Journal of Alzheimer's Disease - Volume 65, issue 1

Article Type: Editorial

DOI: 10.3233/JAD-189007

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 1-2, 2018

Authors: Piton, Morgane | Hirtz, Christophe | Desmetz, Caroline | Milhau, Jacqueline | Lajoix, Anne Dominique | Bennys, Karim | Lehmann, Sylvain | Gabelle, Audrey

Article Type: Review Article

Abstract: As of 2018, Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. It contributes to a progressive neuron loss, deterioration of memory, and cognitive impairment. Current therapies may provide a symptomatic benefit, but do not treat the underlying process. Ongoing researches focus on understanding the causal mechanisms and finding neuropathological hallmarks of AD. Therapeutic approaches targeting senile plaques or neurofibrillary tangles have not yet resulted in a significant cognitive improvement. However, recent data according to the analysis of AD clinical trials (clinicaltrials.gov database) show promising results. This literature review aims at summarizing the recent advances and at highlighting …the most promising results of the ongoing researches. It compares the merits of small-molecules, antibodies, cell, and gene-based therapies and emphasizes the need for treatment at earlier stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, amyloid-β protein precursor secretases, cell- and tissue-based therapy, early onset, genetic therapy, immunotherapy, tau proteins

DOI: 10.3233/JAD-180145

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 3-13, 2018

Authors: Chen, Rui | Shi, Jiangwei | Yin, Qingsheng | Li, Xiaojin | Sheng, Yanyuan | Han, Juan | Zhuang, Pengwei | Zhang, Yanjun

Article Type: Review Article

Abstract: Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment …of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, diabetic encephalopathy, pathological characteristics, vascular dementia

DOI: 10.3233/JAD-180314

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 15-28, 2018

Authors: Aguayo, Sebastian | Schuh, Christina Maria Anna Pia | Vicente, Benjamin | Aguayo, Luis Gerardo

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative condition affecting millions of people worldwide. It is associated with cerebral amyloid-β (Aβ) plaque deposition in the brain, synaptic disconnection, and subsequent progressive neuronal death. Although considerable progress has been made to elucidate the pathogenesis of AD, the specific causes of the disease remain highly unknown. Recent research has suggested a potential association between certain infectious diseases and dementia, either directly due to bacterial brain invasion and toxin production, or indirectly by modulating the immune response. Therefore, in the present review we focus on the emerging issues of bacterial infection and AD, including the …existence of antimicrobial peptides having pore-forming properties that act in a similar way to pores formed by Aβ in a variety of cell membranes. Special focus is placed on oral bacteria and biofilms, and on the potential mechanisms associating bacterial infection and toxin production in AD. The role of bacterial outer membrane vesicles on the transport and delivery of toxins as well as porins to the brain is also discussed. Aβ has shown to possess antimicrobial activity against several bacteria, and therefore could be upregulated as a response to bacteria and bacterial toxins in the brain. Although further research is needed, we believe that the control of biofilm-mediated diseases could be an important potential prevention mechanism for AD development. Show more

Keywords: Alzheimer’s disease, biofilms, infection, periodontal diseases, porins

DOI: 10.3233/JAD-180319

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 29-46, 2018

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: If cerebrospinal and interstitial fluids move through very narrow brain flow channels, these restrictive surroundings generate varying levels of fluid shear and different shear rates, and dissolved amyloid monomers absorb different shear energies. It is proposed that dissolved amyloid-β protein (Aβ) and other amyloid monomers undergo shear-induced conformational changes that ultimately lead to amyloid monomer aggregation even at very low brain flow and shear rates. Soluble Aβ oligomers taken from diseased brains initiate in vivo amyloid formation in non-diseased brains. The brain environment is apparently responsible for this result. A mechanism involving extensional shear is proposed for the formation …of a seed Aβ monomer molecule that ultimately promotes templated conformational change of other Aβ molecules. Under non-quiescent, non-equilibrium conditions, gentle extensional shear within the brain parenchyma, and perhaps even during laboratory preparation of Aβ samples, may be sufficient to cause subtle conformational changes in these monomers. These result from brain processes that significantly lower the high activation energy predicted for the quiescent Aβ dimerization process. It is further suggested that changes in brain location and changes brought about by aging expose Aβ molecules to different shear rates, total shear, and types of shear, resulting in different conformational changes in these molecules. The consequences of such changes caused by variable shear energy are proposed to underlie formation of amyloid strains causing different amyloid diseases. Amyloid researchers are urged to undertake studies with amyloids, anti-amyloid drugs, and antibodies while all of these are under shear conditions similar to those in the brain. Show more

Keywords: Amyloid-β, cerebrospinal fluid, glymphatic pathway, interstitial fluid, shear energy, templated conformation change

DOI: 10.3233/JAD-171003

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 47-70, 2018

Authors: Groot, Colin | Tolboom, Nelleke | Ikonomovic, Milos D. | Lammertsma, Adriaan A. | Boon, Baayla D.C. | Barkhof, Frederik | Scheltens, Philip | Klunk, William E. | Rozemuller, Annemieke J.M. | Ossenkoppele, Rik | van Berckel, Bart N.M.

Article Type: Short Communication

Abstract: This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11 C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND ) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does …not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11 C]PiB-PET to detect atypical forms of amyloid pathology. Show more

Keywords: Amyloid, case study, histology, positron emission tomography

DOI: 10.3233/JAD-180316

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 71-77, 2018

Authors: Chen, Stephen T. | Siddarth, Prabha | Merrill, David A. | Martinez, Jacqueline | Emerson, Natacha D. | Liu, Jie | Wong, Koon-Pong | Satyamurthy, Nagichettiar | Giza, Christopher C. | Huang, Sung-Cheng | Fitzsimmons, Robert P. | Bailes, Julian | Omalu, Bennet | Barrio, Jorge R. | Small, Gary W.

