Journal of Alzheimer's Disease - Volume 35, issue 4

Authors: Xiao, Chun | Davis, Francesca J. | Chauhan, Balwantsinh C. | Viola, Kirsten L. | Lacor, Pascale N. | Velasco, Pauline T. | Klein, William L. | Chauhan, Neelima B.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that …intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice. Show more

Keywords: Alzheimer's immunotherapy, amyloid-β oligomer antibody, brain transit, cerebral amyloid-β immunocytochemistry, intranasal delivery, olfactory pathway, rostral migratory stream pathway, spatial acquisition learning, trigeminal pathway

DOI: 10.3233/JAD-122419

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 777-788, 2013

Authors: Claxton, Amy | Baker, Laura D. | Wilkinson, Charles W. | Trittschuh, Emily H. | Chapman, Darla | Watson, G. Stennis | Cholerton, Brenna | Plymate, Stephen R. | Arbuckle, Matthew | Craft, Suzanne

Article Type: Research Article

Abstract: A previous clinical trial demonstrated that four months of treatment with intranasal insulin improves cognition and function for patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), but prior studies suggest that response to insulin treatment may differ by sex and ApoE ε4 carriage. Thus, responder analyses using repeated measures analysis of covariance were completed on the trial's 104 participants with MCI or AD who received either placebo or 20 or 40 IU of insulin for 4 months, administered by a nasal delivery device. Results indicate that men and women with memory impairment responded differently to intranasal insulin treatment. …On delayed story memory, men and women showed cognitive improvement when taking 20 IU of intranasal insulin, but only men showed cognitive improvement for the 40 IU dose. The sex difference was most apparent for ApoE ε4 negative individuals. For the 40 IU dose, ApoE ε4 negative men improved while ApoE ε4 negative women worsened. Their ApoE ε4 positive counterparts remained cognitively stable. This sex effect was not detected in functional measures. However, functional abilities were relatively preserved for women on either dose of intranasal insulin compared with men. Unlike previous studies with young adults, neither men nor women taking intranasal insulin exhibited a significant change in weight over 4 months of treatment. Show more

Keywords: Alzheimer's disease, insulin, intranasal drug administration, mild cognitive impairment, randomized clinical trials

DOI: 10.3233/JAD-122308

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 789-797, 2013

Authors: Shim, Yong S. | Roe, Catherine M. | Buckles, Virginia D. | Morris, John C.

Article Type: Research Article

Abstract: A definite diagnosis of Alzheimer's disease (AD) can only be made at autopsy. Even at expert research centers, diagnostic accuracy is relatively low. We conducted this study to examine the accuracy of clinical diagnosis of AD and present a list of clinical and neuropsychological findings that could render the clinical diagnosis difficult. Using the National Alzheimer's Coordinating Center database, the records of 533 patients who had been diagnosed clinically with AD, and later underwent autopsy, were reviewed retrospectively. Since the pathologic results of 119 subjects did not meet the criteria for definite AD, we labeled them as Alzheimer “mimics”. The …neuropathological diagnoses of Alzheimer mimics consisted of dementia with Lewy bodies (n = 35, 29%), insufficient AD (n = 22, 18%), vascular disease (n = 15, 13%), frontotemporal lobar degeneration (n = 14, 12%), and hippocampal sclerosis (n = 10, 8%). History of pacemaker insertion (10.92% versus 4.11%, p = 0.005), congestive heart failure (13.45% versus 6.04%, p = 0.007), hypertension (56.30% versus 47.83%, p = 0.037), and resting tremor (14.29% versus 10.87%, p = 0.170) was more prevalent in Alzheimer mimics. Clinical Dementia Rating score and frequency of Neuropsychiatric Inventory Questionnaire items reflecting delusions, agitation, depression, and motor disturbance were more severe in confirmed AD. In addition to Mini-Mental State Examination (16.97 ± 8.29 versus 12.74 ± 15.26, p < 0.001), Logical Memory, Animal Fluency, Boston Naming Test, and Digit Span scores showed more severe impairment in confirmed AD. Continuing systematic comparisons of the current criteria for the clinical and pathological dementia diagnoses are essential to clinical practice and research, and may also lead to further improvement of the diagnostic procedure. Show more

Keywords: Alzheimer's disease, dementia with Lewy bodies, diagnosis, pathology

DOI: 10.3233/JAD-121594

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 799-811, 2013

Authors: Cho, Hanna | Seo, Sang Won | Kim, Jung-Hyun | Suh, Mee Kyung | Lee, Jae-Hong | Choe, Yearn Seong | Lee, Kyung-Han | Kim, Jae Seung | Kim, Geon Ha | Noh, Young | Ye, Byoung Seok | Kim, Hee Jin | Yoon, Cindy W. | Chin, Juhee | Na, Duk L.

