflicting biomarker constellations occur. A MCI subject underwent neuropsychological testing supplemented by FDG and amyloid PET/MRI as well as CSF sampling. In this subject, the biomarkers of Aβ deposition were negative. [18 F]FDG PET, however, showed an AD-typical hypometabolism. Further studies are required to determine frequency and relevance of cases with neurodegeneration-first biomarker constellations to improve our understanding on …pathogenesis and diagnosis of AD. Show more

Keywords: Alzheimer’s disease, amyloid, FDG, mild cognitive impairment, PET

DOI: 10.3233/JAD-150163

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 539-543, 2015

Authors: Peters-Libeu, Clare | Campagna, Jesus | Mitsumori, Michael | Poksay, Karen S. | Spilman, Patricia | Sabogal, Alex | Bredesen, Dale E. | John, Varghese

Article Type: Research Article

Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer’s disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα , the product of the cleavage of AβPP by α -secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and …that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ. Show more

Keywords: Aβ, sAβPPα, sAβPPβ, allosteric, BACE, BACE1, endogenous, inhibitor, SAXS

DOI: 10.3233/JAD-150282

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 545-555, 2015

Authors: Khatoon, Sabiha | Chalbot, Sonia | Bolognin, Silvia | Puoliväli, Jukka | Iqbal, Khalid

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the single major cause of dementia in middle- to old-age individuals, and, as of yet, no disease-modifying therapeutic drug is available for its treatment. A major obstacle in the successful development of disease-modifying therapeutic drugs has been the lack of suitable animal models of the sporadic form of AD as well as a biomarker that can be used both for therapeutic preclinical studies and for human clinical trials. Previously we showed neurogenesis and neuronal plasticity deficits and cognitive impairment and their rescue with a neurotrophic peptidergic compound, DGGLA G named P021, in aged Fisher rats. Here …we show that P021 is blood-brain-barrier-permeable, and chronic oral treatment with this compound can reduce the brain level of total tau in the aged rats. Furthermore, cerebrospinal fluid (CSF) levels of both tau and Aβ/AβPP are elevated in the aged animals, and chronic treatment with P021 can reduce tau but not Aβ/AβPP to that of the levels found in young adult rats. Importantly, P021 does not induce any detectable immune reaction in rats. Collectively, these studies show the therapeutic potential of P021 as a disease-modifying compound and the suitability of the aged Fisher rats as a model of cerebral aging in which the therapeutic efficacy of a tau-reducing compound can be monitored in the CSF. Show more

Keywords: Aged Fisher rat, Alzheimer’s disease, cerebral aging, cerebrospinal fluid, ELISA, rat, tau protein

DOI: 10.3233/JAD-142799

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 557-564, 2015

Authors: Wang, Zi-Xuan | Tan, Lan | Wang, Hui-Fu | Ma, Jing | Liu, Jinyuan | Tan, Meng-Shan | Sun, Jia-Hao | Zhu, Xi-Chen | Jiang, Teng | Yu, Jin-Tai

Article Type: Research Article

Abstract: To evaluate whether iron, zinc, and copper levels in serum are disarranged in Alzheimer’s disease (AD), we performed meta-analyses of all studies on the topic published from 1984 to 2014 and contextually carried out a replication study in serum as well. Our meta-analysis results showed that serum zinc was significantly lower in AD patients. Our replication and meta-analysis results showed that serum copper was significantly higher in AD patients than in healthy controls, so our findings were consistent with the conclusions of four previously published copper meta-analyses. Even if a possible role of iron in the pathophysiology of the disease …could not be ruled out, the results of our meta-analysis showed no change of serum iron levels in AD patients, but this conclusion was not robust and requires further investigation. The meta-regression analyses revealed that in some studies, differences in serum iron levels could be due to the different mean ages, while differences in zinc levels appeared to be due to the different sex ratios. However, the effect of sex ratio on serum zinc levels in our meta-analysis is subtle and needs further confirmation. Also, diverse demographic terms and methodological approaches appeared not to explain the high heterogeneity of our copper meta-analysis. Therefore, when investigating trace elements, covariants such as age and sex have to be taken into account in the analyses. In the light of these findings, we suggest that the possible alteration of serum zinc and copper levels are involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, meta-analysis, serum copper, serum iron, serum zinc

