Journal of Alzheimer's Disease - Volume 53, issue 2

Authors: Akoudad, Saloua | Gurol, M. Edip | Fotiadis, Panagiotis | Koudstaal, Peter J. | Hofman, Albert | Ikram, M. Arfan | Greenberg, Steven M. | Vernooij, Meike W.

Article Type: Research Article

Abstract: Background: In patients with symptomatic cerebral amyloid angiopathy (CAA), cerebrovascular reactivity to visual stimuli is reduced. Lobar microbleeds are a diagnostic hallmark of CAA, but are also highly prevalent in asymptomatic individuals. Recent data suggest that the latter group might have CAA. Objective: We investigated whether cerebrovascular reactivity is impaired in asymptomatic individuals with lobar microbleeds. Methods: From the population-based Rotterdam Study, we invited 35 participants with lobar microbleeds and 15 age-matched controls (all≥55 years) for functional MRI (fMRI) as part of the Early Detection of Angiopathy Network (EDAN) Study. Cerebrovascular reactivity parameters (i.e., amplitude …and time to peak responses) were assessed in response to visual stimulation using fMRI. Student’s t -test and linear regression were used to compare fMRI parameters in participants with and without microbleeds. Results: Amplitude and time to peak responses did not differ between participants with and without microbleeds (respectively, p  = 0.179 and p  = 0.555). Participants with microbleeds had slightly higher amplitude responses compared to participants without microbleeds. After excluding individuals with mixed microbleeds (i.e., lobar and non-lobar microbleeds), we found no significant difference in cerebrovascular reactivity for persons with a single microbleed or multiple microbleeds compared to persons without microbleeds. Conclusions: In the general population, lobar microbleeds may not relate to impaired cerebrovascular reactivity. In asymptomatic individuals, lobar microbleeds may either reflect less advanced CAA pathology insufficient to cause functional vascular impairment, or reflect vascular pathology other than CAA. Show more

Keywords: Cerebral microbleeds, cerebrovascular reactivity, epidemiology, MRI

DOI: 10.3233/JAD-151130

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 497-503, 2016

Authors: Di Carlo, Antonio | Baldereschi, Marzia | Lamassa, Maria | Bovis, Francesca | Inzitari, Marco | Solfrizzi, Vincenzo | Panza, Francesco | Galluzzo, Lucia | Scafato, Emanuele | Inzitari, Domenico | for the Italian Longitudinal Study on Aging Working Group

Article Type: Research Article

Abstract: Background: Preclinical cognitive changes may predict an increased risk of dementia, allowing selection of subgroups as possible targets for preventive or therapeutic interventions. Objective: To evaluate the predictive effect of daily functioning and motor performance (MP) on the progression to dementia in normal cognition, cognitive impairment, no dementia (CIND), and mild cognitive impairment (MCI). Methods: The Italian Longitudinal Study on Aging is a large population-based survey on age-related diseases of the cardiovascular and nervous systems. After the baseline assessment, to detect prevalent cases of cognitive impairment and dementia, participants were re-examined at 4-year and 8-year …follow-ups. Functional independence was evaluated using the Index of Activities of Daily Living (ADL) and the Instrumental Activities of Daily Living (IADL) Scale. A six-test battery was used to assess MP. Results: Overall, 2,386 individuals were included, for a total of 16,545 person-years. Eight-year incidence of dementia (per 1,000 person-years) was 12.69 in total sample, 9.86 in subjects with normal cognition at baseline, 22.99 in CIND, and 21.43 in MCI. Progression to dementia was significantly higher with increasing baseline ADL and IADL impairment, and with a worse MP. In Cox regression analyses controlled for demographics and major age-related conditions, increased IADL impairment was the stronger predictor of progression to dementia (p  < 0.001), with HR ranging from 2.16 (95% CI, 0.82–5.70) to 9.57 (95% CI, 3.40–26.91) in subjects with MCI at baseline. Conclusions: Inclusion of IADL in the MCI construct significantly improves the prediction of dementia. Individuation of different transition rates is required to plan cost-effective interventions. Show more

Keywords: Dementia, instrumental activities of daily living, longitudinal studies, mild cognitive impairment, motor performance

DOI: 10.3233/JAD-160087

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 505-515, 2016

Authors: Yogev-Seligmann, Galit | Oren, Noga | Ash, Elissa L. | Hendler, Talma | Giladi, Nir | Lerner, Yulia

