Journal of Alzheimer's Disease - Volume 58, issue 2

Authors: Tan, Yi Jayne | Ng, Adeline S.L. | Vipin, Ashwati | Lim, Joseph K.W. | Chander, Russell J. | Ji, Fang | Qiu, Yingwei | Ting, Simon K.S. | Hameed, Shahul | Lee, Tih-Shih | Zeng, Li | Kandiah, Nagaendran | Zhou, Juan

Article Type: Research Article

Abstract: Background: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer’s disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. Objective: To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. Methods: We measured peripheral TREM2 mRNA levels in 80 AD, 30 …aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. Results: TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. Conclusion: Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis. Show more

Keywords: Alzheimer’s disease, atrophy, blood-based biomarkers, hippocampus, mild cognitive impairment, TREM2

DOI: 10.3233/JAD-161277

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 413-423, 2017

Authors: Berezuk, Courtney | Zakzanis, Konstantine K. | Ramirez, Joel | Ruocco, Anthony C. | Edwards, Jodi D. | Callahan, Brandy L. | Black, Sandra E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer’s disease may be explained by gender differences in IADL involvement. Objective: We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve. Methods: We cross-sectionally examined men (n  = 502) and women (n  = 340) with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the …dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women. Results: Gender was associated with total FAQ (p  < 0.05) until adjusting for IADL experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p  < 0.001), although IADL experience was the most important single variable (4.8% explained, p  < 0.001). Stratification by gender revealed that IADL experience accounted for 6.6% of the variance in FAQ score in men (p  < 0.001) but only 2.4% in women (p  = 0.001); however, the interaction between gender and experience was not statistically significant. Discussion: A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment. Show more

Keywords: Activities of daily living, cognitive reserve, disability, functional impairment, instrumental activities of daily living, sex differences

DOI: 10.3233/JAD-161227

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 425-434, 2017

Authors: Dublin, Sascha | Walker, Rod L. | Gray, Shelly L. | Hubbard, Rebecca A. | Anderson, Melissa L. | Yu, Onchee | Montine, Thomas J. | Crane, Paul K. | Sonnen, Josh A. | Larson, Eric B.

Article Type: Research Article

Abstract: Background: Opioids may influence the development of Alzheimer’s disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes. Objective: To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes. Methods: Within a community-based autopsy cohort (N = 420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome …measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample. Results: Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64–1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49–1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01–1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease. Conclusion: Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes. Show more

Keywords: Alzheimer’s disease, neuropathology, neurofibrillary tangles, neuritic plaques, non-steroidal anti-inflammatory agents, opioid analgesics

DOI: 10.3233/JAD-160374

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 435-448, 2017

Authors: Sepehry, Amir A. | Lee, Philip E. | Hsiung, Ging-Yuek R. | Beattie, B. Lynn | Feldman, Howard H. | Jacova, Claudia

Article Type: Research Article

Abstract: Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer’s Disease (PDC-dAD) that were formulated to address depression in Alzheimer’s disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, …we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC’s relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence. Show more

Keywords: Alzheimer’s disease, depression, diagnosis, DSM, epidemiology, meta-analysis, NIMH Provisional Diagnostic Criteria, validity

DOI: 10.3233/JAD-161061

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 449-462, 2017

Authors: Sadiq, Dilman | Whitfield, Tim | Lee, Lean | Stevens, Tim | Costafreda, Sergi | Walker, Zuzana

Article Type: Research Article

Abstract: Background: Dementia must be diagnosed accurately and early in the disease course to allow pathology-specific treatments to be effective. Dementia with Lewy bodies (DLB) is often misdiagnosed as Alzheimer’s disease (AD), especially at the prodromal stage. Objective: To compare the clinical and neuropsychological profiles of Mild Cognitive Impairment (MCI) patients who, at follow-up, progressed to AD (retrospectively AD-MCI) or DLB (retrospectively DLB-MCI) or remained MCI. Methods: This longitudinal study used an unselected sample from a memory clinic database. A total of 1,848 new patients were seen at the memory clinic between 1994–2015. Of these, 560 …patients (30%) had an initial diagnosis of MCI and were considered for the study. Inclusion criteria were patients who had a diagnosis of MCI at initial assessment and a minimum of 12 months’ follow-up. Results: Of the 429 MCI patients with follow-up data, 164 (38%) remained MCI, 107 (25%) progressed to AD, and 21 (5%) progressed to DLB. The remainder progressed to alternative diagnoses. At baseline, DLB-MCI patients performed significantly worse on visuospatial function and letter fluency tests than both AD-MCI and stable-MCI groups, and better on episodic memory tests than the AD-MCI group. At baseline, DLB-MCI patients had a significantly higher mean UPDRS score and were more likely to have REM sleep behavior disorder and fluctuating cognition. Conclusion: DLB-MCI patients have a specific cognitive and neuropsychiatric profile which should alert clinicians to the possibility of prodromal DLB. This is relevant when considered in the context of early disease-specific therapy. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, longitudinal studies, Mild Cognitive Impairment, neuropsychology

