Journal of Alzheimer's Disease - Volume 58, issue 1

Authors: Adrait, Arnaud | Perrot, Xavier | Nguyen, Marie-France | Gueugnon, Marine | Petitot, Charles | Collet, Lionel | Roux, Adeline | Bonnefoy, Marc | on behalf of the ADPHA study group

Article Type: Research Article

Abstract: Background: It has been suggested that age-related hearing loss (ARHL) and Alzheimer’s disease (AD) are commonly associated. Objective: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL). Methods: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the …placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer’s disease related quality of life, and simplified Duke scales. Results: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores. Conclusion: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years. Show more

Keywords: Age-related hearing loss, Alzheimer’s disease, behavioral symptoms, hearing aids

DOI: 10.3233/JAD-160792

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 109-121, 2017

Authors: Nguyen, Marie-France | Bonnefoy, Marc | Adrait, Arnaud | Gueugnon, Marine | Petitot, Charles | Collet, Lionel | Roux, Adeline | Perrot, Xavier | on behalf of the ADPHA study group

Article Type: Research Article

Abstract: Background/Objective: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer’s disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization. Methods: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the …change from baseline of the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success. Results: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p  = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p  = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed. Conclusion: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL. Show more

Keywords: Alzheimer’s disease, hearing aids, hearing loss, non-pharmacological treatment, randomized controlledclinical trial

DOI: 10.3233/JAD-160793

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 123-137, 2017

Authors: Garcia, Angeles | Mathur, Shubha | Kalaw, Maria Carmela | McAvoy, Elizabeth | Anderson, James | Luedke, Angela | Itorralba, Justine | Mai, Sabine

Article Type: Research Article

Abstract: This study validates and expands on our previous work that assessed three-dimensional (3D) nuclear telomere profiling in buccal cells of Alzheimer’s disease (AD) patients and non-AD controls (Mathur et al., J Alzheimers Dis 39, 35–48, 2014). While the previous study used age- and gender-matched caregiver controls, the current study consented a new cohort of 44 age- and gender-matched healthy non-caregiver controls and 44 AD study participants. 3D telomeric profiles of buccal cells of AD patients and their non-AD controls were examined with participant information blinded to the analysis. In agreement with our previous study, we demonstrate that 3D telomeric …profiles allow for the distinction between AD and non-AD individuals. This validation cohort provides an indication that the total number of 3D telomeric signals and their telomere lengths may be a suitable biomarker to differentiate between AD and non-AD and between mild, moderate, and severe AD. Further studies with larger sample sizes are required to move this technology further toward the clinic. Show more

Keywords: Alzheimer’s disease, buccal cells, telomeres

DOI: 10.3233/JAD-161169

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 139-145, 2017

Authors: Reddy, P. Hemachandra | Manczak, Maria | Yin, XiangLing

Article Type: Research Article

Abstract: The purpose our study was to determine the protective effects of mitochondria division inhibitor 1 (Mdivi1) in Alzheimer’s disease (AD). Mdivi1 is hypothesized to reduce excessive fragmentation of mitochondria and mitochondrial dysfunction in AD neurons. Very little is known about whether Mdivi1 can confer protective effects in AD. In the present study, we sought to determine the protective effects of Mdivi1 against amyloid-β (Aβ)- and mitochondrial fission protein, dynamin-related protein 1 (Drp1)-induced excessive fragmentation of mitochondria in AD progression. We also studied preventive (Mdivi1+Aβ42 ) and intervention (Aβ42 +Mdivi1) effects against Aβ42 in N2a cells. Using real-time RT-PCR and …immunoblotting analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis, and synaptic genes. We also assessed mitochondrial function by measuring H2 O2 , lipid peroxidation, cytochrome oxidase activity, and mitochondrial ATP. MTT assays were used to assess the cell viability. Aβ42 was found to impair mitochondrial dynamics, lower mitochondrial biogenesis, lower synaptic activity, and lower mitochondrial function. On the contrary, Mdivi1 enhanced mitochondrial fusion activity, lowered fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in Mdivi1-treated cells. Interestingly, Mdivi1 pre- and post-treated cells treated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability, mitochondrial dynamics, mitochondrial biogenesis, and synaptic activity. The protective effects of Mdivi1 were stronger in N2a+Aβ42 pre-treated with Mdivi1, than in N2a+Aβ42 cells than Mdivi1 post-treated cells, indicating that Mdivi1 works better in prevention than treatment in AD like neurons. Show more

