Journal of Alzheimer's Disease - Volume 61, issue 2

Authors: Kimura, Akio | Yoshikura, Nobuaki | Hayashi, Yuichi | Inuzuka, Takashi

Article Type: Research Article

Abstract: Background: Chronic neuroinflammation has been implicated in Alzheimer’s disease (AD) pathology. Objective: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients. Methods: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets …the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Results: CSF CCL2 levels correlated significantly with the severity (p  = 0.023) and the extent (p  = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p  = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p  = 0.020), the extent of VOI atrophy (p  = 0.015), and the ratio of VOI/GM atrophy (r  = –0.358, p  = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p  = 0.0497) and FAB scores (p  = 0.016). Conclusions: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD. Show more

Keywords: Amyloid-β, anti-Aβ autoantibody, chemokine CCL2, cytokine, medial temporal lobe atrophy, voxel-based morphometry

DOI: 10.3233/JAD-170519

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 581-588, 2018

Authors: Slachevsky, Andrea | Barraza, Paulo | Hornberger, Michael | Muñoz-Neira, Carlos | Flanagan, Emma | Henríquez, Fernando | Bravo, Eduardo | Farías, Mauricio | Delgado, Carolina

Article Type: Research Article

Abstract: Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer’s disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the …FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity. Show more

Keywords: Alzheimer’s disease, biomarkers, episodic memory, FCSRT Picture version, FCSRT Word version, Free and Cued Selective Reminding Test, hippocampus, voxel based morphometry

DOI: 10.3233/JAD-160973

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 589-600, 2018

Authors: Dougherty, Ryan J. | Lindheimer, Jacob B. | Stegner, Aaron J. | Van Riper, Stephanie | Okonkwo, Ozioma C. | Cook, Dane B.

Article Type: Research Article

Abstract: Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V ̇ O2peak ) test compared to those who did not; and 3) determine the difference between directly measured V ̇ O2peak values and OUES-predicted V …̇ O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer’s Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V ̇ O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p  < 0.001), and were strongly correlated with V ̇ O2peak (r range  = 0.801–0.909; p  < 0.001). As hypothesized, participants who did not satisfy V ̇ O2peak criteria were significantly older than those who satisfied criteria (p  = 0.049) and attained a directly measured V ̇ O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V ̇ O2peak (p  = 0.003). Older adults are less likely to satisfy V ̇ O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V ̇ O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria. Show more

Keywords: Alzheimer’s disease, cardiopulmonary exercise testing, maximal exercise test, oxygen consumption, oxygen uptake efficiency slope, sub-maximal exercise test

DOI: 10.3233/JAD-170576

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 601-611, 2018

Authors: Wu, Liyong | Liu, Jia | Feng, Xueyan | Dong, Jing | Qin, Wei | Liu, Yang | Wang, Jingjuan | Lu, Jie | Chen, Kewei | Wang, Yuping | Jia, Jianping

Article Type: Research Article

Abstract: Frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neurodegenerative disorder. Most patients with FTDP-17 carry the mutation in the microtubule-associated protein tau (MAPT) gene. Striatum is predominantly and early affected in FTDP-17. Five family members (two symptomatic patients and three presymptomatic mutation carriers) from a Chinese pedigree of FTDP-17 with N279K mutation in MAPT were enrolled. Parkinsonism was the initial symptom for symptomatic patients. 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11 C-CFT) uptake was obviously affected in the putamen of two presymptomatic mutation carriers. Presymptomatic case 3, whose 11 C-CFT uptake in the right putamen was normal at baseline, …was still free of parkinsonism during follow-up. In conclusion, 11 C-CFT-positron emission tomography could be a potential biomarker for the presymptomatic stage of FTDP-17 to predict the disease onset. Show more

Keywords: 11C-CFT-PET, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), microtubule-associated protein tau (MAPT), presymptomatic mutation carriers

DOI: 10.3233/JAD-170561

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 613-618, 2018

Authors: Saksida, Tamara | Koprivica, Ivan | Vujičić, Milica | Stošić-Grujičić, Stanislava | Perović, Milka | Kanazir, Selma | Stojanović, Ivana

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer’s patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production …were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology. Show more

Keywords: 5xFAD mice, amyloid-β, IL-17, mesenteric lymph nodes, Peyer’s patches

DOI: 10.3233/JAD-170538

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 619-630, 2018

Authors: Lao, Patrick J. | Handen, Ben L. | Betthauser, Tobey J. | Mihaila, Iulia | Hartley, Sigan L. | Cohen, Annie D. | Tudorascu, Dana L. | Bulova, Peter D. | Lopresti, Brian J. | Tumuluru, Rameshwari V. | Murali, Dhanabalan | Mathis, Chester A. | Barnhart, Todd E. | Stone, Charles K. | Price, Julie C. | Devenny, Darlynne A. | Johnson, Sterling C. | Klunk, William E. | Christian, Bradley T.