DOI: 10.3233/JAD-161089

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 463-470, 2017

Authors: Kolarova, Michala | Sengupta, Urmi | Bartos, Ales | Ricny, Jan | Kayed, Rakez

Article Type: Research Article

Abstract: Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer’s disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels …positively correlated with aging (Spearman r  = 0.26, p  = 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p  = 0.033) and MCI-AD (p  = 0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain. Show more

Keywords: Alzheimer’s disease, oligomers, serum, tau protein

DOI: 10.3233/JAD-170048

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 471-478, 2017

Authors: Suhonen, Noora-Maria | Haanpää, Ramona M. | Korhonen, Ville | Jokelainen, Jari | Pitkäniemi, Anni | Heikkinen, Anna-Leena | Krüger, Johanna | Hartikainen, Päivi | Helisalmi, Seppo | Hiltunen, Mikko | Hänninen, Tuomo | Remes, Anne M.

Article Type: Research Article

Abstract: While the C9ORF72 expansion is a major cause of behavioral variant frontotemporal dementia (bvFTD), little is known of the resultant cognitive profile. Our aim was to characterize the neuropsychological profile of the C9ORF72 associated bvFTD. We contrasted structured neuropsychological assessments of the C9ORF72 expansion carrier bvFTD patients (n  = 26) with non-carrier bvFTD patients (n  = 47) and those with Alzheimer’s disease (AD) (n  = 47). As compared to the non-carrier bvFTD patients, the C9ORF72 expansion carriers performed at a higher level in an immediate verbal memory test while showing poorer phonemic verbal fluency. Additionally, the expansion carriers committed …more errors in the Stroop test and the Alternating S task relative to the non-carriers. Finally, while the AD patients outperformed both bvFTD patient groups in working memory, their performance was more impaired in episodic memory tasks relative to the bvFTD groups. We conclude that bvFTD patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD may aid in the early diagnosis of the disease as well as in targeting genetic testing. Show more

Keywords: Alzheimer’s disease, C9ORF72, frontotemporal dementia, frontotemporal lobar degeneration, genetics, neuropsychological tests, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-161142

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 479-489, 2017

Authors: Macdonald, Ian R. | Maxwell, Selena P. | Reid, George A. | Cash, Meghan K. | DeBay, Drew R. | Darvesh, Sultan

Article Type: Research Article

Abstract: Amyloid-β (Aβ) plaques are a neuropathological hallmark of Alzheimer’s disease (AD); however, a significant number of cognitively normal older adults can also have Aβ plaques. Thus, distinguishing AD from cognitively normal individuals with Aβ plaques (NwAβ) based on Aβ plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aβ, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n  = 8), NwAβ (n  = 6), cognitively normal without plaques (n  = 8), and other common dementias including corticobasal degeneration, frontotemporal …dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aβ and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aβ and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAβ and AD, due to the virtual absence of BChE-associated plaques in NwAβ brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Aβ (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management. Show more

Keywords: Acetylcholinesterase, α-synucleinopathy, Alzheimer’s disease, amyloid-β, butyrylcholinesterase, tauopathies, thioflavin-S

DOI: 10.3233/JAD-170164

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 491-505, 2017

Authors: Majerova, Petra | Barath, Peter | Michalicova, Alena | Katina, Stanislav | Novak, Michal | Kovac, Andrej

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model …for tauopathy expressing human truncated tau protein (aa 151–391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography – matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation. Show more

Keywords: Cerebrospinal fluid, LC-MALDI MS, peptidomics, rat model, tauopathy

DOI: 10.3233/JAD-170110

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 507-520, 2017

Authors: Nelson, Thomas J. | Sun, Miao-Kun | Lim, Chol | Sen, Abhik | Khan, Tapan | Chirila, Florin V. | Alkon, Daniel L.

Article Type: Research Article

Abstract: Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer’s disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2 ) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p  = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received …drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus –1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 μg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD. Show more

Keywords: Alzheimer’s disease, bryostatin 1, controlled clinical trial, expanded access trials, pharmacokinetics, protein kinase C

DOI: 10.3233/JAD-170161

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 521-535, 2017