Journal of Alzheimer's Disease - Volume 56, issue 3

Authors: Ferrari, Laura | Huang, Su-Chun | Magnani, Giuseppe | Ambrosi, Alessandro | Comi, Giancarlo | Leocani, Letizia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are leading causes of cognitive decline. Optical coherence tomography (OCT) allows the measurement of thickness of retinal neuroaxonal layers. While in AD and mild cognitive impairment (MCI), retinal nerve fiber layer (RNFL) thinning is frequently reported, less information is available on ganglion cell layer-inner plexiform layer (GCL-IPL). Data on FTD are lacking. Objective: To obtain cross-sectional information on RNFL and GCL-IPL thickness among MCI, AD, FTD, and healthy controls (HC), and their correlations with dementia severity. Methods: Peripapillary OCT scans were obtained in 27 MCI, 39 AD, …17 FTD, 49 HC using high-definition Heidelberg Spectral-domain OCT, with RNFL and GCL-IPL thickness measurement. Statistical analysis tested group effects and correlation with gender, disease duration and severity (Mini-Mental State Examination, MMSE). Results: RNFL showed a significant group effect [F(4,132) = 3.786, p  = 0.006], being reduced versus controls in MCI (p  = 0.033), moderate AD (p  = 0.025), and FTD (p  < 0.001), and versus mild AD in FTD (p  = 0.042). GCL-IPL showed a significant group effect as well [F(4,121) = 5.104, p  < 0.001], with reduction in moderate AD versus HC (p  < 0.001), MCI (p  = 0.037), and mild AD (p  = 0.009); in FTD versus HC (p  = 0.002) and mild AD (p  = 0.038). In AD, GCL-IPL correlated with MMSE (r  = 0.487, p  = 0.003), without significant effects of age, gender, or disease duration. Conclusion: Retinal neuroaxonal thinning occurs in MCI/AD consistently with previous reports, as well as in FTD. Correlation with disease severity in AD suggests that retinal and brain neurodegeneration may occur in parallel to some extent, and prompts larger studies aimed at providing surrogate endpoints for clinical trials in AD. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, ganglion cell layer, optical coherence tomography, retinal nerve fiber layer

DOI: 10.3233/JAD-160886

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1101-1107, 2017

Authors: Kaizik, Cassandra | Caga, Jashelle | Camino, Julieta | O’Connor, Claire M. | McKinnon, Colleen | Oyebode, Jan R. | Piguet, Olivier | Hodges, John R. | Mioshi, Eneida

Article Type: Research Article

Abstract: The objectives of this observational study were to (1) compare spousal and child caregiver burden; (2) compare co-resident and live-out child caregiver burden; and (3) investigate factors influencing spousal and child caregiver burden. Data was collected from 90 caregivers of people with frontotemporal degeneration (FTD) recruited from the Frontotemporal Dementia Research Group (Frontier) at Neuroscience Research, Australia. Of this caregiver group, 43 were spousal caregivers and 47 were child caregivers. Caregiver burden and emotional state were evaluated using the short Zarit Burden Interview and the short version of the Depression, Anxiety and Stress Scale-21. The Social Network Index was applied …to ascertain the social network of the caregiver, while the Intimate Bond Measure was used to evaluate the current quality of the relationship between the caregiver and the person with dementia. The Frontotemporal Dementia Rating Scale was used to assess severity of dementia. Spousal and child caregivers experienced similar levels of burden, depression, anxiety, and stress, regardless of disease severity. Co-resident child caregivers had smaller social networks and greater burden than live-out caregivers. Dementia severity was key in spousal caregiver burden, whereas caregiver depression was most important in child caregiver burden. Child and spousal caregivers of individuals with FTD share similar levels of burden, influenced by different factors. Future interventions need to account for these differences. Show more

Keywords: Caregiver, carer burden, children, dementia severity, depression, frontotemporal dementia

DOI: 10.3233/JAD-160852

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1109-1117, 2017

Authors: Loewenstein, David A. | Curiel, Rosie E. | Wright, Clinton | Sun, Xiaoyan | Alperin, Noam | Crocco, Elzabeth | Czaja, Sara J. | Raffo, Arlene | Penate, Ailyn | Melo, Jose | Capp, Kimberly | Gamez, Monica | Duara, Ranjan