Keywords: Amyloid-β, dynamin-related protein 1, mitochondrial division inhibitor 1, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial fission, synaptic pathology

DOI: 10.3233/JAD-170051

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 147-162, 2017

Authors: Van Langenhove, Tim | Piguet, Olivier | Burrell, James R. | Leyton, Cristian | Foxe, David | Abela, Melissa | Bartley, Lauren | Kim, Woojin S. | Jary, Eve | Huang, Yue | Dobson-Stone, Carol | Kwok, John B. | Halliday, Glenda M. | Hodges, John R.

Article Type: Research Article

Abstract: Background: A proportion of patients with frontotemporal dementia (FTD) also develop amyotrophic lateral sclerosis (ALS). Objective: We aimed to establish the risk of developing ALS in patients presenting with FTD and to identify the relevant clinical variables associated with progression from FTD to FTD-ALS. Methods: Of 218 consecutive patients with FTD, 10.1% had a dual FTD-ALS diagnosis at presentation. The remaining 152 FTD patients with follow-up of at least 12 months were included in the present study. We calculated the rate of progression to FTD-ALS and compared the baseline characteristics of FTD patients who developed …ALS to those who did not develop ALS. Results: Five percent of FTD patients developed ALS. The incidence rate of ALS was 6.7/100 patient-years in patients with FTD symptoms since 1 year, which declined with duration of FTD symptoms. No FTD patients developed ALS after 5 years. Five out of 8 FTD patients who developed ALS had presented with a mixed behavioral variant FTD and progressive non-fluent aphasia (bvFTD+PNFA) phenotype, 2 with bvFTD, and 1 with PNFA. Progression to FTD-ALS was significantly more frequent in patients with bvFTD+PNFA compared to those without this phenotype (p  < 0.0001, OR 38.3, 95% CI: 7.3 to 199.2), and in FTD patients who carried the C9orf72 repeat expansion compared to those without the repeat expansion (p  = 0.02, OR 8.0, 95% CI: 1.7 to 38.6). Conclusions: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms. Show more

Keywords: Amyotrophic lateral sclerosis, disease progression, frontotemporal dementia, incidence, primary progressive aphasia, prognosis

DOI: 10.3233/JAD-161272

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 163-170, 2017

Authors: Serra, Laura | Bruschini, Michela | Di Domenico, Carlotta | Gabrielli, Giulia Bechi | Marra, Camillo | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: Changes in the residual memory variance are considered as a dynamic aspect of cognitive reserve (d-CR). We aimed to investigate for the first time the neural substrate associated with changes in the residual memory variance overtime in patients with amnestic mild cognitive impairment (aMCI). Thirty-four aMCI patients followed-up for 36 months and 48 healthy elderly individuals (HE) were recruited. All participants underwent 3T MRI, collecting T1-weighted images for voxel-based morphometry (VBM). They underwent an extensive neuropsychological battery, including six episodic memory tests. In patients and controls, factor analyses were used on the episodic memory scores to obtain a composite memory …score (C-MS). Partial Least Square analyses were used to decompose the variance of C-MS in latent variables (LT scores), accounting for demographic variables and for the general cognitive efficiency level; linear regressions were applied on LT scores, striping off any contribution of general cognitive abilities, to obtain the residual value of memory variance, considered as an index of d-CR. LT scores and d-CR were used in discriminant analysis, in patients only. Finally, LT scores and d-CR were used as variable of interest in VBM analysis. The d-CR score was not able to correctly classify patients. In both aMCI patients and HE, LT1st and d-CR scores showed correlations with grey matter volumes in common and in specific brain areas. Using CR measures limited to assess memory function is likely less sensitive to detect the cognitive decline and predict the evolution of Alzheimer’s disease. In conclusion, d-CR needs a measure of general cognition to identify conversion to Alzheimer’s disease efficiently. Show more

