Journal of Alzheimer's Disease - Volume 70, issue 3

Authors: Terry, Nickolas | Masliah, Alberto | Overk, Cassia | Masliah, Eliezer

Article Type: Obituary

Abstract: Dr. Robert Terry (January 14, 1924-May 20, 2017) studied normal aging and Alzheimer’s disease for more than five decades. He was at a visionary neuropathologist who trained generations of researchers in the field of neurodegenerative disorders and was always at the cutting edge of incorporating ever advancing technology into the fields of neuroscience and neuropathology. He was among the first to study plaques and tangles using electron microscopy, described the effects of aluminum on neurons, and collaborated to develop new approaches to study synaptic pathology in the context of cognitive impairment in Alzheimer’s disease. Dr. Terry made indelible contributions to …our understanding of Alzheimer’s disease and dementia. In memory of Bob: veteran, physician-scientist, collaborator, friend, husband, and father. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-190518

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 621-628, 2019

Authors: LoBue, Christian | Munro, Catherine | Schaffert, Jeffrey | Didehbani, Nyaz | Hart, Jr. , John | Batjer, Hunt | Cullum, C. Munro

Article Type: Review Article

Abstract: Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) …related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature. Show more

Keywords: Alzheimer’s disease, brain imaging, chronic traumatic encephalopathy, cognition, concussion, dementia, frontotemporal dementia, Lewy body dementia, Parkinson’s disease, traumatic brain injury

DOI: 10.3233/JAD-190028

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 629-654, 2019

Authors: López-García, Sara | Jiménez-Bonilla, Julio | López Delgado, Anjana | Orizaola Balaguer, Pedro | Infante Ceberio, Jon | Banzo Marraco, Ignacio | Rodríguez Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Short Communication

Abstract: Dementia is not just a disease of old age. Early-onset dementia affects people younger than 65 and its differential diagnosis is broader than in older people. Nevertheless, although young people are considerably more liable to develop a rare form of dementia, Alzheimer’s disease (AD) remains the most common diagnosis. The aim of this article is to report on an early-onset AD patient associated with the rare pathogenic variant PSEN1 (Leu85Pro) presenting as a possible corticobasal syndrome with asymmetric limb apraxia, parkinsonian signs, and myoclonus.

Keywords: Alzheimer’s disease, amyloid PET, corticobasal syndrome, presenilin-1

DOI: 10.3233/JAD-190107

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 655-658, 2019

Authors: Sakae, Nobutaka | Heckman, Michael G. | Vargas, Emily R. | Carrasquillo, Minerva M. | Murray, Melissa E. | Kasanuki, Koji | Ertekin-Taner, Nilufer | Younkin, Steven G. | Dickson, Dennis W.

Article Type: Short Communication

Abstract:  A number of Alzheimer’s disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOE ɛ 4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B , PICALM , and CR1 . Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and …white matter microglial activity. Show more

Keywords: Alzheimer’s disease, genome-wide association study, microglia, neuropathology, risk variant

DOI: 10.3233/JAD-190451

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 659-666, 2019

Authors: Kang, Seokjo | Son, Sung Min | Baik, Sung Hoon | Yang, Jinhee | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Increased levels of total tau (t-tau) and hyperphosphorylated tau (p-tau) proteins in the cerebrospinal fluid of Alzheimer’s disease (AD) patients are well documented and strongly correlate with AD pathology. Recent studies have further shown that human tau can be released into the extracellular space and transferred to nascent neurons. However, because the tau protein has no signal peptide identity, the mechanisms underlying its secretion remain poorly understood. In the present study, we confirmed that tau protein secretion was promoted by autophagy inducers and downregulated by beclin1 knockdown or autophagy inhibitors derived from human wild type tau (wt-tau)-overexpressing SH-SY5Y cells. …Moreover, both t-tau and p-tau secretion were increased by autophagy activation. Furthermore, we identified that six isoforms of tau protein are secreted in an autophagy-dependent manner. These results indicate that both normal and pathological tau are secreted via an autophagy-mediated secretory pathway in neurons. Understanding this new pathway for tau secretion may provide critical future insights into tau pathologies, such as AD. Show more

Keywords: Alzheimer’s disease, autophagy-mediated secretion, beclin1, SH-SY5Y cells, tau protein

DOI: 10.3233/JAD-190180

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 667-680, 2019

Authors: Heesterbeek, Marelle | van der Zee, Eddy Anton | van Heuvelen, Marieke Joan Gerda

Article Type: Research Article

Abstract: Background: Increasing physical activity levels in patients with dementia can reduce pathology severity and progression of the disease. However, physical activity programs can be challenging to adhere to for this vulnerable population. Three novel forms of passive exercise in a multisensory environment may be feasible alternatives for patients who can no longer be involved in physical activity. Objective: To determine the feasibility of three different forms of passive exercise in a multisensory environment in inactive institutionalized older adults with dementia. Methods: 120 patients with dementia participated in this single blind randomized controlled trial (64.5% female, age …85.3±6.8 years Mini-Mental State Examination range 0–29). Ninety participants were randomly assigned to one of the three intervention groups: Therapeutic Motion Simulation (TMSim), Whole Body Vibration (WBV), and TMSim + WBV. Participants received 6 weeks of passive exercise, 4 sessions a week, 4 (WBV) to 12 (TMSim and TMSim + WBV) minutes per session. Feasibility of the novel forms of passive exercise was evaluated based on attendance, compliance, (proxy) experience scores, adverse events and drop-out rates. Results: On average 87.9% of the offered intervention sessions were attended. All three forms of passive exercise were well appreciated by the participants (7.3 on a scale from 0 to 10). Intervention related drop-out rates were reasonable (12.2%) and no serious adverse events occurred. Conclusion: The novel passive exercise interventions TMSim, WBV, and TMSim + WBV are feasible to apply in patients at all stages of dementia. More research is needed to establish effectiveness of passive exercise to limit adverse effects of dementia. Show more

