Journal of Alzheimer's Disease - Volume 55, issue 2

Authors: Jansen, Willemijn J. | Handels, Ron L.H. | Visser, Pieter Jelle | Aalten, Pauline | Bouwman, Femke | Claassen, Jurgen | van Domburg, Peter | Hoff, Erik | Hoogmoed, Jan | Leentjens, Albert F.G. | Rikkert, Marcel Olde | Oleksik, Ania M. | Smid, Machiel | Scheltens, Philip | Wolfs, Claire | Verhey, Frans | Ramakers, Inez H.G.B.

Article Type: Research Article

Abstract: Background: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. Methods: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer’s disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before …and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n  = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n  = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n  = 1) correctly reclassified, etiology: NRI = –0.05, prognosis: NRI = –0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression. Show more

Keywords: Alzheimer’s disease, cognitive disorders, consensus, diagnosis, prognosis, mild cognitive impairment, neuropsychological tests, outpatient clinic, reclassification

DOI: 10.3233/JAD-160126

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 679-689, 2017

Authors: Wucherer, Diana | Eichler, Tilly | Hertel, Johannes | Kilimann, Ingo | Richter, Steffen | Michalowsky, Bernhard | Thyrian, Jochen René | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Potentially inappropriate medication (PIM) in older people is a risk factor for adverse drug effects. This risk is even higher in older people with dementia (PWD). Objective: Our study aimed to determine (1) the prevalence of PIM among primary care patients who were screened positive for dementia and (2) the sociodemographic and clinical variables associated with the use of PIM. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg–Western Pomerania) is a general practitioner-based, cluster-randomized, controlled intervention study to implement and evaluate an innovative concept of collaborative dementia care management in Germany. The comprehensive …baseline assessment includes a home medication review. The present analyses are based on the data from 448 study participants (age 70+, DemTect <9). PIMs were identified using the list of Potentially Inappropriate Medications in the Elderly (Priscus). Results: (1) A total of 99 study participants (22%) received at least one PIM. The highest prevalence was found for antidepressants, benzodiazepines, and analgetics. The most frequently prescribed PIMs were amitriptyline, etoricoxib, and doxazosin. (2) Use of a PIM was significantly associated with a diagnosis of a mental or behavioral disorder. Conclusions: The prescription rate of PIMs for community-dwelling PWD was comparable with the rates found for the general population of older people in Germany (20–29%). Antidepressants with anticholinergic properties and long-acting benzodiazepines were the most prescribed PIMs, despite having an unfavorable benefit-risk ratio. This high prevalence of PIM prescriptions in a vulnerable population of PWD indicates that standard care for dementia should include careful medication review and management. Show more

Keywords: Dementia, PIM List, potentially inappropriate medications, primary health care

DOI: 10.3233/JAD-160581

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 691-701, 2017

Authors: Wawrziczny, Emilie | Berna, Guillaume | Ducharme, Francine | Kergoat, Marie-Jeanne | Pasquier, Florence | Antoine, Pascal

Article Type: Research Article

Abstract: Background: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress. Objective: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress. Methods: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the …disease and the gender of the caregiver (Step 2). Results: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD’s symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient’s impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress. Conclusions: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, “preparedness modules”; second, “dyadic modules” (especially for caregivers of PEOD); and third, “family modules”. Specific attention should be given to female caregivers who report poor self-rated health. Show more

Keywords: Caregivers, dementia, early onset Alzheimer disease, late onset Alzheimer disease, psychological model, spouses

DOI: 10.3233/JAD-160558

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 703-716, 2017

Authors: Ulstein, Ingun | Bøhmer, Thomas

Article Type: Research Article

Abstract: Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer’s disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given …as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (μmol/l), 63 (18), 61 (16), and 63 (29); A (μmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3 (0.5); E (μmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p ≤0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, vitamin deficiencies

DOI: 10.3233/JAD-160393

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 717-725, 2017

Authors: An, Hoyoung | Choi, Booyeol | Park, Kun-woo | Kim, Do-Hoon | Yang, Dong-Won | Hong, Chang Hyung | Kim, Seong Yoon | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: Effective treatments to alleviate depression in Alzheimer’s disease (AD) have been scarce. Objective: To investigate the efficacy and tolerability of escitalopram in the treatment of depression in AD. Methods: In this 12-week randomized, double-blind, placebo-controlled trial with open-label, 12-week extension, AD subjects over 50 years of age, with depression defined by Olin’s provisional diagnostic criteria, were enrolled. The Cornell Scale for Depression in Dementia (CSDD), and other measures of depression and cognition were repeated. Results: 91 subjects were screened, and 84 were randomized into either the study group or placebo group (n … = 42 for both groups). Twenty-four subjects (29%) were unable to finish the study, yielding a per protocol population of 60 subjects (study group: n  = 27; placebo group: n  = 33). At week 12, differences in measures of depression and cognition between the two groups were not statistically significant. However, exploratory analysis suggested that further research on a subset of subjects with ‘definite major depression’ (baseline CSDD score ≥18) is needed. The number of treatment-related adverse-events (AE) did not differ between groups (p  = 0.83) and no serious treatment-related AE were observed. Conclusion: The use of escitalopram was well tolerated in depressive dementia patients. Future studies focusing on subjects with more severe levels of depression, and with more statistical power, will be needed. Show more

Keywords: Alzheimer’s disease, clinical trial, depression, escitalopram, placebo

DOI: 10.3233/JAD-160225

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 727-735, 2017

Authors: Coskun, Pinar | Helguera, Pablo | Nemati, Zahra | Bohannan, Ryan C. | Thomas, Jean | Samuel, Schriner E. | Argueta, Jocelyn | Doran, Eric | Wallace, Douglas C. | Lott, Ira T. | Busciglio, Jorge

Article Type: Research Article

Abstract: Background: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer’s disease (AD) and these alterations in mitochondria occur systemically in both conditions. Objective: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. Methods: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We …assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. Results: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. Conclusion: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes. Show more

Keywords: Alzheimer’s disease, autophagy, dementia, Down syndrome, growth retardation, lymphoblastoid cell lines, metabolic alterations, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-160278

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 737-748, 2017

Authors: Rueli, Rachel H.L.H. | Torres, Daniel J. | Dewing, Andrea S.T. | Kiyohara, Arlene C. | Barayuga, Stephanie M. | Bellinger, Miyoko T. | Uyehara-Lock, Jane H. | White, Lon R. | Moreira, Paula I. | Berry, Marla J. | Perry, George | Bellinger, Frederick P.

