Journal of Alzheimer's Disease - Volume 65, issue 4

Authors: Finan, John D. | Udani, Shreya V. | Patel, Vimal | Bailes, Julian E.

Article Type: Review Article

Abstract: Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the …central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results. Show more

Keywords: Brain-derived neurotrophic factor, precision medicine, single nucleotide polymorphism, traumatic brain injury

DOI: 10.3233/JAD-180585

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1055-1064, 2018

Authors: Serra, Laura | Gelfo, Francesca | Petrosini, Laura | Di Domenico, Carlotta | Bozzali, Marco | Caltagirone, Carlo

Article Type: Review Article

Abstract: The concept of brain, cognitive , and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer’s disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, …the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy. Show more

Keywords: Alzheimer’s disease, animal studies, environmental enrichment, human studies, MRI, reserve mechanisms

DOI: 10.3233/JAD-180609

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1065-1078, 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: Short Communication

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. 65, no. 4, pp. 1079-1086, 2018

Authors: Amen, Daniel G. | Egan, Sachit | Meysami, Somayeh | Raji, Cyrus A. | George, Noble

Article Type: Research Article

Abstract: Background: Understanding the influence of aging on the brain remains a challenge in determining its role as a risk factor for Alzheimer’s disease. Objective: To identify patterns of aging in a large neuroimaging cohort. Methods: A large psychiatric cohort of 31,227 individuals received brain SPECT at rest and during a concentration task for a total of 62,454 scans. ANOVA was done to identify the mean age trends over the course of the age range in this group, 0–105 years. A regression model in which brain SPECT regions of interest was used to predict chronological age (CA) …was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain aging in common disorders in our sample such as depression, dementia, substance use, and anxiety. Results: Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late life. Increased brain aging was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men. Conclusion: Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders. Show more

Keywords: Aging, alcohol use, attention-deficit/hyperactivity disorder, bipolar, brain SPECT, cannabis use, schizophrenia

DOI: 10.3233/JAD-180598

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1087-1092, 2018

Authors: Wang, Bin | Miao, Liwen | Niu, Yan | Cao, Rui | Li, Dandan | Yan, Pengfei | Guo, Hao | Yan, Tianyi | Wu, Jinglong | Xiang, Jie | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) disrupts the topological architecture of whole-brain connectivity. Minimum spanning tree (MST), which captures the most important connections in a network, has been considered an unbiased method for brain network analysis. However, the alterations in the MST of functional brain networks during the progression of AD remain unclear. Here, we performed an MST analysis to examine the alterations in functional networks among normal controls (NCs), mild cognitive impairment (MCI) patients, and AD patients. We identified substantial differences in the connections among the three groups. The maximum betweenness centrality, leaf number, and tree hierarchy of the MSTs showed significant …group differences, indicating a more star-like topology in the MCI patients and a more line-like topology in the NCs and AD patients. These findings may correspond to changes in the core of the functional brain networks. For nodal properties (degree and betweenness centrality), we determined that brain regions around the cingulate gyrus, occipital lobes, subcortex, and inferior temporal gyrus showed significant differences among the three groups and contributed to the global topological alterations. The leaf number and tree hierarchy, as well as the nodal properties, were significantly correlated with clinical features in the MCI and AD patients, which demonstrated that more star-to-line topology changes were associated with worse cognitive performance in these patients. These findings indicated that MST properties could capture slight alterations in network topology, particularly for the differences between NCs and MCI patients, and may be applicable as neuroimaging markers of the early stage of AD. Show more

Keywords: Alzheimer’s disease, brain networks, functional magnetic resonance imaging, mild cognitive impairment, minimum spanning tree

DOI: 10.3233/JAD-180603

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1093-1107, 2018

Authors: Domínguez-Prieto, Marta | Velasco, Ana | Tabernero, Arantxa | Medina, José M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides, Aβ40 , Aβ42 , and recently Aβ25 - 35 , have been directly implicated in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that all three peptides decrease neuronal viability, but Aβ40 also promotes synaptic disassembling. In this work, we have studied the effects of these peptides on astrocytes in primary culture and found that the three Aβ peptides were internalized by astrocytes and significantly decreased astrocyte viability, while increasing ROS production. Aβ peptide internalization is temperature-dependent, a fact that supports the idea that Aβ peptides are actively endocytosed by astrocytes. However, inhibiting caveolae formation by …methyl-beta-cyclodextrin or by silencing caveolin-1 with RNA interference did not prevent Aβ endocytosis, which suggests that Aβ peptides do not use caveolae to enter astrocytes. Conversely, inhibition of clathrin-coated vesicle formation by chlorpromazine or by silencing clathrin with RNA interference significantly decreased Aβ internalization and partially reverted the decrease of astrocyte viability caused by the presence of Aβ. These results suggest that Aβ is endocytosed by clathrin-coated vesicles in astrocytes. Aβ-loaded astrocytes, when co-incubated with non-treated astrocytes in separate wells but with the same incubation medium, promoted cell death in non-treated astrocytes; a fact that was associated with the presence of Aβ inside previously unloaded astrocytes. This phenomenon was inhibited by the presence of chlorpromazine in the co-incubation medium. These results suggest that astrocyte may perform Aβ transcytosis, a process that could play a role in the clearance of Aβ peptides from the brain to cerebrospinal fluid. Show more

Keywords: Alzheimer’s disease, amyloid-β , astrocytes, clathrin-mediated endocytosis, transcytosis

DOI: 10.3233/JAD-180332

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1109-1124, 2018

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

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. 65, no. 4, pp. 1125-1137, 2018

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

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. 65, no. 4, pp. 1139-1146, 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. 65, no. 4, pp. 1147-1157, 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. 65, no. 4, pp. 1159-1174, 2018