Journal of Alzheimer's Disease - Volume 46, issue 2

Authors: de la Torre Jack, C.

Article Type: Editorial

Abstract: In the popular nursery rhyme, Humpty Dumpty’s great fall and the inability to put him together again has been used to demonstrate the second law of thermodynamics. An oversimplification of this law states that all things in the universe tend to move from order to disorder, an occurrence that can be applied allegorically to the development and clinical outcome of Alzheimer’s disease (AD). An important argument relevant to the future use of resources and primary focus of AD research arises from the question, do we make it a priority to mend the shattered brain of AD patients or attempt to …prevent the brain from shattering? If the former approach continues to be the priority it has become, how exactly do we mend the irreparable neuronal loss and associated cognitive failure in advanced cases of AD? Or, must we change direction and make prevention the primary goal of AD research? The latter approach would identify asymptomatic or mildly symptomatic patients with high risk of developing dementia by means of establishing multidisciplinary heart-brain clinics that would provide either close observation or a tailored therapeutic intervention. This is an important challenge that needs to be achieved if the AD incidence, societal costs and suffering, is to be significantly reduced. Show more

Keywords: Alzheimer’s disease, amyloid-β hypothesis, cognition, entropy, heart-brain clinics, memory, prevention

DOI: 10.3233/JAD-150124

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 289-296, 2015

Authors: Portbury, Stuart D. | Adlard, Paul A.

Article Type: Review Article

Abstract: Alzheimer’s disease, traumatic brain injury, and chronic traumatic encephalopathy represent conditions that have a profound socioeconomic impact for both the individual and the wider community. They are all characterized by specific protein aggregation that results in synaptic dysfunction, neuronal death, and consequent cognitive decline and memory loss. In this review, we present evidence to support the notion that the common pathologies found in all conditions, and indeed their associated cognitive deficits, may be linked by zinc (Zn2 + ) ion dyshomeostasis. Elucidation of this hypothesis may present new therapeutic avenues for these devastating conditions.

Keywords: Alzheimer’s disease, amyloid-β, brain injury, cognition, tau protein, TDP-43, zinc

DOI: 10.3233/JAD-143048

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 297-311, 2015

Authors: Ellis, Ben | Hye, Abdul | Snowden, Stuart G.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative dementia, with the accumulation of extracellular amyloid-β and formation of neurofibrillary tau tangles as leading explanations of pathology. With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology. The present review identified 705 distinct metabolite reports representing 448 structurally distinct metabolites in six human biofluids, with 147 metabolites increased and 214 metabolites decreased with AD, while 80 metabolites showed inconsistent shifts. Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly …associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2-nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult. The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology. Show more

Keywords: Antioxidant, glutamate, metabolism, metabolomics, neurodegeneration, sphingolipid

DOI: 10.3233/JAD-141899

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 313-327, 2015

Authors: Wojsiat, Joanna | Prandelli, Chiara | Laskowska-Kaszub, Katarzyna | Martín-Requero, Angeles | Wojda, Urszula

Article Type: Review Article

Abstract: In Alzheimer’s disease (AD), molecular changes are observed not only in patients’ neurons but also in peripheral cells, such as blood lymphocytes. These include changes in the level of oxidative stress markers, mitochondria impairment, and aberrant cell cycle regulation in AD blood lymphocytes. While the concepts of early causes of AD are currently highly controversial, these findings provide support for the cell cycle hypothesis of AD pathomechanism and emphasize the systemic nature of the disease. Moreover, because of difficulties in studying dynamic processes in the human brain, lymphocytes seem to be useful for readout of AD molecular mechanisms. In addition, …lymphocytes as easily accessible human cells have potential diagnostic value. We summarize current perspectives for the development of new therapeutic strategies based on oxidative stress and cell cycle dysregulation in AD, and for diagnostic methodologies involving new markers in AD lymphocytes. Show more

Keywords: Amyloid, biomarkers, cell cycle, familial Alzheimer’s disease, human lymphocytes, mild cognitive impairment, mitochondria, neurodegeneration, presenilin, oxidative stress, sporadic Alzheimer’s disease

DOI: 10.3233/JAD-141977

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 329-350, 2015

Authors: Migliaccio, Raffaella | Agosta, Federica | Possin, Katherine L. | Canu, Elisa | Filippi, Massimo | Rabinovici, Gil D. | Rosen, Howard J. | Miller, Bruce L. | Gorno-Tempini, Maria Luisa

Article Type: Research Article

Abstract: The term early-onset Alzheimer’s disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial …parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. Show more