DOI: 10.3233/JAD-143108

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 565-581, 2015

Authors: Suvorina, Mariya Yu. | Selivanova, Olga M. | Grigorashvili, Elizaveta I. | Nikulin, Alexey D. | Marchenkov, Victor V. | Surin, Alexey K. | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: The aim of this study was to investigate the process of amyloidogenesis of amyloid-β (Aβ)42 peptide, by means of fluorescence spectroscopy, electron microscopy, X-ray diffraction, and mass spectrometry. It has been repeatedly reported in the literature that the process of fibril formation by Aβ 42 peptide depends considerably not only upon the specific conditions (ionic conditions, pH, temperature, mixing, etc.), as well as the manufacturing route (synthetic or recombinant), but also on the methods of synthesis and purification. We have, for the first time, systematically analyzed samples of Aβ 42 peptide supplied by five different companies (Anaspec, …Invitrogen, Enzo, Sigma-Aldrich, and SynthAssist) and obtained evidence of significant variability, including lot to lot variations. All studied samples formed amyloid-like fibrils at pH3-6, and the fibrils contained cross-β structures. Samples from Anaspec, Invitrogen, and Enzo formed one particular type of amyloid-like fibrils, while the samples from Sigma-Aldrich and SynthAssist formed another distinct type of fibrils. The observed polymorphism emphasizes the capacity of the Aβ 42 peptide to act as a prion agent with varying structural characteristics. The presented data have allowed us to propose a possible mechanism of formation of amyloid-like fibrils. Show more

Keywords: Aβ 42 peptide, Alzheimer’s disease, amyloid fibril, electron microscopy, mass spectroscopy, oligomer, prion-like behavior, protofibril

DOI: 10.3233/JAD-150147

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 583-593, 2015

Authors: Li, Lisha | Peng, Yahui | Hui, Yang | Zhang, Shuai | Zhou, You | Li, Dan | Li, Jihong | Si, Zizhen | Li, Jing | Wang, Dayong | Li, Yanze | Dong, Min | Gao, Xu

Article Type: Research Article

Abstract: The expression of heme oxygenase 1 (HO-1) in the cortex and hippocampus is higher in Alzheimer’s disease (AD) and mild cognitive impairment patients than healthy individuals, and epidemiological studies suggest that HO-1 is an important factor for AD. However, its influence on nerve function is poorly understood. Here, we studied the effect of the overexpression of HO-1 on the cognitive and synaptic plasticity in 3-month-old mice. We found that the overexpression of HO-1 induced spatial learning and memory deficits with an apparent decrease of AMPKR, NMDAR, postsynaptic density protein 95, synapsin I, synaptophysin, and microtubule-associated protein 2, all of which …are memory-related synaptic proteins. Concurrently, HO-1 could co-express and induce the aggregation of Aβ 42 and Aβ oligomer in the hippocampus area. Additionally, our research is the first to demonstrate that HO-1 changes the morphology of the synapse to impair the neural circuit. These results indicate that the overexpression of HO-1 can damage synaptic plasticity in early stages to induce AD-like pathology and cognitive abnormality in mice. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomer, dendritic spine, heme oxygenase 1, synaptic plasticity

