Journal of Alzheimer's Disease - Volume 67, issue 1

Authors: Koseoglu, Mehmet Murat | Norambuena, Andrés | Sharlow, Elizabeth R. | Lazo, John S. | Bloom, George S.

Article Type: Review Article

Abstract: Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer’s disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling “hotspots” in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, …may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD. Show more

Keywords: Alzheimer’s disease, amyloid, cell cycle re-entry, tau

DOI: 10.3233/JAD-180874

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 1-11, 2019

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Wei, Na | Almansob, Yusra A. M. | He, Wei | Liu, Dan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases that is characterized by progressive memory loss and two main pathological hallmarks, including the extracellular amyloid plaques and intracellular neurofibrillary tangles. The microtubule-related protein tau is involved in the pathogenesis of many neurological diseases commonly known as tauopathies and is found to be abnormally hyperphosphorylated in AD and accumulated in neurons. Besides hyperphosphorylation, tau also undergoes abnormal glycosylation, ubiquitination, glycation, and other posttranslational modifications. These abnormalities lead to the aberrant aggregation of tau in the synaptic loci in AD. In this review, we highlighted the most recent studies about …how tau is abnormally regulated and how those abnormalities play important roles in the pathogenesis of AD. Show more

Keywords: Aggregation, Alzheimer’s disease, hyperphosphorylation, post-translational modifications, tau

DOI: 10.3233/JAD-180868

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 13-33, 2019

Authors: Medeiros, André de Macêdo | Silva, Regina Helena

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that drastically compromises patients’ and relatives’ quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, …full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective. Show more

Keywords: Aging, animal models, hormones, humans, immune system, oxidative stress, stress

DOI: 10.3233/JAD-180213

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 35-60, 2019

Authors: Rizzo, Giovanni | De Blasi, Roberto | Capozzo, Rosa | Tortelli, Rosanna | Barulli, Maria Rosaria | Liguori, Rocco | Grasso, Daniela | Logroscino, Giancarlo

Article Type: Short Communication

Abstract: We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer’s disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p  < 0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53%) but specificity increased (82–100%). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

Keywords: Dementia with Lewy bodies, magnetic resonance imaging, nigrosome, swallow tail sign, susceptibility-weighted imaging

DOI: 10.3233/JAD-180687

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 61-65, 2019

Authors: Royall, Donald R. | Palmer, Raymond F. | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Dementia can be empirically described by the latent dementia phenotype “δ” and its various composite “homologs”. We have explored δ’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). To this end, we have engineered a δ homolog from observed cognitive performance measures common to both projects. Our findings were replicated in randomly selected 50% splits of TARCC data (Group 1, N = 1,747; Group 2, N = 1,755), and then independently in ADNI (N = 1,737). The new δ homolog, i.e., “dT2A” (d-TARCC to ADNI), …fit the data of both studies well, and was strongly correlated with dementia severity, as rated by the Clinical Dementia Rating Scale “sum of boxes” (TARCC: r  = 0.99, p  < 0.001; ADNI: r  = 0.96, p  < 0.001). dT2A achieved an area under the receiver operating characteristic curve of 0.981 (0.976–0.985) for the discrimination of Alzheimer’s disease from normal controls in TARCC, and 0.988 (0.983–0.993) in ADNI. dT2A is the 12th δ homolog published to date, and opens the door to independent replications across these and similar studies. Show more

Keywords: Aging, Alzheimer Disease Neuroimaging Initiative, cognition, dementia, g , intelligence, TARCC

DOI: 10.3233/JAD-171053

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 67-79, 2019

Authors: Pappas, Colleen | Small, Brent J. | Andel, Ross | Laczó, Jan | Parizkova, Martina | Ondrej, Lerch | Hort, Jakub

Article Type: Research Article

Abstract: Background: Identifying protective factors that promote healthy cognitive aging is of importance due to the growing older adult population. Preventing chronic hyperglycemia may be one such way to preserve cognitive abilities, as high blood glucose levels have been associated with cognitive impairment and decline. Objective: To evaluate the influence of blood glucose levels on cognition among older adults using common neuropsychological tests and a spatial navigation task. Methods: The association between cognitive performance and blood glucose levels was assessed among 117 older adults classified as cognitively healthy, subjective cognitive decline, amnestic mild cognitive impairment, or Alzheimer’s …disease dementia from the Czech Brain Aging Study. Cognitive abilities were measured by tests of verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function. A test of spatial navigation known as the Hidden Goal Task was also used. Blood glucose levels were measured by glycosylated hemoglobin A1c (HbA1c). Analyses were performed using multiple linear regression controlling for age, gender, education, depressive symptoms, diabetes, and cognitive status. Results: A significant relationship was observed for HbA1c and executive function performance (beta = –2.46, SE  = 0.92, p  = 0.008). Following moderation analysis, this relationship was significant only among those with cognitive impairment (beta = –4.37, SE  = 1.28, p  = 0.001, 95% CI [–6.91, –1.83]). Associations between HbA1c and other cognitive domains were not significant (p s > 0.05). Conclusions: Higher HbA1c was associated with poorer executive function among persons with cognitive impairment, but not with performance on other cognitive domains. Maintaining proper glucoregulation may help preserve executive function performance among cognitively impaired older adults. Show more