Keywords: Dynamic cognitive reserve, memory, mild cognitive impairment, voxel-based morphometry

DOI: 10.3233/JAD-170086

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 171-184, 2017

Authors: García, Beatriz | Martín, Carla | García-Suárez, Olivia | Muñiz-Alonso, Bárbara | Ordiales, Helena | Fernández-Menéndez, Santiago | Santos-Juanes, Jorge | Lorente-Gea, Laura | Castañón, Sonia | Vicente-Etxenausia, Ikerne | Piña Batista, Kelvin Manuel | Ruiz-Díaz, Irune | Caballero-Martínez, María Cristina | Merayo-Lloves, Jesús | Guerra-Merino, Isabel | Quirós, Luis M. | Fernández-Vega, Iván

Article Type: Research Article

Abstract: Background: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer’s disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. Objective: To analyze HPSE and HPSE2 expressions at different stages of AD. Methods: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. Results: Both …proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. Conclusion: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β, glycosaminoglycan, heparan sulfate, heparanase

DOI: 10.3233/JAD-161298

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 185-192, 2017

Authors: Gardener, Samantha L. | Rainey-Smith, Stephanie R. | Sohrabi, Hamid R. | Weinborn, Michael | Verdile, Giuseppe | Fernando, W.M.A.D. Binosha | Lim, Yen Ying | Harrington, Karra | Burnham, Samantha | Taddei, Kevin | Masters, Colin L. | Macaulay, Stuart L. | Rowe, Christopher C. | Ames, David | Maruff, Paul | Martins, Ralph N. | for the AIBL Research Group

Article Type: Research Article

Abstract: Evidence suggests that a diet low in carbohydrates can impact on cognitive performance among those with Alzheimer’s disease (AD). However, there is a lack of data assessing this relationship among cognitively normal (CN) older adults at increased future risk of developing AD due to carriage of the apolipoprotein E (APOE ) ɛ 4 allele. We assessed the cross-sectional association between carbohydrate intake, cognitive performance, and cerebral amyloid-β (Aβ) load in CN older adults, genotyped for APOE ɛ 4 allele carrier status. Greater carbohydrate intake was associated with poorer performance in verbal memory in APOE ɛ 4 allele non-carriers, …and poorer performance in attention in APOE ɛ 4 allele carriers. There were no associations between carbohydrate intake and cerebral Aβ load. These results provide support to the idea that decreasing carbohydrate intake may offer neurocognitive benefits, with specific cognitive domains affected in an APOE genotype-dependent manner. These findings warrant further investigation utilizing a longitudinal study design. Show more

Keywords: Amyloid load, apolipoprotein E, attention, carbohydrates, cognition, PiB PET, verbal memory

DOI: 10.3233/JAD-161158

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 193-201, 2017

Authors: Kehoe, Patrick Gavin | Hibbs, Elliott | Palmer, Laura E. | Miners, J. Scott

Article Type: Research Article

Abstract: Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer’s disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and …metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n  = 90) and age-matched non-demented controls (n  = 59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, aminopeptidase-A, aminopeptidase-P, angiotensin-II, angiotensin-III, renin-angiotensin system

DOI: 10.3233/JAD-161265

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 203-214, 2017

Authors: Baazaoui, Narjes | Iqbal, Khalid

Article Type: Research Article

Abstract: To date, neither any effective treatment nor prevention of Alzheimer’s disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD …mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, mortality rate, neurodegeneration, secondary prevention, tau, 3xTg-AD mice

DOI: 10.3233/JAD-170075

Citation: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 215-230, 2017