Keywords: Age of onset, Alzheimer’s disease, atrophy progression, default mode network, tensor based morphometry, voxel based morphometry

DOI: 10.3233/JAD-142292

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 351-364, 2015

Authors: Zhou, Ye | Zhao, Wenjuan | Al-muhtasib, Nour | Rebeck, G. William

Article Type: Research Article

Abstract: Apolipoprotein E (APOE) alleles are strongly related to the risk of Alzheimer’s disease (AD). APOE genotype also affects inflammatory processes in response to damage. We tested whether APOE genotype affected the levels of specific immunoglobulins in healthy, uninfected APOE knock-in mice. We measured specific immunoglobulins in brain, spleen, and plasma. Levels of total IgG in brain and spleen were highest in APOE-ɛ 3 mice, significantly higher than in APOE-ɛ 2 and APOE-ɛ 4 mice; no differences were observed for levels of total IgG in plasma. We also measured specific subtypes of IgG. IgG1 was only detectable in plasma and did …not differ by APOE genotype. IgG3 was detectable in plasma and spleen, and also did not differ by APOE genotype. IgG2b showed the same pattern as levels of total IgG by APOE genotype, with the highest levels of IgG2b in brain, spleen, and plasma of APOE-ɛ 3 mice. IgG2a showed an entirely different pattern, with significantly higher levels in spleen and plasma of APOE-ɛ 4 mice compared to APOE-ɛ 2 and APOE-ɛ 3 mice. We also measured IgM and IgA in spleens and plasma of these mice. In spleen, APOE-ɛ 4 mice had the lowest IgA levels and the highest levels of IgM; both being significantly different from APOE-ɛ 2 mice. In total, murine IgG2a and IgM were highest in APOE-ɛ 4 mice, while total IgG and Ig2b were highest in APOE-ɛ 3 mice. These dramatically different distributions of immunoglobulins could allow for human AD risk biomarkers based on specific immunoglobulin subtypes. Show more

Keywords: Apolipoprotein E, brain, immunoglobulin, inflammation, plasma, spleen

DOI: 10.3233/JAD-142184

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 365-374, 2015

Authors: Körtvélyessy, Peter | Gukasjan, Angela | Sweeney-Reed, Catherine M. | Heinze, Hans-Jochen | Thurner, Lorenz | Bittner, Daniel M.

Article Type: Research Article

Abstract: Background: Analysis of cerebrospinal fluid (CSF) has improved over the last few years; thus specific markers for different diseases have emerged, e.g., amyloid-β (Aβ) for Alzheimer’s disease (AD) and progranulin for frontotemporal dementia (FTD). Objective: Evaluation of correlation between biomarkers in CSF and cognitive performance in populations with AD and FTD. Methods: 27 patients with AD and 16 with FTD were included. CSF tau, P-tau181P , Aβ42 , and progranulin (PGRN) were measured and a standardized neuropsychological test battery applied. Olfactory testing was additionally included where available. Results: For all patients across both …groups, an association between PGRN and categoric (p  = 0.016) and letter fluency (p  = 0.029), naming (p  = 0.003), and overall cognition (Mini-Mental State Examination: p  = 0.04) was observed. Aβ42 was strongly associated with memory function (learning: p  = 0.001; recall: p  = 0.002). A correlation between Aβ42 and memory performance was moreover found for each group separately, while PGRN also showed a correlation with recognition memory (p  = 0.04) in AD. Furthermore, an association between reduced PGRN and olfactory dysfunction was revealed (p  = 0.01). Conclusions: CSF-levels of PGRN and Aβ42 levels express deficits in cognition differentially, with PGRN being predominantly associated with frontal and Aβ42 with temporal dysfunction. This mirrors the cerebral occurrence of these proteins. These associations appear to be consistent across both disease groups. The relationship between PGRN and olfaction further underpins the association between PRGN and frontal dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cerebrospinal fluid, cognitive neuropsychology in dementia, frontotemporal dementia, progranulin

DOI: 10.3233/JAD-150069

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 375-380, 2015

Authors: Velayudhan, Latha | Gasper, Amy | Pritchard, Megan | Baillon, Sarah | Messer, Charlotte | Proitsi, Petroula