Article Type: Research Article

Abstract: Background: Patients with early-onset Alzheimer’s disease (EOAD) may differ from those with late-onset Alzheimer’s disease (LOAD) in cognitive impairment profiles and clinical course. Postmortem studies also reported that EOAD has a greater pathologic burden than LOAD. We examined the effects of age at onset on the burden and distribution of amyloid plaques in patients with AD, using a statistical parametric mapping (SPM) and regions of interest (ROIs) analyses of the Pittsburgh compound B (PiB)-PET. Methods: We initially recruited 72 patients with AD who had completed the [11 C] PiB-PET scan, but four patients were excluded due to familial …AD or incomplete MRI data. Of the 68 patients, 61 were classified as PiB-positive (PiB+) and seven as PiB-negative (PiB–) using the measured global PiB uptake ratio values. Of the 61 patients with PiB+ AD, in order to maximize the effect of onset age, we excluded 20 patients in their 60 s. Thus among the remaining 41 patients, the amyloid deposition of only 17 patients with EOAD (age onset <60 years) and 24 patients with LOAD (onset age ≥70 years) were compared. Results: There were no significant differences in the global mean PiB index between EOAD and LOAD patients, whereas SPM and ROIs analyses showed that those with EOAD retained higher levels of PiB in the bilateral basal ganglia, bilateral thalamus, left superior temporal cortex, and left cuneus compared to those with LOAD. Conclusion: Our findings demonstrated that EOAD patients differed from those with LOAD in the topography of amyloid deposition, which may partly account for the findings from previous studies that extrapyramidal symptoms and frontal dysfunction are more common in EOAD than in LOAD patients. Show more

Keywords: Alzheimer's disease, amyloid, early onset, onset age, Pittsburgh compound B (PiB)-PET

DOI: 10.3233/JAD-121927

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 813-821, 2013

Authors: Kryscio, Richard J. | Abner, Erin L. | Lin, Yushun | Cooper, Gregory E. | Fardo, David W. | Jicha, Gregory A. | Nelson, Peter T. | Smith, Charles D. | Van Eldik, Linda J. | Wan, Lijie | Schmitt, Frederick A.

Article Type: Research Article

Abstract: Risk factors for mild cognitive impairment (MCI) and dementia are often investigated without accounting for the competing risk of mortality, which can bias results and lead to spurious conclusions, particularly regarding protective factors. Here, we apply a semi-Markov modeling approach to 531 participants in the University of Kentucky Biologically Resilient Adults in Neurological Studies (BRAiNS) longitudinal cohort, over one-third of whom died without transitioning to a cognitively impaired clinical state. A semi-Markov approach enables a statistical study of clinical state transitions while accounting for the competing risk of death and facilitates insights into both the odds that a risk factor …will affect clinical transitions as well as the age at which the transition to MCI or dementia will occur. Risk factors assessed in the current study were identified by matching those reported in the literature with the data elements collected on participants. The presence of Type II diabetes at baseline shortens the time it takes cognitively intact individuals to transition to MCI by seven years on average while use of estrogen replacement therapy at enrollment (baseline) decreases the time required to convert from MCI to dementia by 1.5 years. Finally, smoking and being overweight do not promote transitions to impaired states but instead hasten death without a dementia. In contrast, conventional statistical analyses based on Cox proportional hazards models fail to recognize diabetes as a risk, show that being overweight increases the risk of clinical MCI, and that high blood pressure at baseline increases the risk of a dementia. Show more

Keywords: Competing events, dementia, mild cognitive impairment, multi-state models, risk factors, semi-Markov

DOI: 10.3233/JAD-122146

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 823-832, 2013

Authors: Rispoli, Vincenzo | Ragusa, Salvatore | Nisticò, Robert | Marra, Rosario | Russo, Emilio | Leo, Antonio | Felicitá, Vera | Rotiroti, Domenicantonio