DOI: 10.3233/JAD-150027

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 595-608, 2015

Authors: Nakano, Yumiko | Matsuzono, Kosuke | Yamashita, Toru | Ohta, Yasuyuki | Hishikawa, Nozomi | Sato, Kota | Deguchi, Kentaro | Abe, Koji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most significant diseases affecting an increasingly aging society. Objective: To determine the long-term efficacy of galantamine treatment in a Japanese population. Methods: We performed “Okayama Galantamine Study (OGS)” to retrospectively analyze the clinical effects of galantamine in 279 AD patients using 7 batteries for assessing dementia at baseline, 3, 6, 12, and 24 months. We further analyzed the effects of galantamine based on gender and the severity of their baseline cognitive, affective, and activity of daily living (ADL) functions. Results: In …all 279 AD patients (80.6 ± 7.2 years old, MMSE 20.0 ± 4.5), cognitive functions were well preserved until 12 months and even frontal assessment battery improved after 12 months although Hasegawa dementia scale-revised finally worsened at 24 months ( * p  <  0.05) with galantamine treatment. Affective and ADL functions were also well maintained after galantamine treatment with significant improvement of Geriatric Depression Scale scores at 3 months ( * p  <  0.05). Subanalyses showed the better response to galantamine for male and lower baseline function subgroups. Conclusions: Our present study (OGS) revealed a long-term efficacy of galantamine in very elderly AD patients, and suggested a better efficacy for male and baseline lower cognitive, affective, and ADL functions. Show more

Keywords: Activity of daily living, affective function, Alzheimer’s disease, cognitive function, dementia, galantamine

DOI: 10.3233/JAD-150308

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 609-617, 2015

Authors: Hessen, Erik | Nordlund, Arto | Stålhammar, Jacob | Eckerström, Marie | Bjerke, Maria | Eckerström, Carl | Göthlin, Mattias | Fladby, Tormod | Reinvang, Ivar | Wallin, Anders

Article Type: Research Article

Abstract: Background: There is a need to find very early markers for pre-clinical Alzheimer’s disease as interventions early in the disease process are thought to be most effective. Objective: The present study aimed to address the potential relation between cerebrospinal fluid (CSF) biomarkers and reduced cognitive function in a relatively young cohort of memory clinic patients with subjective cognitive decline. Methods: 122 patients (mean age 63 years) with subjective cognitive decline were recruited from two university memory clinics and followed for two years. Results: The main finding was that the …subgroup with objective memory decline during the study period had significantly higher T-tau at baseline than the group with improved memory. Baseline CSF variables showed a trend toward more pathological values in the patients with memory decline compared to those who improved or remained stable. The baseline memory score of those who declined was significantly better than the baseline score of those who improved over two years. The general trend for the whole group was improved memory and executive test scores. There were no differences in cognitive scores based on CSF quartiles at baseline, nor were there differences in cognitive outcome for patients with early amnestic mild cognitive impairment versus average cognitive function at baseline. Conclusions: The main finding that T-tau rather than amyloid-β was associated with memory decline do not support the prevailing opinion about the chain of events assumed to take place in Alzheimer’s disease. In addition, memory decline was not associated with poor baseline memory score. Thus, a memory cut-off indicating low baseline memory would not would have identified the declining group. Show more

Keywords: Cerebrospinal fluid biomarkers, early amnestic MCI, memory decline, mild cognitive impairment (MCI), pre-clinical AD, pre-clinical dementia, subjective cognitive decline, T-tau

DOI: 10.3233/JAD-150109

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 619-628, 2015

Authors: Virk, Sohaib A. | Eslick, Guy D.

Article Type: Research Article

Abstract: Background: Aluminum is the most studied environmental agent linked with Alzheimer’s disease (AD). However, it remains unclear whether levels are significantly elevated in AD sufferers. Objective: To systematically assess levels of aluminum in brain, serum, and cerebrospinal fluid (CSF) of AD cases and controls. Methods: Electronic searches of Medline, Embase, PubMed, and Cochrane Library were conducted up to June 2015. Studies reporting brain, serum, or CSF aluminum levels in individuals with AD and non-demented controls were included. Meta-analyses were performed using random-effects models and the pooled standardized mean difference (SMD) reported with …95% confidence intervals (CI). Results: Overall, 34 studies involving 1,208 participants and 613 AD cases met the criteria for inclusion. Aluminum was measured in brain tissue in 20 studies (n  = 386), serum in 12 studies (n  = 698), and CSF in 4 studies (n  = 124). Compared to control subjects, AD sufferers had significantly higher levels of brain (SMD 0.88; 95% CI, 0.25–1.51), serum (SMD 0.28; 95% CI, 0.03–0.54), and CSF (SMD 0.48; 95% CI, 0.03–0.93) aluminum. Sensitivity analyses excluding studies without age-matched controls did not impact upon these results. Conclusions: The findings of the present meta-analyses demonstrate that aluminum levels are significantly elevated in brain, serum, and CSF of patients with AD. These findings suggest that elevated aluminum levels, particularly in serum, may serve as an early marker of AD and/or play a role in the development of the disease. These results substantially clarify the existing evidence examining the link between chronic aluminum exposure and the development of AD. Show more

