Journal of Alzheimer's Disease - Volume 62, issue 2

Authors: Tao, Qiushan | Zhu, Haihao | Chen, Xi | Stern, Robert A. | Kowall, Neil | Au, Rhoda | Blusztajn, Jan Krzysztof | Qiu, Wei Qiao | for the Alzheimer’s Disease Metabolomics Consortium

Article Type: Research Article

Abstract: Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer’s disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as …individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p  < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI. Show more

Keywords: Alzheimer’s disease, amylin, mild cognitive impairment, phosphatidylcholine, pramlintide

DOI: 10.3233/JAD-170948

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 597-609, 2018

Authors: Alegret, Montserrat | Peretó, Mar | Pérez, Alba | Valero, Sergi | Espinosa, Ana | Ortega, Gemma | Hernández, Isabel | Mauleón, Ana | Rosende-Roca, Maitée | Vargas, Liliana | Rodríguez-Gómez, Octavio | Abdelnour, Carla | Berthier, Marcelo L. | Bak, Thomas H. | Ruíz, Agustín | Tárraga, Lluís | Boada, Mercè

Article Type: Research Article

Abstract: Background: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. Objective: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. Methods: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and …a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. Results: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). Conclusion: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia. Show more

Keywords: Alzheimer’s disease, cognitively healthy, mild cognitive impairment, verb fluency, verbal fluency

DOI: 10.3233/JAD-170826

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 611-619, 2018

Authors: Scharre, Douglas W. | Weichart, Emily | Nielson, Dylan | Zhang, Jun | Agrawal, Punit | Sederberg, Per B. | Knopp, Michael V. | Rezai, Ali R. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimer’s disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating–Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial …2-Deoxy-2-[18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, executive function, positron-emission tomography, ventral striatum

DOI: 10.3233/JAD-170082

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 621-633, 2018

Authors: Ekblad, Laura L. | Toppala, Sini | Johansson, Jouni K. | Koskinen, Seppo | Sundvall, Jouko | Rinne, Juha O. | Puukka, Pauli | Viitanen, Matti | Jula, Antti

Article Type: Research Article

Abstract: Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were …tested in the Finnish nationwide, population-based Health 2000 Survey (n  = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n  = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline. Show more

Keywords: Albuminuria, cognition, cognitive decline, longitudinal study, microalbuminuria

DOI: 10.3233/JAD-170972

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 635-648, 2018

Authors: Barbera, Mariagnese | Mangialasche, Francesca | Jongstra, Susan | Guillemont, Juliette | Ngandu, Tiia | Beishuizen, Cathrien | Coley, Nicola | Brayne, Carol | Andrieu, Sandrine | Richard, Edo | Soininen, Hilkka | Kivipelto, Miia | for the HATICE study group

Article Type: Research Article

Abstract: Background: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. Objective: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. Methods: A comparative analysis of national and European …guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. Results: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. Conclusion: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally. Show more

Keywords: Cardiovascular disease prevention, cardiovascular risk factors, dementia prevention, e-Health, multidomain intervention

DOI: 10.3233/JAD-170858

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 649-663, 2018

Authors: He, Xue-Ying | Isaacs, Charles | Yang, Song-Yu

Article Type: Research Article

Abstract: 17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer’s disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are …inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis. Show more

Keywords: Data integrity, mitochondria, neurosteroid, short chain 3-hydroxyacyl-CoA dehydrogenase, steroidogenesis

DOI: 10.3233/JAD-170974

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 665-673, 2018

Authors: Liew, Tau Ming | Yu, Junhong | Mahendran, Rathi | Ng, Tze-Pin | Kua, Ee-Heok | Feng, Lei

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders. Objective: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD. Methods: …Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD. Results: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92– 1.00), while Subtype 3 conferred a moderate risk (OR 4.47– 4.85) and Subtype 4 had the highest risk (OR 7.95– 8.63). Conclusion: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity. Show more

Keywords: Latent class analysis, mild behavioral impairment, neuropsychiatric symptoms, neurocognitive disorder

DOI: 10.3233/JAD-170947

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 675-686, 2018

Authors: Giannoccaro, Maria Pia | Bartoletti-Stella, Anna | Piras, Silvia | Casalena, Alfonsina | Oppi, Federico | Ambrosetto, Giovanni | Montagna, Pasquale | Liguori, Rocco | Parchi, Piero | Capellari, Sabina

Article Type: Research Article

Abstract: Background: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. Objective: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). Methods: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. Results: Eight patients presented with ALS, four with …FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. Conclusion: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD. Show more

Keywords: Amyotrophic lateral sclerosis, C9orf72 gene, familial ALS/FTD, frontotemporal dementia, FTDALS1, ITM2B

DOI: 10.3233/JAD-170913

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 687-697, 2018

Authors: D’Onofrio, Grazia | Panza, Francesco | Sancarlo, Daniele | Addante, Filomena | Solfrizzi, Vincenzo | Cantarini, Chiara | Mangiacotti, Antonio | Lauriola, Michele | Cascavilla, Leandro | Paris, Francesco | Lozupone, Madia | Daniele, Antonio | Greco, Antonio | Seripa, Davide

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB …score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p  = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect. Show more

Keywords: Alzheimer’s disease, comprehensive geriatric assessment, dementia, executive function, vascular dementia

DOI: 10.3233/JAD-170365

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 699-711, 2018

Authors: Falsetti, Lorenzo | Viticchi, Giovanna | Buratti, Laura | Grigioni, Francesco | Capucci, Alessandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. Objective: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer’s disease (AD) in the presence of vascular or genetic risk factors. Methods: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, …Framingham cardiovascular risk profile (FCRP), CHA2 DS2 -VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. Results: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ 4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2 DS2 -VASc, or mIMT. Conclusions: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ 4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration. Show more

Keywords: Alzheimer’s disease, atherosclerosis, Framingham cardiovascular risk profile, non-valvular atrial fibrillation

DOI: 10.3233/JAD-170544

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 713-725, 2018