Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Rahman-Filipiak, Annalise M. | Giordani, Bruno | Heidebrink, Judith | Bhaumik, Arijit | Hampstead, Benjamin M.

Article Type: Research Article

Abstract: Background: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups. Objective: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3). …Methods: Baseline evaluation data were drawn from 488 participants (M age  = 70.49 years; M edu  = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer’s disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire. Results: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups. Conclusions: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process. Show more

DOI: 10.3233/JAD-180083

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2018

Authors: Liang, Jia-Wei | Fang, Zheng-Yu | Huang, Yong | Liuyang, Zhen-yu | Zhang, Xiao-Lin | Wang, Jing-Lin | Hui, Wei | Wang, Jian-Zhi | Wang, Xiao-Chuan | Zeng, Ji | Liu, Rong

Article Type: Research Article

Abstract: Background: Weighted co-expression network analysis (WGCNA) is a powerful systems biology method to describe the correlation of gene expression based on the microarray database, which can be used to facilitate the discovery of therapeutic targets or candidate biomarkers in diseases. Objective: To explore the key genes in the development of Alzheimer’s disease (AD) by using WGCNA. Methods: The whole gene expression data GSE1297 from AD and control human hippocampus was obtained from the GEO database in NCBI. Co-expressed genes were clustered into different modules. Modules of interest were identified through calculating the correlation coefficient between the …module and phenotypic traits. GO and pathway enrichment analyses were conducted, and the central players (key hub genes) within the modules of interest were identified through network analysis. The expression of the identified key genes was confirmed in AD transgenic mice through using qRT-PCR. Results: Two modules were found to be associated with AD clinical severity, which functioning mainly in mineral absorption, NF-κ B signaling, and cGMP-PKG signaling pathways. Through analysis of the two modules, we found that metallothionein (MT), Notch2, MSX1, ADD3, and RAB31 were highly correlated with AD phenotype. Increase in expression of these genes was confirmed in aged AD transgenic mice. Conclusion: WGCNA analysis can be used to analyze and predict the key genes in AD. MT1 , MT2 , MSX1, NOTCH2 , ADD3, and RAB31 are identified to be the most relevant genes, which may be potential targets for AD therapy. Show more

Keywords: ADD3, Alzheimer’s disease, metallothionein, MSX1, Notch2, neurofibrillary tangles, RAB31, WGCNA

DOI: 10.3233/JAD-180400

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Vicente, Mariane C. | Almeida, Maria C. | Bícego, Kênia C. | Carrettiero, Daniel C. | Gargaglioni, Luciane H.

Article Type: Research Article

Abstract: Besides the typical cognitive decline, patients with Alzheimer’s disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation ( V ̇ E ), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses …for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2 -drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V ̇ E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption. Show more

Keywords: Breathing, chemosensitivity, dementia, hypoxia, locus coeruleus, streptozotocin

DOI: 10.3233/JAD-180397

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Rodríguez-Cruz, Fanny | Torres-Cruz, Francisco Miguel | Monroy-Ramírez, Hugo Christian | Escobar-Herrera, Jaime | Basurto-Islas, Gustavo | Avila, Jesús | García-Sierra, Francisco

Article Type: Research Article

Abstract: Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer’s disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and …several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect. Show more

Keywords: Alzheimer’s disease, confocal microscopy, Golgi apparatus, immunofluorescence, microtubule lattice, tau

DOI: 10.3233/JAD-180547

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2018

Authors: Grames, Mychal S. | Dayton, Robert D. | Lu, Xiaohong | Schilke, Robert M. | Alexander, J. Steven | Orr, A. Wayne | Barmada, Sami J. | Woolard, Matthew D. | Klein, Ronald L.

Article Type: Research Article

Abstract: A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer’s disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

Keywords: Adeno-associated virus, Alzheimer’s disease, amyloid-β plaques, cardiovascular disease, gene transfer, hypercholesterolemia, PCSK9

DOI: 10.3233/JAD-180494

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Benvenutto, Agnès | Giusiano, Bernard | Koric, Lejla | Gueriot, Claude | Didic, Mira | Felician, Olivier | Guye, Maxime | Guedj, Eric | Ceccaldi, Mathieu

Article Type: Research Article

Abstract: Background: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer’s disease (AD). Objective: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18 FDG-PET, in the assessment of neurodegeneration in AD dementia. Methods: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18 FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18 FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to …healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers. Results: Fifty-two patients were included. The MMSE score was significantly lower in the “Extensive hypometabolism” group than in the “Limited hypometabolism” group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p  = 0.04). There were more patients with low educational level in the “Extensive atrophy” group, while a higher educational level was more found in the “Limited atrophy” group (p  = 0.005). Conclusion: 18 FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation. Show more

Keywords: Alzheimer’s disease, dementia, magnetic resonance imaging, neuroimaging biomarkers, positron emission tomography imaging

DOI: 10.3233/JAD-180292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Parra-Anguita, Laura | Moreno Cámara, Sara | Dolores Lípez-Franco, María | L. Pancorbo-Hidalgo, Pedro

Article Type: Research Article

Abstract: Background: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer’s disease care in the Spanish language. Objective: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp). Methods: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal …consistency (Cronbach’s alpha). Results: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach’s alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p  <  0.0001 for mean difference), supporting construct validity. Conclusion: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts. Show more

Keywords: Alzheimer’s disease, dementia, knowledge, nursing care, validation

DOI: 10.3233/JAD-180290

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Hang Wong, Tsz | Pottier, Cyril | Hondius, David | H.H. Meeter, Lieke | G.J. van Rooij, Jeroen | Melhem, Shami | Brain bank, The Netherlands | van Minkelen, Rick | M. van Duijn, Cornelia | J.M. Rozemuller, Annemieke | Seelaar, Harro | Rademakers, Rosa | C. van Swieten, John

Article Type: Research Article

Abstract: Valosin-containing protein (VCP ) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget’s disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT , GRN , and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from …the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, next generation sequencing, TDP-43, VCP gene

DOI: 10.3233/JAD-180301

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: E. Baker, Jenalle | Ying Lim, Yen | Jaeger, Judith | Ames, David | T. Lautenschlager, Nicola | Robertson, Joanne | H. Pietrzak, Robert | J. Snyder, Peter | L. Villemagne, Victor | C. Rowe, Christopher | L. Masters, Colin | Maruff, Paul

Article Type: Research Article

Abstract: Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer’s disease (AD) equates to 0.15–0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aβ – CN; n  = 50); Aβ + positive healthy older adults (preclinical AD; n  = 25); and Aβ + …positive individuals diagnosed with mild cognitive impairment (prodromal AD; n  = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen’s d  = – 0.63, [– 1.12, – 0.14]) and the prodromal AD group (Cohen’s d  = – 0.36, [– 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aβ . Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, cognitive decline, learning curve, memory and learning tests, mild cognitive impairment, neuropsychology, transfer of learning

DOI: 10.3233/JAD-180344

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Bulk, Marjolein | Kenkhuis, Boyd | Graaf, Linda M. van der | Goeman, Jelle J. | Natté, Remco | Weerd, Louise van der

Article Type: Research Article

Abstract: The value of iron-based MRI changes for the diagnosis and staging of Alzheimer’s disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2 * -weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed …that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo . Show more

Keywords: Amyloid, cortex, iron, magnetic resonance imaging, tau

DOI: 10.3233/JAD-180317

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018