Article Type: Research Article

Abstract: Huperzine A (Hup-A), an alkaloid isolated from Huperzia serrata (Thunb.) Trevis. (Lycopodiaceae), acts as a selective inhibitor of acetylcholinesterase and shows memory-enhancing properties. Although Hup-A has shown promising expectation for Alzheimer's disease (AD) patients, controlled clinical trials supporting its use are limited. The aim of this work was to study in vivo, in an animal model of AD, the pharmacological activity of systemic administration of Hup-A on cortex- and hippocampus-dependent memory. With this purpose, a set of experiments was planned to evaluate attention, learning, working and spatial memory with respect to cortical and hippocampal electroencephalogram (EEG) theta rhythm during the …object recognition test and Morris water maze in animals with lesion of the nucleus basalis of Meynert (NBM). In NBM-lesioned animals, compared with control, an increased theta power in the cortex and a reduced theta rhythm oscillation in the hippocampus were found. These EEG changes were correlated with worse performance in learning and memory tasks. In rats with damaged NBM, Hup-A (0.5 mg/kg i.p.) was able to restore EEG architecture, producing cortical desynchronization and reduction in theta power, while in the hippocampus the drug increased theta oscillation and reduced the impairment in attention/working memory as well as spatial navigation performance in the behavioral tasks. Taken together, the present data suggest that Hup-A is able to restore cholinergic cortico-hippocampal functional connectivity. In conclusion, the present results are in agreement with other experimental evidence that promote the clinical use of this natural drug. Show more

Keywords: Alzheimer's disease, attention, cholinesterase inhibitors, electroencephalography, hippocampus, huperzine a, learning, memory, nucleus basalis of meynert

DOI: 10.3233/JAD-130278

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 833-846, 2013

Authors: Aso, Ester | Juvés, Salvador | Maldonado, Rafael | Ferrer, Isidro

Article Type: Research Article

Abstract: The specific CB2 cannabinoid receptor agonist JWH-133 induced cognitive improvement in double AβPP/PS1 transgenic mice, a genetic model of Alzheimer's disease. This effect was more pronounced when administered at the pre-symptomatic rather than the early symptomatic stage. The cognitive improvement was associated with decreased microglial reactivity and reduced expression of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and IFNγ. In addition, JWH-133 reduced the expression of active p38 and SAPK/JNK, increased the expression of inactive GSK3β, and lowered tau hyperphosphorylation at Thr181 in the vicinity of amyloid-β plaques. Moreover, JWH-133 produced a decrease in the expression of hydroxynonenal adducts, and enhanced …the expression of SOD1 and SOD2 around plaques. In contrast, the chronic treatment with JWH-133 failed to modify the amyloid-β production or deposition in cortex and hippocampus. In conclusion, the present study lends support to the idea that stimulation of CB2 receptors ameliorates several altered parameters in Alzheimer's disease such as impaired memory and learning, neuroinflammation, oxidative stress damage and oxidative stress responses, selected tau kinases, and tau hyperphosphorylation around plaques. Show more

Keywords: Alzheimer's disease, CB2 cannabinoid receptor, cognition, neuroinflammation, oxidative stress, tau kinases

DOI: 10.3233/JAD-130137

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 847-858, 2013

Authors: Burgmans, Saartje | van de Haar, Harm J. | Verhey, Frans R. J. | Backes, Walter H.

Article Type: Research Article

Abstract: To date, the exact pathogenesis of dementia is still unknown. The most frequently hypothesized initiating factor is an accumulation of the protein amyloid-β in the brain, which has been associated with dementia of the Alzheimer type. Another potentially important initiating factor is a disrupted blood-brain barrier. This can initiate cerebral microangiopathy, which has frequently been associated with vascular dementia. Although amyloid-β and blood-brain barrier dysfunction have both been associated with one particular type of dementia (Alzheimer's disease and vascular dementia, respectively), they co-exist in most demented patients. In fact, increasing evidence indicates that amyloid-β and blood-brain barrier disruption may interact …and facilitate each other in their effect on neurodegeneration. The present systematic analysis describes the available evidence for a significant interplay between amyloid-β and blood-brain barrier function in dementia. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, dementia, vascular dementia

DOI: 10.3233/JAD-122155

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 859-873, 2013

Article Type: Correction

DOI: 10.3233/JAD-139901

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 875-875, 2013

Article Type: Correction

DOI: 10.3233/JAD-139902

Citation: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 877-877, 2013