Article Type: Research Article

Abstract: Olfactory dysfunction in general, and impaired odor identification in particular, have been reported in Alzheimer’s disease (AD). Olfactory testing may be a useful diagnostic aid for AD, but the types of odor most commonly affected need to be identified. This study aimed to determine pattern and types of odor affected in AD with the goal of improving clinical applicability. 54 outpatients with mild to moderate AD and 40 age and gender-matched non-demented controls (NDC) were tested using British version of University of Pennsylvania Smell Identification Test (UPSIT; Sensonics, Inc., Haddon Heights, NJ) and data analyzed to identify an optimal subset …of UPSIT to best differentiate AD patients from controls. AD subjects had significantly lower UPSIT total scores than NDC. Random Forest with backward elimination identified 12 UPSIT items which accurately differentiated AD patients compared to controls (sensitivity, 0.89 and specificity, 0.83, positive predictive value of 0.889, and negative predictive value of 0.833). The 12 smell items found to be most affected in AD subjects reflects important attributes such as safety and food, known to be affected in people with AD and that has the potential to impair activities of daily living. The 12 items of British UPSIT most affected in AD subjects provides a potential brief scale for early detection of AD in clinical settings. Independent replication is needed to validate these findings. Show more

Keywords: Alzheimer’s disease, odor, olfaction, pattern of deficits, smell identification

DOI: 10.3233/JAD-142838

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 381-387, 2015

Authors: Budolfson, Katherine | Malek-Ahmadi, Michael | Belden, Christine M. | Powell, Jessica | Davis, Kathryn | Jacobson, Sandra | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Informant-based assessments of cognition and function are commonly used to differentiate individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) from those who are cognitively normal. However, determining the extent to which informant-based measures correlate to objective neuropsychological tests is important given the widespread use of neuropsychological tests in making clinical diagnoses of aMCI and AD. The aim of the current study is to determine how well the Alzheimer’s Questionnaire (AQ) correlates with objective neuropsychological tests. The study utilized data from 300 individuals participating in a brain and body donation program. Individuals diagnosed with aMCI (n  = 83) and …AD (n  = 67) were matched on age, gender, and education to a control individual (n  = 150). The average age for the entire sample was 83.52±6.51 years with an average education level of 14.57±2.55 years. Results showed that the AQ correlated strongly with the Mini-Mental State Exam (r  =−0.71, p  <  0.001) and the Mattis Dementia Rating Scale-2 (r  =−0.72, p  <  0.001), and moderate correlations were noted for the AQ with memory function (Rey Auditory Verbal Learning Test Delayed Recall, r  =−0.61, p  <  0.001) and executive function (Trails B, r  = 0.53, p  <  0.001). The findings of this study suggest that the AQ correlates well with several neuropsychological tests and lend further support to the validity of the AQ as a screening instrument for cognitive impairment. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-142388

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 389-397, 2015

Authors: Jang, Hyemin | Kim, Jong Hun | Choi, Seong Hye | Lee, Yunhwan | Hong, Chang Hyung | Jeong, Jee Hyang | Han, Hyun Jeong | Moon, So Young | Park, Kyung Won | Han, Seol-Hee | Park, Kee Hyung | Kim, Hee Jin | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background: A relationship between body weight, cognitive impairment, and the onset of Alzheimer’s disease (AD) was recently reported. However, to our knowledge, no studies have investigated the relationship between body weight and mortality in Asian AD patients. Objective: We evaluated the relationship between body mass index (BMI) and mortality rate in Korean AD cohorts. Methods: Participants were consecutively included from two Korean representative registries: 579 AD patients from Samsung Medical Center and 1911 AD patients from the Clinical Research Center for Dementia of South Korea study. We combined these two AD cohorts to evaluate the …association between BMI and mortality. BMI was used to categorize the participants into underweight, normal-weight, overweight, and obesity subgroups. All deaths were confirmed through the nationwide mortality database of Statistics Korea. Results: 53 of 181 (29.3%), 208 of 1,127 (18.5%), 88 of 626 (14.1%), and 115 of 556 (20.7%) patients died in the underweight, normal-weight, overweight, and obese subgroups during 43.7 months of follow-up. The time-dependent cox proportional hazards model showed that, relative to the normal-weight subgroup, the underweight group had higher mortality (HR 1.82 (95% CI, 1.07–3.09)) while overweight group had lower mortality rate (HR 0.60 (95% CI, 0.38–0.95)) The effects of underweight and overweight were prominent in younger and older elderly group, respectively. However, there were no interactive effects of dementia severity or gender and BMI on survival rate. Conclusion: Relative to AD patients of normal weight, those who were underweight had an increased mortality rate, and overweight predicted decreased mortality in AD patients. Furthermore, our findings may help facilitate mortality stratification in AD patients by using baseline BMI. Show more

Keywords: Alzheimer’s disease, body mass index, mortality, obesity, survival analysis

DOI: 10.3233/JAD-142790

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 399-406, 2015