Article Type: Research Article

Abstract: Background: Our group has shown that in vivo tau brain binding patterns from FDDNP-PET scans in retired professional football players with suspected chronic traumatic encephalopathy differ from those of tau and amyloid aggregate binding observed in Alzheimer’s disease (AD) patients and cognitively-intact controls. Objective: To compare these findings with those from military personnel with histories of mild traumatic brain injury(mTBI). Methods: FDDNP-PET brain scans were compared among 7 military personnel and 15 retired players with mTBI histories and cognitive and/or mood symptoms, 24 AD patients, and 28 cognitively-intact controls. Nonparametric ANCOVAs with Tukey-Kramer adjusted post-hoc …comparisons were used to test for significant differences in regional FDDNP binding among subject groups. Results: FDDNP brain binding was higher in military personnel compared to controls in the amygdala, midbrain, thalamus, pons, frontal and anterior and posterior cingulate regions (p < 0.01–0.0001). Binding patterns in the military personnel were similar to those of the players except for the amygdala and striatum (binding higher in players; p = 0.02–0.003). Compared with the AD group, the military personnel showed higher binding in the midbrain (p = 0.0008) and pons (p = 0.002) and lower binding in the medial temporal, lateral temporal, and parietal regions (all p = 0.02). Conclusion: This first study of in vivo tau and amyloid brain signals in military personnel with histories of mTBI shows binding patterns similar to those of retired football players and distinct from the binding patterns in AD and normal aging, suggesting the potential value of FDDNP-PET for early detection and treatment monitoring in varied at-risk populations. Show more

Keywords: Alzheimer’s disease, brain tau and amyloid, chronic traumatic encephalopathy, FDDNP-PET, mild traumatic brain injury, military personnel, retired professional football players

DOI: 10.3233/JAD-171152

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 79-88, 2018

Authors: Oliveira, Francisco P.M. | Moreira, Ana Paula | de Mendonça, Alexandre | Verdelho, Ana | Xavier, Carolina | Barroca, Dalila | Rio, Joana | Cardoso, Eva | Cruz, Ângela | Abrunhosa, Antero | Castelo-Branco, Miguel

Article Type: Research Article

Abstract: Background: Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration. Objective: Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1 ) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition. Methods: We selected 52 patients with cognitive impairment who underwent …a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals. Results: All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise within-subjects r > 0.92). The higher correlation was found for FDG-R1 (MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1 (MRTM) and statistically significant in the whole brain analysis. Conclusion: All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation. Show more

Keywords: Alzheimer’s disease, 11C-PIB, compartmental models, 18F-FDG, neurodegeneration, perfusion

DOI: 10.3233/JAD-180274

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 89-97, 2018

Authors: Feng, Lei | Langsetmo, Lisa | Yaffe, Kristine | Sun, Ye | Fink, Howard A. | Shikany, James M. | Leung, P.C. | Lane, Nancy E. | Cauley, Jane A. | Osteoporotic Fractures in Men (MrOS) Study Group

Article Type: Research Article

Abstract: Background: Accumulating evidence supports the neuroprotective effects of bioactive compounds from tea leaves. There are limited data from black tea consumption populations. Objective: To determine whether black tea consumption is associated with cognitive decline among older men. Methods: We chose to study the association between black tea consumption and cognition using data from the Osteoporotic Fractures in Men (MrOS) cohort, which collected information on tea consumption at baseline and has repeatedly assessed cognitive function in 3,844 men aged 65+ years (mean = 72.4 years). We defined tea drinkers as those who drank black tea at least …once per week and further grouped them into weekly drinkers and daily drinkers. Cognitive function was assessed at baseline and approximately 7 years later using the Modified Mini-Mental State Examination (3MSE). Multivariable logistic regression and linear regression models were constructed to assess the association between black tea consumption and risk of fast cognitive decline as a binary variable and change in 3MSE scores as continuous variable. Fast cognitive decline was defined as decline in 3MSE >1.5 standard deviation of mean change score. Models were adjusted for age, education level, and baseline cognitive scores. Results: Weekly and daily black tea drinkers were 24.8% and 12.4% of the study cohort, respectively. Fast cognitive decline occurred in 243 (6.3%) participants. Tea consumption was not associated with risk of cognitive decline, nor was tea associated with cognitive decline measured by absolute change in 3MSE scores. Conclusions: There was no association of black tea consumption and cognitive decline among older men in the US. Show more

Keywords: Aging, black tea, cognitive decline, men

DOI: 10.3233/JAD-180103

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 99-105, 2018

Authors: Guzmán-Vélez, Edmarie | Jaimes, Sehily | Aguirre-Acevedo, Daniel C. | Norton, Daniel J. | Papp, Kathryn V. | Amariglio, Rebecca | Rentz, Dorene | Baena, Ana | Henao, Eliana | Tirado, Victoria | Muñoz, Claudia | Giraldo, Margarita | Sperling, Reisa A. | Lopera, Francisco | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer’s disease (AD), and that can be used to reliably measure cognitive decline. Objective: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1 ) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. Methods: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included …in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). Results: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals’ estimated age of clinical onset. Conclusions: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD. Show more

Keywords: Confirmatory factor analysis, cognitive factors, episodic memory, executive function, preclinical Alzheimer’s disease, processing speed, contstartabstract

DOI: 10.3233/JAD-180078

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 107-115, 2018