Journal of Alzheimer's Disease - Volume 63, issue 3

Authors: Lee, Wha Jin | Han, Cheol E. | Aganj, Iman | Seo, Sang Won | Seong, Joon-Kyung

Article Type: Research Article

Abstract: Recent advances in neuroimaging technology have shown that rich club organization in human brain networks plays a crucial role in global communication and cognitive functionality. In this study, we investigated rich club organization within white matter structural brain networks in two common types of dementia, Alzheimer’s disease (AD) and subcortical vascular dementia (SVaD). We recruited 30 AD patients ([11C] Pittsburgh compound-B (PiB) PET positive), 39 SVaD patients (PiB negative), and 72 age-, gender-, and education-matched cognitively normal (CN) subjects. Rich club organization was significantly disrupted in both dementia patient groups, which exhibited higher rich club coefficients than the CN group. …Rich club organization in the patient groups was primarily disrupted over the left frontal and left middle temporal areas when compared to the CN group. The number of rich club nodes was significantly reduced in the dementia groups, which was more severe in SVaD (p  = 0.0107, permutation-based t -test). Although rich club organization was disrupted both in the patient groups, its disruption pattern is different between them. The rich-club connections normalized by degree-and-strength preserved random networks were significantly increased in the dementia groups with SVaD more severely, and feeder connections were reduced more significantly than in AD. Furthermore, SVaD patients exhibited more sporadic disruption in white matter connectivity than AD patients, with local connections showing a more significant degree of deterioration. Combined with the distinct disruption in rich club nodes, these findings may imply a differing role for rich club organization in AD and SVaD, due to different pathological mechanisms. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, diffusion tractography, subcortical vascular dementia

DOI: 10.3233/JAD-180027

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 977-987, 2018

Authors: Akiba, Chihiro | Nakajima, Madoka | Miyajima, Masakazu | Ogino, Ikuko | Motoi, Yumiko | Kawamura, Kaito | Adachi, Satoshi | Kondo, Akihide | Sugano, Hidenori | Tokuda, Takahiko | Irie, Kazuhiro | Arai, Hajime

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1– 42 (Aβ42 ) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity. Objective: This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH. Methods: The first cohort consisted of patients with AD (n  = 17) and iNPH (n  = 17), and cognitively normal individuals (CN, n  = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups …according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer/Aβ42×100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42 , and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively. Results: In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement. Conclusions: Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group. Show more

Keywords: Alzheimer’s disease, amyloid-β 1-42, amyloid clearance, cerebrospinal-fluid shunting, cognitive function, idiopathic normal pressure hydrocephalus, oligomer, phosphorylated tau, toxic conformer

DOI: 10.3233/JAD-180059

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 989-1002, 2018

Authors: Alvarez, X. Anton | Alvarez, Irene | Aleixandre, Manuel | Linares, Carlos | Muresanu, Dafin | Winter, Stefan | Moessler, Herbert

Article Type: Research Article

Abstract: Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer’s disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p  < 0.05) and showed a progressive increase with clinical severity in the whole study population (p  < 0.01). Among AD patients, severity-related VEGF elevations …were significant in ApoE4 carriers (p  < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p  < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy. Show more

Keywords: Alzheimer’s disease, apolipoprotein E epsilon-4 allele, clinical severity, cognition, serum, vascular endothelial growth factor

DOI: 10.3233/JAD-160477

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1003-1013, 2018

Authors: Baschi, Roberta | Nicoletti, Alessandra | Restivo, Vincenzo | Recca, Deborah | Zappia, Mario | Monastero, Roberto

Article Type: Research Article

Abstract: Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer’s disease. Dementia/MCI have been described with a high prevalence in Parkinson’s disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson’s disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological …evaluation and PD-MCI was diagnosed according to Litvan’s criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR = 3.93, 95% CI = 1.18–13.03), while PD-SMC-MCI related to motor progression (OR = 5.29, 95% CI = 1.12–24.86), and instrumental disability (OR = 6.98, 95% CI = 2.08–23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD-SMC-MCI would depict motor progression and disability. Show more

Keywords: Anxiety, cognitive impairment, disability, motor impairment, Parkinson’s disease, subjective complaints

DOI: 10.3233/JAD-171172

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1015-1024, 2018

Authors: Lage, Carmen | Suarez, Andrea Gonzalez | Pozueta, Ana | Riancho, Javier | Kazimierczak, Martha | Bravo, Maria | Jimenez Bonilla, Julio | de Arcocha Torres, Marıa | Quirce, Remedios | Banzo, Ignacio | Vazquez-Higuera, Jose Luis | Rabinovici, Gil D. | Rodriguez-Rodriguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer’s disease treatment …plan. The association between PiB/FDG results and changes in management was evaluated using χ 2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p  < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p  = 0.0002). Changes in treatment were associated with concordant PiB (p  = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, FDG, PET, PiB

DOI: 10.3233/JAD-170985

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1025-1033, 2018

Authors: Hong, Yun Jeong | Choi, Seong Hye | Jeong, Jee Hyang | Park, Kyung Won | Na, Hae Ri

Article Type: Research Article

Abstract: Background/Objective: There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer’s disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment. Methods: In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD-continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks …in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores. Results: The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5-point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group. Conclusion: Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS). Show more

Keywords: Alzheimer’s disease, discontinuation, donepezil, memantine

DOI: 10.3233/JAD-180159

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1035-1044, 2018

Authors: Horváth, András | Szűcs, Anna | Hidasi, Zoltán | Csukly, Gábor | Barcs, Gábor | Kamondi, Anita

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. Objective: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. Methods: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using …logistic regression analysis. Results: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). Conclusion: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage. Show more

Keywords: Alzheimer’s disease, epilepsy, long-term EEG, seizures, semiology, risk factors

DOI: 10.3233/JAD-170925

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1045-1054, 2018

Authors: Grill, Joshua D. | Hoang, Dan | Gillen, Daniel L. | Cox, Chelsea G. | Gombosev, Adrijana | Klein, Kirsten | O’Leary, Steve | Witbracht, Megan | Pierce, Aimee

Article Type: Research Article

Abstract: Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer’s disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical …data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries. Show more

Keywords: Clinical trial, preclinical Alzheimer’s disease, recruitment, registries

DOI: 10.3233/JAD-180069

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1055-1063, 2018

Authors: Dominguez, Jacqueline | Fe de Guzman, Ma. | Reandelar Jr, Macario | Thi Phung, Thien Kieu

Article Type: Research Article

Abstract: Background: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines. Objectives: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population. Methods: 1460 participants 60 years and older were randomly selected from the Marikina City’s senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer’s Disease 8, …and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer’s Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression. Results: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6% (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7% VaD, and 2.7% other dementias. In this population, 82.0% of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD. Conclusion: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines. Show more

Keywords: Dementia, Philippines, prevalence, risk factors

DOI: 10.3233/JAD-180095

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1065-1073, 2018

Authors: Tyumentsev, Mikhail A. | Stefanova, Natalia A. | Muraleva, Natalia A. | Rumyantseva, Yulia V. | Kiseleva, Elena | Vavilin, Valentin A. | Kolosova, Nataliya G.

Article Type: Research Article

Abstract: Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer’s disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4–5 months), and at the well-pronounced stages (18–24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts …of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans. Show more

Keywords: Alzheimer’s disease, mitochondrial dysfunction, senescence-accelerated OXYS rats

DOI: 10.3233/JAD-180065

Citation: Journal of Alzheimer's Disease, vol. 63, no. 3, pp. 1075-1088, 2018