Keywords: Biomarkers, cognition, cognitive impairments, executive function

DOI: 10.3233/JAD-180693

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 81-89, 2019

Authors: Reed, May J. | Damodarasamy, Mamatha | Pathan, Jasmine L. | Chan, Christina K. | Spiekerman, Charles | Wight, Thomas N. | Banks, William A. | Day, Anthony J. | Vernon, Robert B. | Keene, C. Dirk

Article Type: Research Article

Abstract: Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) 1–3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1–3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0– II, n  = 12–21), intermediate AD (CERAD = 2, Braak = III–IV, n … = 13–18), and high AD (CERAD = 3, Braak = V–VI, n  = 32–40) neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥ 90 years versus <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression. Show more

Keywords: Alzheimer’s disease, extracellular matrix, hyaluronan, TSG-6

DOI: 10.3233/JAD-180797

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 91-102, 2019

Authors: Helman, Alex M. | Siever, Morgan | McCarty, Katie L. | Lott, Ira T. | Doran, Eric | Abner, Erin L. | Schmitt, Frederick A. | Head, Elizabeth

Article Type: Research Article

Abstract: Cerebrovascular pathology is a significant mediator in Alzheimer’s disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2–83 years). Sections were immunostained against Aβ …1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials. Show more

Keywords: Cerebral amyloid angiopathy, microhemorrhages, Prussian blue, trisomy 21

DOI: 10.3233/JAD-180589

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 103-112, 2019

Authors: Ducharme, Simon | Pearl-Dowler, Leora | Gossink, Flora | McCarthy, Jillian | Lai, Jimmy | Dickerson, Bradford C. | Chertkow, Howard | Rapin, Lucile | Vijverberg, Everard | Krudop, Welmoed | Dols, Annemieke | Pijnenburg, Yolande

Article Type: Research Article

Abstract: Background: Differentiating early behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is complex and biomarkers have limited accuracy, leading to inaccurate diagnoses. Objectives: Develop a simple bedside clinical tool to differentiate bvFTD from PPD. Methods: A checklist of clinical features differentiating bvFTD from PPD was developed based on literature and clinical experience. The checklist was filled prospectively for 29 consecutive patients (Montreal Neurological Hospital) with late-onset (≥ age 40) behavioral changes suggestive of bvFTD. The checklist was subsequently retrospectively completed on the baseline visit (N = 137) of the Late-Onset Frontal Lobe study …(Amsterdam). In both cohorts, patients were followed 2 years to establish a final best clinical diagnosis, categorizing patients into Probable FTD (N = 46), Possible FTD (N = 8), Other Cognitive Disorder (N = 36), Other Neurological Disorder (N = 10), or PPD (N = 66). Results: All items distinguished the two groups except “duration more than 5 years”, which was removed to create a final 17-item version. Mean checklist scores were significantly different across all groups (Oneway ANOVA F(4,161) = 27.462, p  < 0.001). The PPD group had lower scores than all other dementia categories, with the largest difference between Probable FTD ( X ¯ = 12.04) and PPD ( X ¯ = 7.48). A score ≥11 was found to be strongly indicative of bvFTD (specificity 93.9%, sensitivity 71.1%, PPV 89.2%). Scores ≤8 were strongly indicative of a PPD (specificity 91.3%, sensitivity 77.3%, PPV 92.7%). Patient with scores of 9–10 are considered indeterminate. Conclusions: Although further prospective validation is required, the “FTD vs PPD Checklist” could provide a simple tool to improve diagnostic accuracy, particularly in non-specialized settings. Show more

Keywords: Behavioral variant frontotemporal dementia, diagnosis, frontotemporal dementia, psychiatric disorders, scale

DOI: 10.3233/JAD-180839

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 113-124, 2019

Authors: Zammit, Andrea R. | Muniz-Terrera, Graciela | Katz, Mindy J. | Hall, Charles B. | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. Objective: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. …Methods: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. Results: LCA resulted in a 5-class model: Mixed-Domain Impairment (n  = 71, 4.3%), Memory-specific-Impairment (n  = 274, 16.5%), Average (n  = 767, 46.1%), Frontal Impairment (n  = 222, 13.4%), and a class of Superior Cognition (n  = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer’s disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer’s disease when compared to the Average class. Conclusions: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests. Show more

Keywords: Alzheimer’s disease, dementia, latent class analysis, neuropsychological profiles

DOI: 10.3233/JAD-180737

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 125-135, 2019