Article Type: Research Article

Abstract: Background: There is growing evidence that proactive semantic interference (PSI) and failure to recover from PSI may represent early features of Alzheimer’s disease (AD). Objective: This study investigated the association between PSI, recovery from PSI, and reduced MRI volumes in AD signature regions among cognitively impaired and unimpaired older adults. Methods: Performance on the LASSI-L (a novel test of PSI and recovery from PSI) and regional brain volumetric measures were compared between 38 cognitively normal (CN) elders and 29 older participants with amnestic mild cognitive impairment (MCI). The relationship between MRI measures and performance on …the LASSI-L as well as traditional memory and non-memory cognitive measures was also evaluated in both diagnostic groups. Results: Relative to traditional neuropsychological measures, MCI patients’ failure to recover from PSI was associated with reduced volumes in the hippocampus (rs = 0.48), precuneus (rs = 0.50); rostral middle frontal lobules (rs = 0.54); inferior temporal lobules (rs = 0.49), superior parietal lobules (rs = 0.47), temporal pole (rs = 0.44), and increased dilatation of the inferior lateral ventricle (rs = –0.49). For CN elders, only increased inferior lateral ventricular size was associated with vulnerability to PSI (rs = –0.49), the failure to recover from PSI (rs = –0.57), and delayed recall on the Hopkins Verbal Learning Test-Revised (rs = –0.48). Discussion: LASSI-L indices eliciting failure to recover from PSI were more highly associated with more MRI regional biomarkers of AD than other traditional cognitive measures. These results as well as recent amyloid imaging studies with otherwise cognitively normal subjects, suggest that recovery from PSI may be a sensitive marker of preclinical AD and deserves further investigation. Show more

Keywords: Alzheimer’s disease, LASSI-L, memory, mild cognitive impairment, MRI, proactive interference, semantic interference

DOI: 10.3233/JAD-160881

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1119-1126, 2017

Authors: Peters, Kirsten E. | Davis, Wendy A. | Taddei, Kevin | Martins, Ralph N. | Masters, Colin L. | Davis, Timothy M.E. | Bruce, David G.

Article Type: Research Article

Abstract: Background: Plasma amyloid-β (Aβ) levels have rarely been investigated in type 2 diabetes despite its known associations with Alzheimer’s disease. Objective: To compare blood plasma Aβ concentrations (Aβ40 and Aβ42 ) in cognitively normal individuals with and without type 2 diabetes. Methods: Plasma Aβ40 and Aβ42 were measured in 194 participants with diabetes recruited from the community-based Fremantle Diabetes Study Phase II cohort (mean age 71 years, 59% males) and 194 age-, sex-, and APOE ɛ 4 allele-matched, control subjects without diabetes from the Australian Imaging, Biomarkers and Lifestyle Study using …a multiplex microsphere-based immunoassay. Results: Plasma Aβ40 and Aβ42 were normally distributed in the controls but were bimodal in the participants with diabetes. Median Aβ40 and Aβ42 concentrations were significantly lower in those with type 2 diabetes (Aβ40 median [inter-quartile range]: 125.0 [52.6–148.3] versus 149.3 [134.0–165.6] pg/mL; Aβ42 : 26.9 [14.5–38.3] versus 33.6 [28.0–38.9] pg/mL, both p  < 0.001) while the ratio Aβ42 :Aβ40 was significantly higher (0.26 [0.23–0.32] versus 0.22 [0.19–0.25], p  < 0.001). After adjustment, participants with diabetes and plasma Aβ40 levels in the low peak of the bimodal distribution were significantly more likely to have normal to high estimated glomerular filtration rates (odds ratio (95% CI): 2.40 (1.20–4.80), p  = 0.013) although the group with diabetes had lower renal function overall. Conclusion: Type 2 diabetes is associated with altered plasma concentrations of Aβ peptides and is an important source of variation that needs to be taken into account when considering plasma Aβ peptides as biomarkers for Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, peptides, blood biomarkers, type 2 diabetes mellitus

DOI: 10.3233/JAD-161050

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1127-1133, 2017

Authors: Kunz, Lukas | Reuter, Martin | Axmacher, Nikolai | Montag, Christian

Article Type: Research Article

Abstract: The etiology of late onset Alzheimer’s disease (LOAD) depends on multiple factors, among which the APOE ɛ4 allele is the most adverse genetic determinant and conscientiousness represents an influential personality trait. A potential association of both factors with brain structure in young adulthood may constitute a constellation that sets the course toward or against the subtle disease progression of LOAD that starts decades before clinical manifestation. Hence, in the present study, we examined the modulating effects of APOE ɛ4 on the relation between personality dimensions, including conscientiousness, and total grey matter volume (GMV) in young healthy adults using …an a priori genotyping design. 105 participants completed an inventory assessing the Five Factor Model of Personality (NEO-FFI) and a structural MRI scan. Total GMV was estimated using both Freesurfer as well as VBM8. Across all participants, total GMV was positively associated with extraversion and negatively related to age. In APOE ɛ4-carriers— but not in APOE ɛ4-non-carriers— conscientiousness was negatively associated with total GMV. In line with the hypothesis of antagonistic pleiotropy of the APOE ɛ4 allele, this result suggests that young APOE ɛ4-carriers with increased total GMV may particularly benefit from cognitive advantages and thus have a lower need to engage in conscientious behavior. In this subset of young APOE ɛ4-carriers, the reduction in conscientiousness could then bring along adverse health behavior in the long run, potentiating the risk for LOAD. Hence, young APOE ɛ4-carriers with increased total GMV may be at a particularly high risk for LOAD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, big five, Freesurfer, NEO-FFI, personality, voxel-based morphometry