Keywords: Alzheimer disease, aluminum, meta-analysis, systematic review

DOI: 10.3233/JAD-150193

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 629-638, 2015

Authors: Cho, Sun-Jung | Yun, Sang-Moon | Lee, Dae-hoon | Jo, Chulman | Ho Park, Moon | Han, Changsu | Ho Koh, Young

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common type of dementia in the elderly. The accumulation of amyloid-β peptides and tau proteins is the major pathogenic event of AD. There is accumulating evidence that both tau and amyloid-β linked to the small ubiquitin-like modifier (SUMO), which is increased in the brain of AD model mouse. The present study focused on the determination of SUMO1 protein level in AD blood plasma by the ELISA methods. We compared plasma from 80 dementia patients (average age 75.3 y), 89 persons with amnestic mild cognitive impairment (MCI) (average age 73.71 y),and 133 cognitively normal controls …(average age 71.97 y). The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r  =−0.123, p  = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD. Show more

Keywords: Alzheimer’s disease, biomarker, plasma, SUMO1

DOI: 10.3233/JAD-150103

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 639-643, 2015

Authors: Tang, Xiaoying | Holland, Dominic | Dale, Anders M. | Miller, Michael I. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: This paper examines how age intervenes in the effects of APOE ɛ 4 allele on the volume and shape morphometrics of the hippocampus and the amygdala in mild cognitive impairment (MCI) and Alzheimer’s disease. We evaluate the structural morphological differences between ɛ 4 carriers and non-carriers in two age-dependent subgroups; younger than 75 years (Young-Old) and older than 80 years (Very-Old). While we show that the four structures of interest atrophy significantly in the ɛ 4 carriers, relative to the non-carriers, of the Young-Old group, this effect is not observed in their Very-Old counterparts. The structures in the right hemisphere …are found to be more affected by the APOE genotype than those in the left hemisphere and we identify the relevant regions in which significant atrophy occurs to be parts of the basolateral, centromedial, and lateral nucleus subregions of the amygdala and the CA1 and subiculum subregions of the hippocampus. We also observe that the APOE genotype only affects MCI patients that deteriorated to dementia within 3 years while leaving their “non-converting” counterparts unaffected. Show more

Keywords: Age intervention, Alzheimer’s disease, amygdala, apolipoprotein E, conversion, hippocampus, mild cognitive impairment, shape morphometrics

DOI: 10.3233/JAD-150262

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 645-660, 2015

Authors: Farid, Karim | Carter, Stephen F. | Rodriguez-Vieitez, Elena | Almkvist, Ove | Andersen, Pia | Wall, Anders | Blennow, Kaj | Portelius, Erik | Zetterberg, Henrik | Nordberg, Agneta

