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

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