Article Type: Research Article

Abstract: The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information …processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI. Show more

Keywords: Aging, functional MRI, mild cognitive impairment, processing time scales, real-life stimulation

DOI: 10.3233/JAD-150845

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 517-533, 2016

Authors: Russu, Alberto | Samtani, Mahesh N. | Xu, Steven | Adedokun, Omoniyi J. | Lu, Ming | Ito, Kaori | Corrigan, Brian | Raje, Sangeeta | Liu, Enchi | Brashear, H. Robert | Styren, Scot | Hu, Chuanpu

Article Type: Research Article

Abstract: Background: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer’s disease (AD) patients. Objective: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Methods: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11 C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary …shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE* E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Results: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE* E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Conclusions: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated. Show more

Keywords: Amyloid PET, APOE*E4, bapineuzumab, brain volume, cerebrospinal fluid, disease severity, exposure-response modeling, p-tau

DOI: 10.3233/JAD-151065

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 535-546, 2016

Authors: Kantarci, Kejal | Lowe, Val J. | Lesnick, Timothy G. | Tosakulwong, Nirubol | Bailey, Kent R. | Fields, Julie A. | Shuster, Lynne T. | Zuk, Samantha M. | Senjem, Matthew L. | Mielke, Michelle M. | Gleason, Carey | Jack Jr, Clifford R. | Rocca, Walter A. | Miller, Virginia M.

Article Type: Research Article

Abstract: Background: It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer’s disease (AD). Objective: To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. Methods: Participants within 5–36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11 C Pittsburgh compound …B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. Results: Women (age = 52–65) randomized to transdermal 17β-estradiol (n  = 21) had lower PiB SUVR compared to placebo (n  = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11–0.83)]. In the APOE ɛ 4 carriers, transdermal 17β-estradiol treated women (n  = 10) had lower PiB SUVR compared to either placebo (n  = 5) [odds ratio (95% CI) = 0.04(0.004–0.44)], or the oral CEE treated group (n  = 3) [odds ratio (95% CI) = 0.01(0.0006–0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOE ɛ 4 non-carriers. Conclusion: In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOE ɛ 4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive function, estrogen, hormone therapy, menopause, PET, prevention

DOI: 10.3233/JAD-160258

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 547-556, 2016

Authors: Kasza, Ágnes | Hunya, Ákos | Frank, Zsuzsa | Fülöp, Ferenc | Török, Zsolt | Balogh, Gábor | Sántha, Miklós | Bálind, Árpád | Bernáth, Sándor | Blundell, Katie L.I.M. | Prodromou, Chrisostomos | Horváth, Ibolya | Zeiler, Hans-Joachim | Hooper, Philip L. | Vigh, László | Penke, Botond

Article Type: Research Article

Abstract: Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer’s disease (AD) is thought to be caused by amyloid-β peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their …ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD. Show more

Keywords: Alzheimer’s disease, dihydropyridines, heat-shock proteins, Hsp co-induction, neuroprotection

DOI: 10.3233/JAD-150860

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 557-571, 2016

Authors: Wennberg, Alexandra M.V. | Gustafson, Deborah | Hagen, Clinton E. | Roberts, Rosebud O. | Knopman, David | Jack Jr, Clifford | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: Adiponectin, a protein involved in inflammatory pathways, may impact the development and progression of Alzheimer’s disease (AD). Adiponectin levels have been associated with mild cognitive impairment (MCI) and AD; however, its association with Alzheimer-associated neuroimaging and cognitive outcomes is unknown. Objective: Determine the cross-sectional association between plasma adiponectin and neuroimaging and cognitive outcomes in an older population-based sample. Methods: Multivariable adjusted regression models were used to investigate the association between plasma adiponectin and hippocampal volume (HVa), PiB-PET, FDG PET, cortical thickness, MCI diagnosis, and neuropsychological test performance. Analyses included 535 non-demented participants aged 70 …and older enrolled in the Mayo Clinic Study of Aging. Results: Women had higher adiponectin than men (12,631 ng/mL versus 8,908 ng/mL, p  < 0.001). Among women, higher adiponectin was associated with smaller HVa (B = –0.595; 95% CI –1.19, –0.005), poorer performance in language (B = –0.676; 95% CI –1.23, –0.121), and global cognition (B = –0.459; 95% CI –0.915, –0.002), and greater odds of a MCI diagnosis (OR = 6.23; 95% CI 1.20, 32.43). In analyses stratified by sex and elevated amyloid (PiB-PET SUVR >1.4), among women with elevated amyloid, higher adiponectin was associated with smaller HVa (B = –0.723; 95% CI –1.43, –0.014), poorer performance in memory (B = –1.02; 95% CI –1.73, –0.312), language (B = –0.896; 95% CI –1.58, –0.212), global cognition (B = –0.650; 95% CI –1.18, –0.116), and greater odds of MCI (OR = 19.34; 95% CI 2.72, 137.34). Conclusion: Higher plasma adiponectin was associated with neuroimaging and cognitive outcomes among women. Longitudinal analyses are necessary to determine whether higher adiponectin predicts neurodegeneration and cognitive decline. Show more