Article Type: Research Article

Abstract: Amyotrophic lateral sclerosis (ALS), a fatal disease of unknown origin, affects motor neurons in the primary motor cortex, brainstem, and spinal cord. Cognitive impairment may occur before the motor symptoms. We present a patient who was initially diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) but who developed ALS-like symptoms during follow-up and died shortly thereafter. A 60-year-old subject with cognitive impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) analysis, structural imaging (computed tomography and magnetic resonance imaging) and functional imaging [11 C]-Pittsburgh compound B (PIB) positron emission tomography (PET), [18 F]-fluorodeoxyglucose (FDG) PET, and [11 C]-deuterium-L-deprenyl (DED) …PET. Neuropsychological testing showed episodic memory impairment. CSF P-tau and T-tau levels were elevated. CSF amyloid-β (Aβ)42 levels were initially normal but became pathological during follow-up. MCI was diagnosed. [18 F]-FDG PET showed hypometabolism in the left temporal and prefrontal cortices and [11 C]-PIB PET demonstrated amyloid plaque deposition in the prefrontal, posterior cingulate, and parietal cortices. [11 C]-DED PET showed high brain accumulation consistent with astrocytosis. The memory impairment progressed and AD was diagnosed. Motor impairments developed subsequently and, following additional neurological evaluation, ALS was diagnosed. The disease progressed rapidly and the patient died with pronounced motor symptoms three years after the initial cognitive assessment. Since relatives refused autopsy, postmortem analysis was not possible. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, [11C]-deprenyl, [11C]-PIB, cerebrospinal fluid biomarkers, [18F]-FDG, frontotemporal dementia, PET imaging, magnetic resonance imaging

DOI: 10.3233/JAD-141965

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 661-667, 2015

Authors: Saleem, Mahwesh | Herrmann, Nathan | Swardfager, Walter | Eisen, Rebecca | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Reports of elevated inflammatory markers in mild cognitive impairment (MCI) suggest that inflammation may be a potential early marker of the neurodegenerative cascade associated with Alzheimer’s disease (AD). The aim of this study was to quantitatively summarize the data on peripheral blood concentrations of inflammatory factors in patients with MCI compared to controls. Mean (±SD) blood concentrations of inflammatory factors for MCI and control subjects were extracted from original English language peer-reviewed studies for meta-analysis. Twenty-two studies measuring concentrations of cytokines, chemokines, acute phase reactant proteins, immunoglobulins, intercellular adhesion molecules, and fibrinogen were included. No significant differences in inflammatory factors …studied were found between subjects with MCI and healthy controls. These findings do not support the involvement of inflammatory markers at the MCI stage of cognitive decline although significant heterogeneity was observed in some comparisons. It remains to be established whether inflammation may predict increased rate of conversion to dementia. Show more

Keywords: Alzheimer’s disease, biological marker, cell adhesion molecules, chemokines, cytokines, fibrinogen, immunoglobulins, inflammation, meta-analysis, mild cognitive impairment

DOI: 10.3233/JAD-150042

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 669-679, 2015

Authors: Jensen-Dahm, Christina | Waldemar, Gunhild | Staehelin Jensen, Troels | Malmqvist, Lasse | Moeller, Michelle Mai | Andersen, Birgitte Bo | Høgh, Peter | Ballegaard, Martin

Article Type: Research Article

Abstract: Background: Autonomic function has received little attention in Alzheimer’s disease (AD). AD pathology has an impact on brain regions which are important for central autonomic control, but it is unclear if AD is associated with disturbance of autonomic function. Objective: To investigate autonomic function using standardized techniques in patients with AD and healthy age-matched controls. Method: Thirty-three patients with mild to moderate AD and 30 age- and gender-matched healthy controls, without symptoms of autonomic dysfunction, underwent standardized autonomic testing with deep breathing, Valsalva maneuver, head-up tilt, and isometric handgrip test. Brachial pressure …curve and electrocardiogram were recorded for off-line analysis of blood pressure and beat-to-beat heart rate (HR). Results: AD patients had impaired blood pressure responses to Vasalva maneuver (p  < 0.0001) and HR response to isometric contraction (p  = 0.0001). A modified composite autonomic scoring scale showed greater degree of autonomic impairment in patients compared to controls (patient: 2.1 ± 1.6; controls: 0.9 ± 1.1, p  = 0.001). HR response to deep breathing and Valsalva ratio were similar in the two groups. Conclusion: We identified autonomic impairment ranging from mild to severe in patients with mild to moderate AD, who did not report autonomic symptoms. Autonomic impairment was mainly related to impairment of sympathetic function and evident by impaired blood pressure response to the Vasalva maneuver. The clinical implications of this finding are that AD may be associated with autonomic disturbances, but patients with AD may rarely report symptoms of autonomic dysfunction. Future research should systematically evaluate symptoms of autonomic function and characterize risk factors associated with autonomic dysfunction. Show more