DOI: 10.3233/JAD-160854

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1135-1144, 2017

Authors: Zyśk, Marlena | Bielarczyk, Hanna | Gul-Hinc, Sylwia | Dyś, Aleksandra | Gapys, Beata | Ronowska, Anna | Sakowicz-Burkiewicz, Monika | Szutowicz, Andrzej

Article Type: Research Article

Abstract: Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional …distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions. Show more

Keywords: N-acetyl-L-aspartate, acetyl-CoA, aspartate N-acetyltransferase, ATP, cholinergic neurons neurotoxicity, zinc

DOI: 10.3233/JAD-160693

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1145-1158, 2017

Authors: Khan, Wasim | Giampietro, Vincent | Banaschewski, Tobias | Barker, Gareth J. | Bokde, Arun L.W. | Büchel, Christian | Conrod, Patricia | Flor, Herta | Frouin, Vincent | Garavan, Hugh | Gowland, Penny | Heinz, Anreas | Ittermann, Bernd | Lemaître, Hervé | Nees, Frauke | Paus, Tomas | Pausova, Zdenka | Rietschel, Marcella | Smolka, Michael N. | Ströhle, Andreas | Gallinat, Jeurgen | Vellas, Bruno | Soininen, Hilkka | Kloszewska, Iwona | Tsolaki, Magda | Mecocci, Patrizia | Spenger, Christian | Villemagne, Victor L. | Masters, Colin L. | Muehlboeck, J-Sebastian | Bäckman, Lars | Fratiglioni, Laura | Kalpouzos, Grégoria | Wahlund, Lars-Olof | Schumann, Gunther | Lovestone, Simon | Williams, Steven C.R. | Westman, Eric | Simmons, Andrew | Alzheimer–s Disease Neuroimaging Initiative | AddNeuroMed Consortium, Australian, Imaging, Biomarkers, and Lifestyle Study Research Group | the IMAGEN consortium

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer’s disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n  = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n  = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging …dataset, hippocampal comparisons were performed in each APOE group and in ɛ 4 carriers with positron emission tomography (PET) Aβ who were dichotomized (Aβ+/Aβ–) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ 4 carriers possessing the smallest volumes, ɛ 3 carriers possessing intermediate volumes, and ɛ 2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ 4 carriers possessed the smallest hippocampal volumes and control ɛ 2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ 4 and Aβ positivity had the lowest hippocampal volumes when compared to Aβ- ɛ 4 carriers, suggesting a synergistic relationship between APOE ɛ 4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ 4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, hippocampus, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-161097

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1159-1174, 2017

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

Article Type: Research Article

Abstract: Background: The reported prevalence of epilepsy in Alzheimer’s disease (AD) is variable, probably due to the different methodological approaches. Objective: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients. Methods: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated. Results: Significant high correlation was identified between the sensitivity of EEG and the …length of recordings (r  = 0.972, p  = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p  = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p  < 0.001). Conclusion: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease. Show more

Keywords: Alzheimer’s disease, EEG sensitivity, epilepsy, epileptiform discharges, long-term EEG

DOI: 10.3233/JAD-160994

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1175-1183, 2017

Authors: Polcher, Alexandra | Frommann, Ingo | Koppara, Alexander | Wolfsgruber, Steffen | Jessen, Frank | Wagner, Michael

Article Type: Research Article

Abstract: Background: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the preclinical stage of Alzheimer’s disease (AD). Associative memory is a cognitive function supported by the hippocampus and affected early in the process of AD. Objective: We developed a short computerized face-name associative recognition test (FNART) and tested whether it would detect memory impairment in memory clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Methods: We recruited 61 elderly patients with either SCD (n  = 32) or MCI (n  = 29) and 28 healthy controls (HC) …and compared performance on FNART, self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced sample (n  = 46), performance on the visual Paired Associates Learning of the CANTAB battery. Results: A significant effect of group on FNART test performance in the total sample was found (p  < 0.001). Planned contrasts indicated a significantly lower associative memory performance in the SCD (p  = 0.001, d  = 0.82) and MCI group (p  < 0.001, d  = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory in SCD patients (p  = 0.024) but not in MCI patients. Conclusions: Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes. Show more

Keywords: Alzheimer’s disease, associative memory, cognition, early detection, hippocampus, mild cognitive impairment, neuropsychological tests, recognition, subjective cognitive decline

DOI: 10.3233/JAD-160637

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1185-1196, 2017

Authors: Ebel, Dalton L. | Torkilsen, Christopher G. | Ostrowski, Tim D.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant …astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD. Show more

Keywords: Astrocytosis, brainstem, chemoreflex, hypercapnia, hypoxia, nucleus tractus solitarii, ventilation

DOI: 10.3233/JAD-160974

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1197-1211, 2017