Keywords: Dementia, exercise therapy, feasibility studies, long-term care, nursing home, randomized controlled trial, sensory art therapies, vulnerable populations

DOI: 10.3233/JAD-190309

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 681-690, 2019

Authors: Piras, Ignazio S. | Krate, Jonida | Delvaux, Elaine | Nolz, Jennifer | Mastroeni, Diego F. | Persico, Antonio M. | Jepsen, Wayne M. | Beach, Thomas G. | Huentelman, Matthew J. | Coleman, Paul D.

Article Type: Research Article

Abstract: We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer’s disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p  < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r  = 0.504; p  = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender …specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1 ), antemortem MMSE (e.g., AEBP1 and GFAP ), and tangle density (e.g., RNU1G2, and DNALI1 ). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD. Show more

Keywords: Alzheimer’s disease, microarray, middle temporal gyrus, postmortem brains, RNA profiling

DOI: 10.3233/JAD-181113

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 691-713, 2019

Authors: Romano, Raymond R. | Anderson, Alison R. | Failla, Michelle D. | Dietrich, Mary S. | Atalla, Sebastian | Carter, Michael A. | Monroe, Todd B.

Article Type: Research Article

Abstract: Background: Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer’s disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment. Objective: This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum. Methods: We conducted a secondary analysis of data from an age- and sex-matched …between-groups cross-sectional study examining the psychophysical response to contact heat in people with and without dementia. Results: Median age of males (n  = 38) and females (n  = 38) was 73 (range: 68–87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11–30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r  = –0.41, p  = 0.010; males: r  = –0.33, p  = 0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p  = 0.033). Females demonstrated a positive association of MMSE with unpleasantness (r  = 0.30, p  = 0.072), while males demonstrated an inverse association at that respective threshold (r  = –0.20, p  = 0.221). Conclusions: Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception. Show more

Keywords: Cognition, dementia, pain, sex differences

DOI: 10.3233/JAD-190142

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 715-722, 2019

Authors: Alves, Carolina | Jorge, Lília | Canário, Nádia | Santiago, Beatriz | Santana, Isabel | Castelhano, João | Ambrósio, António Francisco | Bernardes, Rui | Castelo-Branco, Miguel

Article Type: Research Article

Abstract: This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer’s disease (AD). Twenty-three healthy controls (mean age = 63.4±7.5 years) and seventeen AD patients (mean age = 66.5±6.6 years) were recruited for this study. By combining two imaging techniques—optical coherence tomography and diffusion tensor imaging (DTI)—the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using …tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p  = 0.016, Cohen’s d  = 1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p  = 0.084, Cohen’s d  = 0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p  < 0.05, r  = 0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, optical coherence tomography, retrograde degeneration, white matter

DOI: 10.3233/JAD-190152

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 723-732, 2019

Authors: Ilomäki, Jenni | Fanning, Laura | Keen, Claire | Sluggett, Janet K. | Page, Amy T. | Korhonen, Maarit J. | Meretoja, Atte | Mc Namara, Kevin P. | Bell, J. Simon

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) are less likely to use oral anticoagulants than people without AD. Objective: We investigated incidence and prevalence of warfarin and direct oral anticoagulant (DOAC) use, and determined predictors of DOAC and warfarin initiation in older people with AD and the general population. Methods: Australian Pharmaceutical Benefits Scheme data for 356,000 people aged ≥65 years dispensed warfarin or DOACs during July 2013-June 2017 were analyzed. Changes in annual incidence and prevalence were estimated using Poisson regression. Predictors of DOAC versus warfarin initiation were estimated using multivariable logistic regression separately for people …with AD and the general population. Results: Oral anticoagulant prevalence increased from 8% in people with AD and 9% in the general population to 12% in both groups from 2013/2014 to 2016/2017. DOAC prevalence increased (from 2.4% to 7.8% in people with AD, 3.2% to 7.7% in the general population) while warfarin prevalence declined (6.6% to 4.5%, 7.0% to 4.3%, correspondingly). The incidence of warfarin use decreased by 45–55%. In people with AD, women were less likely to initiate DOACs than men, whereas presence of arrhythmias or pain/inflammation increased likelihood of initiating DOACs. Age ≥85 years, cardiovascular diseases, gastric acid disorder, diabetes, and end-stage renal disease were associated with lower odds of DOAC initiation in the general population. Conclusion: DOAC introduction has coincided with increased anticoagulation rates in people with AD. Rates are now similar in older people with AD and the general population. Compared to previous years, DOACs are now more likely to be initiated, particularly for those aged ≥85 years. Show more

Keywords: Alzheimer’s disease, anticoagulants, atrial fibrillation, Australia, dementia, direct oral anticoagulants, incidence, prevalence, trends, warfarin

DOI: 10.3233/JAD-190094

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 733-745, 2019