Keywords: Alzheimer’s disease, autonomic function, orthostatic hypotension, tilt test, Valsalva maneuver

DOI: 10.3233/JAD-150169

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 681-689, 2015

Authors: Nordberg, Agneta | Kadir, Ahmadul | Andreasen, Niels | Almkvist, Ove | Wall, Anders | , Kaj Blennow | Långström, Bengt | Zetterberg, Henrik

Article Type: Research Article

Abstract: New therapeutic strategies in Alzheimer’s disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble …amyloid-β protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Aβ 40 , sAβPPα, and sAβPPβ, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects. Show more

Keywords: Alzheimer’s disease, cerebral glucose metabolism, cerebrospinal fluid, phenserine, positron emission tomography

DOI: 10.3233/JAD-132474

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 691-704, 2015

Authors: Pike, Kerryn E. | Zeneli, Amina | Ong, Ben | Price, Sarah | Kinsella, Glynda J.

Article Type: Research Article

Abstract: Background: Cognitive interventions for neurodegenerative diseases, such as Alzheimer’s disease (AD), are best targeted at the preclinical stages, and subjective memory decline (SMD) without objective memory impairment on standard tests in older adults may represent a very early preclinical stage. Elaborated encoding effectively enhances memory performance for healthy older adults (HOAs), but has not been examined in people with SMD. Objective : To examine elaborated encoding in people with SMD, compared with HOAs. Methods : Participants were 32 HOAs and 22 people with SMD, defined using the Memory Complaint Questionnaire. Participants completed a verbal …paired associate learning (PAL) task with delayed recall under elaborated and non-elaborated encoding conditions, as well as the California Verbal Learning Test–II. Results : On the PAL learning trials, with age controlled, a significant interaction of group X encoding condition emerged, F (1, 51) =  6.47, MSE  = 6.54, p  = 0.014, η p 2  = 0.11. Simple main effects revealed no differences between groups in the non-elaborated condition, but in the elaborated condition HOAs recalled more pairs than SMD, although both groups benefited from elaboration. At delayed recall, HOA recalled more pairs than SMD, F (1, 51) =  4.59, p  = 0.037, η p 2  = 0.08, and both groups benefited from elaboration, F (1, 52) =  19.25, p  <  0.001, η p 2  = 0.27. Conclusion : People with SMD benefit from elaborated encoding, although not to the same extent as HOAs. This objective difference in complex learning and memory suggests neural changes in SMD that may represent preclinical AD. Elaborated encoding is a promising technique to help maintain memory and decrease anxiety in this at-risk population. Show more

Keywords: Memory strategies, paired associate learning, preclinical dementia, semantic elaboration, subjective memory complaints

DOI: 10.3233/JAD-150062

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 705-713, 2015

Authors: Salameh, Therese S. | Bullock, Kristin M. | Hujoel, Isabel A | Niehoff, Michael L. | Wolden-Hanson, Tami | Kim, Junghyun | Morley, John E. | Farr, Susan A. | Banks, William A.

Article Type: Research Article

Abstract: Intranasal insulin has shown efficacy in patients with Alzheimer’s disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. …In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain. Show more