Article Type: Research Article

Abstract: Background: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer’s disease (AD). Objective: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11 C]PiB, [18 F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results: Positive associations …of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions. Show more

Keywords: Alzheimer’s disease, amyloid-β, Down syndrome, fluorodeoxyglucose, glucose metabolism, gray matter, magnetic resonance imaging, Pittsburgh compound B

DOI: 10.3233/JAD-170720

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 631-644, 2018

Authors: Chen, Dong-Wan | Wang, Jun | Zhang, Li-Li | Wang, Yan-Jiang | Gao, Chang-Yue

Article Type: Research Article

Abstract: Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer’s disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. …However, no significant difference was found in Aβ40 , total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, sleep disorder, tau

DOI: 10.3233/JAD-170032

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 645-651, 2018

Authors: Flanagan, Margaret E. | Larson, Eric B. | Walker, Rod L. | Keene, C. Dirk | Postupna, Nadia | Cholerton, Brenna | Sonnen, Joshua A. | Dublin, Sascha | Crane, Paul K. | Montine, Thomas J.

Article Type: Research Article

Abstract: Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer’s disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated …pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuropathology, non-steroidal anti-inflammatory drugs, opioids

DOI: 10.3233/JAD-170414

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 653-662, 2018

Authors: El Haj, Mohamad | Coello, Yann | Kapogiannis, Dimitrios | Gallouj, Karim | Antoine, Pascal

Article Type: Research Article

Abstract: Relatively to “standard” prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer’s disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when …the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD. Show more

Keywords: Alzheimer’s disease, commission, inhibition, negative prospective memory, prospective memory

DOI: 10.3233/JAD-170807

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 663-672, 2018

Authors: Law, Bernard M. | Guest, Amy L. | Pullen, Matthew W. J. | Perkinton, Michael S. | Williams, Robert J.

Article Type: Research Article

Abstract: Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer’s disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven …luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α -secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD. Show more

Keywords: AICD, Akt, Alzheimer’s disease, amyloid-β protein precursor, apoptosis, β-secretase, Forkhead transcription factor, FOXO3 protein, γ-secretase, neurodegeneration

DOI: 10.3233/JAD-170393

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 673-688, 2018

Authors: Valech, Natalia | Tort-Merino, Adrià | Coll-Padrós, Nina | Olives, Jaume | León, María | Rami, Lorena | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer’s disease (preAD). Objectives: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging. Methods: 68 cognitively normal older adults were classified as controls (n  = 52) or preAD (n  = 16) according to amyloid-β (Aβ) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available. Results: Four SCD-Q factors were extracted: EM-factor …(episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p  = 0.014) and A-factor (F(1) = 4.04; p  = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig-items. ) Significant discriminative powers for Aβ-positivity were found for L-factor (AUC = 0.75; p  = 0.003) and A-factor (AUC = 0.74; p  = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items . A significant time ×group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year. Conclusions: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, preclinical Alzheimer’s disease, subjective cognitive decline

DOI: 10.3233/JAD-170627

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 689-703, 2018

Authors: Burrell, James R. | Ballard, Kirrie J. | Halliday, Glenda M. | Hodges, John R.

Article Type: Research Article

Abstract: Background: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA). Objective: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks. Methods: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception …of Grammar (TROG). Results: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests. Conclusion: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA. Show more

Keywords: Clinicopathological correlation, primary progressive aphasia, progressive non-fluent aphasia, progressive supranuclear palsy

DOI: 10.3233/JAD-170743

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 705-715, 2018

Authors: Sinai, Amanda | Mokrysz, Claire | Bernal, Jane | Bohnen, Ingrid | Bonell, Simon | Courtenay, Ken | Dodd, Karen | Gazizova, Dina | Hassiotis, Angela | Hillier, Richard | McBrien, Judith | McCarthy, Jane | Mukherji, Kamalika | Naeem, Asim | Perez-Achiaga, Natalia | Rantell, Khadija | Sharma, Vijaya | Thomas, David | Walker, Zuzana | Whitham, Sarah | Strydom, Andre

Article Type: Research Article

Abstract: Background: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer’s disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. Objective: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. Methods: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in …England. Survival times when considering different risk factors were calculated. Results: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. Conclusion: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future. Show more

Keywords: Alzheimer’s disease, dementia, Down syndrome, mental retardation, survival

DOI: 10.3233/JAD-170624

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 717-728, 2018

Authors: Ding, Kan | Tarumi, Takashi | Zhu, David C. | Tseng, Benjamin Y. | Thomas, Binu P. | Turner, Marcel | Repshas, Justin | Kerwin, Diana R. | Womack, Kyle B. | Lu, Hanzhang | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Background: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies. Objective: To determine the associations of CRF measured by maximal oxygen uptake (VO2 max) with WM fiber integrity and neurocognitive performance in older adults with MCI. Methods: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2 max test to measure CRF, …diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach. Results: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2 max. VO2 max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2 max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2 max were associated with executive function performance in MCI patients. Conclusions: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients. Show more

Keywords: Cardiorespiratory fitness, executive function, mild cognitive impairment, white matter

DOI: 10.3233/JAD-170415

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 729-739, 2018

Authors: Harris, Rachel | Miners, James Scott | Allen, Shelley | Love, Seth

Article Type: Research Article

Abstract: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer’s disease (AD), probably in response to amyloid-β , vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of …VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p  = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p  = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD. Show more