Article Type: Research Article

Abstract: Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer’s disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer’s disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer’s disease. SelS expression increased with ER stress and …decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer’s disease and potentially other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, endoplasmic reticulum stress, neurofibrillary tangle, selenium, selenoprotein, tau

DOI: 10.3233/JAD-151208

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 749-762, 2017

Authors: Dekens, Doortje W. | Naudé, Petrus J.W. | Engelborghs, Sebastiaan | Vermeiren, Yannick | Van Dam, Debby | Oude Voshaar, Richard C. | Eisel, Ulrich L.M. | De Deyn, Peter P.

Article Type: Research Article

Abstract: Co-existing depression worsens Alzheimer’s disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD–D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n  = 19), AD–D (n  = 19), and AD+D (n  = 21) patients. NGAL levels in AD–D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in …AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression. Show more

Keywords: 24p3R, Alzheimer’s disease, depression, hippocampus, inflammation, lipocalin 2, megalin, NGAL

DOI: 10.3233/JAD-160330

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 763-776, 2017

Authors: Sun, Lin | Chen, Kathryn | Li, Xia | Xiao, Shifu

Article Type: Research Article

Abstract: Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. …We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease. Show more

Keywords: Early onset dementia, frontotemporal dementia, G389R mutation, MAPT, protein structure predicting

DOI: 10.3233/JAD-160802

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 777-785, 2017

Authors: Han, Ji Won | Lee, Hyeonggon | Hong, Jong Woo | Kim, Kayoung | Kim, Taehyun | Byun, Hye Jin | Ko, Ji Won | Youn, Jong Chul | Ryu, Seung-Ho | Lee, Nam-Jin | Pae, Chi-Un | Kim, Ki Woong

Article Type: Research Article

Abstract: We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental …State Examination (effect size = 0.47, p  = 0.013) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p  = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p  = 0.046) and self-rated Quality of Life – Alzheimer’s Disease (effect size = 0.39, p  = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did. Show more

Keywords: Cognitive interventions, cognitive therapy, cognitive training, dementia, mild cognitive impairment, mild dementia, multimodal cognitive enhancement therapy, non-pharmacologic treatment, randomized controlled trials

DOI: 10.3233/JAD-160619

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 787-796, 2017

Authors: McClure, Richard | Ong, Henry | Janve, Vaibhab | Barton, Shawn | Zhu, Meiying | Li, Bo | Dawes, Mary | Jerome, W. Gray | Anderson, Adam | Massion, Pierre | Gore, John C. | Pham, Wellington

Article Type: Research Article

Abstract: We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer’s disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Keywords: Aerosol, amyloid-β, curcumin, nebulization

DOI: 10.3233/JAD-160289

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 797-811, 2017

Authors: Lewczuk, Piotr | Matzen, Anja | Blennow, Kaj | Parnetti, Lucilla | Molinuevo, Jose Luis | Eusebi, Paolo | Kornhuber, Johannes | Morris, John C. | Fagan, Anne M.

Article Type: Research Article

Abstract: Background: Decreased concentrations of amyloid-β 1-42 (Aβ42 ) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status …and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n  = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n  = 150 PET-negative, n  = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p  < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p  < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-160722

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 813-822, 2017

Authors: Peh, Chao Xu | Abdin, Edimansyah | Vaingankar, Janhavi A. | Verma, Swapna | Chua, Boon Yiang | Sagayadevan, Vathsala | Seow, Esmond | Zhang, YunJue | Shahwan, Shazana | Ng, Li Ling | Prince, Martin | Chong, Siow Ann | Subramaniam, Mythily

Article Type: Research Article

Abstract: Background: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data. Objective: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above. Methods: δ was constructed using items from the Community Screening Instrument for Dementia (CSI’D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT …dementia. Divergent validity was examined with GMS-AGECAT depression. Results: The δ model demonstrated fit to the data, χ2 (df ) = 249.71(55), p  < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β= 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education. Conclusion: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates. Show more

Keywords: Cognition, dementia, functional status, Singapore, validation studies

DOI: 10.3233/JAD-160575

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 823-833, 2017

Authors: Shen, Yijun | Xia, Yiling | Meng, Shiquan | Lim, Nastasia K.H. | Wang, Wenan | Huang, Fude

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved …in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42 . Partial knockout of neuronal SH2B in the Aβ42 -expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42 , as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42 -expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42 . Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β accumulation, diabetes, SH2B1 protein

DOI: 10.3233/JAD-160233

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 835-847, 2017

Authors: de la Monte, Suzanne M. | Tong, Ming | Schiano, Irio | Didsbury, John

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model. Objective: This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model. Methods: Long Evans rats were treated with …i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs. Results: i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42 , ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9 -GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9 -GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation. Conclusion: AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain. Show more

Keywords: Alzheimer’s disease, cytokines, insulin resistance, neurodegeneration, PPAR delta, rat model, T3D-959

DOI: 10.3233/JAD-160656

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 849-864, 2017