Keywords: Alzheimer’s disease, cognition, insulin, intranasal administration

DOI: 10.3233/JAD-150307

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 715-728, 2015

Authors: Michaud, Tzeyu L. | Kane, Robert L. | McCarten, J. Riley | Gaugler, Joseph E. | Nyman, John A. | Kuntz, Karen M. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers can distinguish Alzheimer’s disease (AD) patients from normal controls; however, their interpretation and potential for use in patients with mild cognitive impairment (MCI) remains unclear. Objective: To examine whether biomarker levels allow for risk stratification among MCI patients who are at increased risk to develop AD, thus allowing for improved targeting of early interventions for those whose risk are higher. Methods: We analyzed data from the Alzheimer’s Disease Neuroimaging Initiative on MCI patients (n  = 195) to estimate their risk of developing AD for up to 6 years …on the basis of baseline CSF biomarkers. We used time-dependent receiver operating characteristic analysis to identify the best combination of biomarkers to discriminate those who converted to AD from those who remained stable. We used these data to construct a multi-biomarker score and estimated the risk of progression to AD for each quintile of the multi-biomarker score. Results: We found that Aβ 1-42 and P-tau181p were the best combination among CSF biomarkers to predict the overall risk of developing AD among MCI patients (area under the curve = 0.77). The hazard ratio of developing AD among MCI patients with high-risk (3rd–5th quintiles) biomarker levels was about 4 times greater than MCI patients with low-risk (1st quintile) levels (95% confidence interval, 1.93–7.26). Conclusion: Our study identifies MCI patients at increased risk of developing AD by applying a multi-biomarker score using CSF biomarker results. Our findings may be of value to MCI patients and their clinicians for planning purposes and early intervention as well as for future clinical trials. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, discriminatory ability, mild cognitive impairment, risk stratification

DOI: 10.3233/JAD-150066

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 729-740, 2015

Authors: Chiam, Justin Tao Wen | Lunnon, Katie | Voyle, Nicola | Proitsi, Petroula | Coppola, Giovanni | Geschwind, Daniel | Nelson, Sally | Johnston, Caroline | Soininen, Hilkka | Kłoszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Hodges, Angela | Lovestone, Simon | Newhouse, Stephen | Dobson, Richard James Butler | Kiddle, Steven John | Sattlecker, Martina

Article Type: Research Article

Abstract: Background: There is an urgent need to discover Alzheimer’s disease (AD) biomarkers that are both easily measured and reliable. Research into blood-based biomarkers for AD using transcriptomics and proteomics has been an attractive and promising area of research. However, to date researchers have not looked into the possibility of AD medication being a confounding factor in these studies. Objective: This study explored whether acetylcholinesterase inhibitors (AChEIs), the main class of AD medication, are a confounding factor in AD blood biomarker studies. Methods: The most promising blood transcriptomic and proteomic biomarkers from two …recent studies were analyzed to determine if they were differentially expressed between AD subjects on AChEIs and subjects that were not. Results: None of the gene or protein biomarkers analyzed were found to be significantly altered between subjects in either group. Conclusion: This study found no evidence that AChEIs are a confounding factor in these published AD blood biomarker studies. Further work is needed to confirm that this is also the case for other proposed biomarkers. Show more

Keywords: Alzheimer’s disease, blood, cholinesterase inhibitors, gene expression, microarray, protein, proteomics

DOI: 10.3233/JAD-150289

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 741-750, 2015

Authors: Caroppo, Paola | Habert, Marie-Odile | Durrleman, Stanley | Funkiewiez, Aurélie | Perlbarg, Vincent | Hahn, Valérie | Bertin, Hugo | Gaubert, Malo | Routier, Alexandre | Hannequin, Didier | Deramecourt, Vincent | Pasquier, Florence | Rivaud-Pechoux, Sophie | Vercelletto, Martine | Edouart, Geoffrey | Valabregue, Romain | Lejeune, Pascal | Didic, Mira | Corvol, Jean-Christophe | Benali, Habib | Lehericy, Stephane | Dubois, Bruno | Colliot, Olivier | Brice, Alexis | Le Ber, Isabelle | the Predict-PGRN study group

Article Type: Research Article

Abstract: The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+ ) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in …the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n  = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset. Show more

Keywords: Cortical thickness, dementia, frontotemporal dementia, frontotemporal lobar degeneration, GRN, longitudinal, preclinical study, presymptomatic, progranulin, PET

DOI: 10.3233/JAD-150270

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 751-759, 2015

Authors: Bradley-Whitman, Melissa A. | Abner, Erin | Lynn, Bert C. | Lovell, Mark A.