Keywords: Adiponectin, amyloid-PET, cognition, FDG-PET, hippocampal volume, mild cognitive impairment

DOI: 10.3233/JAD-151201

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 573-581, 2016

Authors: Ivachtchenko, Alexandre V. | Lavrovsky, Yan | Okun, Ilya

Article Type: Research Article

Abstract: Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a …very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6 , 5-HT2A , and 5HT-2C receptors (Ki = 1.2–2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α 2A, α 2B, and α 2C (Ki = 0.41–3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer’s disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis. Show more

Keywords: Adrenergic alpha-2 antagonists, Alzheimer’s disease, anxiety, central nervous system agents, histamine H1 receptor antagonists, 5-HT7 receptor antagonists, memory, Parkinson’s disease, serotonin receptor antagonists

DOI: 10.3233/JAD-151146

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 583-620, 2016

Authors: Tajeddinn, Walid | Fereshtehnejad, Seyed-Mohammad | Seed Ahmed, Mohammed | Yoshitake, Takashi | Kehr, Jan | Shahnaz, Tasmin | Milovanovic, Micha | Behbahani, Homira | Höglund, Kina | Winblad, Bengt | Cedazo-Minguez, Angel | Jelic, Vesna | Järemo, Petter | Aarsland, Dag

Article Type: Research Article

Abstract: Introduction: Serotonin (5-HT) is involved in the pathology of Alzheimer’s disease (AD). Objective: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-β 1-42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms. Methods: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Results: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients …both after normalization against total protein (p  = 0.008) or platelet count (p  = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p  = 0.026) and tau/Aβ42 ratio (p  = 0.001), compared to those with high 5-HT levels. Conclusion: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, platelet, serotonin

DOI: 10.3233/JAD-160022

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 621-630, 2016

Authors: Lovas, Joel | Fereshtehnejad, Seyed-Mohammad | Cermakova, Pavla | Lundberg, Catarina | Johansson, Björn | Johansson, Kurt | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: Driving constitutes a very important aspect of daily life and is dependent on cognitive functions such as attention, visuo-spatial skills and memory, which are often compromised in dementia. Therefore, the driving fitness of patients with dementia needs to be addressed by physicians and those that are deemed unfit should not be allowed to continue driving. Objective: We aimed at investigating to what extent physicians assess driving fitness in dementia patients and determinant factors for revoking of their licenses. Methods: This study includes 15113 patients with newly diagnosed dementia and driver’s license registered in the …Swedish Dementia Registry (SveDem). The main outcomes were reporting to the licensing authority and making an agreement about driving eligibility with the patients. Results: Physicians had not taken any action in 16% of dementia patients, whereas 9% were reported to the authority to have their licenses revoked. Males (OR = 3.04), those with an MMSE score between 20–24 (OR = 1.35) and 10–19 (OR = 1.50), patients with frontotemporal (OR = 3.09) and vascular dementia (OR = 1.26) were more likely to be reported to the authority. Conclusion: For the majority of patients with dementia, driving fitness was assessed. Nevertheless, physicians did not address the issue in a sizeable proportion of dementia patients. Type of dementia, cognitive status, age, sex and burden of comorbidities are independent factors associated with the assessment of driving fitness in patients with dementia. Increased knowledge on how these factors relate to road safety may pave the way for more specific guidelines addressing the issue of driving in patients with dementia. Show more

Keywords: Dementia, Alzheimer’s disease, frontotemporal dementia, driving license, cognitive status, agreement

DOI: 10.3233/JAD-160254

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 631-638, 2016