Keywords: Alzheimer’s disease, brain ischemia, microvessels, vascular endothelial growth factor A, vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2

DOI: 10.3233/JAD-170745

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 741-752, 2018

Authors: Fostinelli, Silvia | Ciani, Miriam | Zanardini, Roberta | Zanetti, Orazio | Binetti, Giuliano | Ghidoni, Roberta | Benussi, Luisa

Article Type: Research Article

Abstract: A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN , C9orf72 , and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees …had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to “high risk” pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history. Show more

Keywords: C9orf72, frontotemporal lobar degeneration, genetic counseling, GRN, MAPT, mutation, pedigree

DOI: 10.3233/JAD-170661

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 753-760, 2018

Authors: Dodich, Alessandra | Cerami, Chiara | Cappa, Stefano F. | Marcone, Alessandra | Golzi, Valeria | Zamboni, Michele | Giusti, Maria Cristina | Iannaccone, Sandro

Article Type: Research Article

Abstract: Background: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer’s disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. Objectives: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. Methods: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n  = 48) or typical AD (n  = 47) pathology. …A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. Results: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. Conclusion: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, neurodegenerative disease, neuropsychology, social skills

DOI: 10.3233/JAD-170650

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 761-772, 2018

Authors: Ahmed, Rebekah M. | Highton-Williamson, Elizabeth | Caga, Jashelle | Thornton, Nicolette | Ramsey, Eleanor | Zoing, Margaret | Kim, Woojin Scott | Halliday, Glenda M. | Piguet, Olivier | Hodges, John R. | Farooqi, I. Sadaf | Kiernan, Matthew C.

Article Type: Research Article

Abstract: Background: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. Objective: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. Methods: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density …lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. Results: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p  < 0.001), total cholesterol/HDL ratio (p  < 0.001), and lower HDL levels (p  = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p  = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. Conclusion: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival. Show more

Keywords: Amyotrophic lateral sclerosis, cholesterol, eating, frontotemporal dementia, hypothalamus, metabolism,neurodegeneration, neuroendocrine

DOI: 10.3233/JAD-170660

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 773-783, 2018

Authors: Ferrari, Camilla | Lombardi, Gemma | Polito, Cristina | Lucidi, Giulia | Bagnoli, Silvia | Piaceri, Irene | Nacmias, Benedetta | Berti, Valentina | Rizzuto, Debora | Fratiglioni, Laura | Sorbi, Sandro

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors. Objective: The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients. Methods: We retrospectively selected 160 AD patients diagnosed at the Neurology Unit …of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period. Results: Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ 4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ 4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ 4-carriers. Conclusion: At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches. Show more

Keywords: Alzheimer’s disease, APOE, aspirin, decline, dementia, progression, risk factors

DOI: 10.3233/JAD-170665

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 785-791, 2018

Authors: Chai, Yuek Ling | Xing, Huayang | Chong, Joyce R. | Francis, Paul T. | Ballard, Clive G. | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer’s disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. Objectives: To correlate TOM subunits with OXPHOS complex proteins in AD. Methods: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS …complex I–V by immunoblotting. Results: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV. Conclusion: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study. Show more

Keywords: Alzheimer’s disease, mitochondria, oxidative phosphorylation, translocase of the outer membrane

DOI: 10.3233/JAD-170613

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 793-801, 2018

Authors: Kehoe, Patrick G. | Blair, Peter S. | Howden, Beth | Thomas, David L. | Malone, Ian B. | Horwood, Jeremy | Clement, Clare | Selman, Lucy E. | Baber, Hannah | Lane, Athene | Coulthard, Elizabeth | Passmore, Anthony Peter | Fox, Nick C. | Wilkinson, Ian B. | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Background: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer’s disease (AD) pathology and reduce the rate of disease progression. Objective: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR). Methods: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide …at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. Results: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. Conclusion: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted. Show more

Keywords: Alzheimer’s disease, clinical trial, hypertension, parental history, renin-angiotensin system, vascular risk

DOI: 10.3233/JAD-170101

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 803-814, 2018

Authors: Wharton, Whitney | Goldstein, Felicia C. | Tansey, Malú G. | Brown, Alexandra L. | Tharwani, Sonum D. | Verble, Danielle D. | Cintron, Amarallys | Kehoe, Patrick G.

Article Type: Research Article

Abstract: Research indicates that certain antihypertensive medications alter Alzheimer’s disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify …the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45–70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design. Show more

Keywords: Alzheimer’s disease, clinical trial, hypertension, parental history, renin angiotensin system, vascular risk

DOI: 10.3233/JAD-161198

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 815-824, 2018

Authors: Jang, Hyemin | Ye, Byoung Seok | Woo, Sookyoung | Kim, Sun Woo | Chin, Juhee | Choi, Seong Hye | Jeong, Jee Hyang | Yoon, Soo Jin | Yoon, Bora | Park, Kyung Won | Hong, Yun Jeong | Kim, Hee Jin | Lockhart, Samuel N. | Na, Duk L. | Seo, Sang Won

Article Type: Correction

DOI: 10.3233/JAD-179010

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 825-825, 2018