Article Type: Research Article

Abstract: Specific biomarkers in a readily accessible biological fluid, such as blood, could aid in the identification, characterization, validation, and routine monitoring of Alzheimer’s disease (AD) progression. In the current study, levels of the previously described novel cerebrospinal fluid aberrant protein complex composed of prostaglandin-D-synthase (PDS) and transthyretin (TTR) were quantified in plasma by a custom two-probe sandwich ELISA and compared to amyloid-β (Aβ)1-42 as a standard plasma biomarker of AD. Plasma was analyzed from 140 probable AD subjects, 135 subjects with mild cognitive impairment (MCI), 74 normal control subjects (NC) prior to MCI transition, 23 diseased control (DC) subjects …with either frontotemporal dementia or dementia with Lewy bodies, and 182 normal control (NC) subjects who did not progress to MCI or dementia. Levels of Aβ 1-42 were significantly elevated in NC subjects prior to MCI conversion but significantly reduced in probable AD subjects compared to NC subjects. Similarly, levels of the PDS-TTR complex were significantly reduced in both MCI and probable AD subjects compared to NC subjects. Furthermore, levels of Aβ 1-42 and the PDS-TTR complex were not significantly different in DC subjects compared to NC subjects. MMSE scores were weakly but significantly correlated with plasma levels of the PDS-TTR complex and Aβ 1-42 . Trail B scores were weakly but significantly correlated with plasma levels of Aβ 1-42 . Comparison of receiver operating curves shows the PDS-TTR complex is comparable to Aβ 1-42 in both MCI and probable AD subjects. Show more

Keywords: Alzheimer’s disease, biomarker, PDS-TTR complex, plasma

DOI: 10.3233/JAD-150183

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 761-771, 2015

Authors: Valotassiou, Varvara | Papatriantafyllou, John | Sifakis, Nikolaos | Tzavara, Chara | Tsougos, Ioannis | Psimadas, Dimitrios | Fezoulidis, Ioannis | Kapsalaki, Eftychia | Hadjigeorgiou, George | Georgoulias, Panagiotis

Article Type: Research Article

Abstract: Early diagnosis of Alzheimer’s disease (AD) based on clinical criteria alone may be problematic, while current and future treatments should be administered earlier in order to be more effective. Thus, various disease biomarkers could be used for early detection of AD. We evaluated brain perfusion with 99m Tc-HMPAO single photon emission computed tomography (SPECT) and Brodmann areas (BAs) mapping in mild AD using an automated software (NeuroGamTM ) for the semi-quantitative evaluation of perfusion in BAs and the comparison with the software’s normal database. We studied 34 consecutive patients with mild AD: 9 men, 25 women, mean age 70.9±8.1 years, …mean Mini-Mental State Examination 22.6±2.5. BAs 25L, 25R, 38L, 38R, 28L, 28R, 36L, and 36R had the lower mean perfusion values, while BAs 31L, 31R, 19R, 18L, 18R, 17L, and 17R had the higher mean values. Compared with healthy subjects of the same age, perfusion values in BAs 25L, 25R, 28R, 28L, 36L, and 36R had the greatest deviations from the healthy sample, while the lowest deviations were found in BAs 32L, 32R, 19R, 24L, 17L, 17R, 18L, and 18R. A percentage of ≥94% of patients had perfusion values more than -2SDs below the mean of healthy subjects in BAs 38R, 38L, 36L, 36R, 23L, 23R, 22L, 44L, 28L, 28R, 25L, and 25R. The corresponding proportion was less than 38% for BAs 11L, 19R, 32L, 32R, 18L, 18R, 24L, and 17R. In conclusion, brain SPECT studies with automated perfusion mapping could be useful as an ancillary tool in daily practice, revealing perfusion impairments in early AD. Show more

Keywords: Brain perfusion imaging, Brodmann areas, mild Alzheimer’s disease, SPECT

DOI: 10.3233/JAD-150068

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 773-785, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150461

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 787-791, 2015