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Authors: Tales, Andrea | Jessen, Frank | Butler, Christopher | Wilcock, Gordon | Phillips, Judith | Bayer, Tony

Article Type: Research Article

DOI: 10.3233/JAD-150719

Citation: Journal of Alzheimer's Disease, vol. 48, no. s1, pp. S1-S3, 2015

Authors: Polcher, Alexandra | Frommann, Ingo | Koppara, Alexander | Wolfsgruber, Steffen | Jessen, Frank | Wagner, Michael

Article Type: Research Article

Abstract: Background: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the preclinical stage of Alzheimer’s disease (AD). Associative memory is a cognitive function supported by the hippocampus and affected early in the process of AD. Objective: We developed a short computerized face-name associative recognition test (FNART) and tested whether it would detect memory impairment in memory clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Methods: We recruited 61 elderly patients with either SCD (n  = 32) or MCI (n  = 29) and 28 healthy controls (HC) and compared performance on FNART, …self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced sample (n  = 46), performance on the visual Paired Associates Learning of the CANTAB battery. Results: A significant effect of group on FNART test performance in the total sample was found (p  < 0.001). Planned contrasts indicated a significantly lower associative memory performance in the SCD (p  = 0.001, d  = 0.82) and MCI group (p  < 0.001, d  = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory in SCD patients (p  = 0.024) but not in MCI patients. Conclusions: Associative memory is substantially impaired in memory clinic patients with SCD and correlates specifically with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes. Show more

Keywords: Alzheimer’s disease, associative memory, cognition, early detection, hippocampus, mild cognitive impairment, neuropsychological tests, recognition, subjective cognitive decline

DOI: 10.3233/JAD-160637

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1185-1196, 2017

Authors: Luck, Tobias | Roehr, Susanne | Jessen, Frank | Villringer, Arno | Angermeyer, Matthias C. | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: Studies have shown that dementia and cognitive impairment can increase mortality, but less is known about the association between subjectively perceived cognitive deficits (subjective cognitive decline, SCD) and mortality risk. Objective: In this study, we analyzed mortality in non-demented individuals with SCD in a general population sample aged 75+ years. Method: Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate survival times of individuals with and without SCD and multivariable Cox proportional hazards regression to assess the association between SCD and mortality risk, controlled for covariates. Results: Out …of 953 non-demented individuals at baseline, 117 (12.3% ) expressed SCD. Participants with SCD showed a significantly higher case-fatality rate per 1,000 person-years (114.8, 95% CI = 90.5–145.7 versus 71.7, 95% CI = 64.6–79.5) and a significantly shorter mean survival time than those without (5.4 versus 6.9 years, p  <  0.001). The association between SCD and mortality remained significant in the Cox analysis; SCD increased mortality risk by about 50% (adjusted Hazard Ratio = 1.51) during the study period. Besides SCD, older age, male gender, diabetes mellitus, stroke, and lower global cognitive functioning were also significantly associated with increased mortality. Conclusion: Our findings suggest an increased mortality risk in non-demented older individuals with SCD. Even though further studies are required to analyze potential underlying mechanisms, subjective reports on cognitive deficits may be taken seriously in clinical practice not only for an increased risk of developing dementia and AD but also for a broader range of possible adverse health outcomes. Show more

Keywords: Dementia, epidemiology, mortality, subjective cognitive decline

DOI: 10.3233/JAD-150090

Citation: Journal of Alzheimer's Disease, vol. 48, no. s1, pp. S33-S42, 2015

Authors: Rodríguez-Gómez, Octavio | Abdelnour, Carla | Jessen, Frank | Valero, Sergi | Boada, Merçé

Article Type: Review Article

Abstract: Subjective cognitive decline (SCD) has been proposed as a marker of neurodegeneration in cognitively normal elderly. This idea is supported by the growing evidence that SCD is associated with Alzheimer’s disease (AD) biomarkers and increases the risk of future cognitive impairment. Nevertheless, this evidence is not complete, since other studies have not found these associations. This discrepancy could have a methodological basis. It is well known that across the broad spectrum of degenerative disease from healthy controls to dementia, the research setting affects key characteristics of the sample such as age, educational level, or family history of dementia. However, virtually …no studies have specifically tested the influence of sampling and recruitment methods in SCD research. Population-based samples are less biased and therefore they probably are more suitable for the study of memory complaints as a symptom at the population level. On the other hand, the memory clinic setting could introduce a set of biases that make these patients more likely to develop cognitive impairment. Thus, memory clinic would be the most cost-effective context in which to study the phenomenology of SCD due to AD and eventually recruit patients for secondary prevention trials. However, this general hypothesis needs to be tested. Studies that compare samples of patients with SCD from different settings are necessary. Sometimes it is difficult for patients with subtle forms of cognitive impairment to access specialized diagnostic centers. Based in our experience we state that Open House type initiatives may be useful for attracting these individuals to memory clinics. Show more

Keywords: Alzheimer’s disease, epidemiologic research design, epidemiologic studies, patient selection, risk, sampling, selection bias, subjective cognitive decline

DOI: 10.3233/JAD-150189

Citation: Journal of Alzheimer's Disease, vol. 48, no. s1, pp. S99-S107, 2015

Authors: Popp, Julius | Lewczuk, Piotr | Frommann, Ingo | Kölsch, Heike | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1–42 (Aβ1–42 ) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1–42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1–42 and pTau181 concentrations in 280 adults with normal cognition …across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1–42 and pTau181, and of the APOEε4 genotype on the Aβ1–42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1–42 concentrations in middle-aged and older participants. In the group of participants with AD, the Aβ1–42 levels were significantly lower in the APOEε4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF Aβ1–42 and pTau181 across lifespan. They also suggest that the decrease of Aβ1–42 , but not the increase of pTau181 CSF levels is accelerated by the APOEε4 genotype in middle-aged and older adults with normal cognition. Show more

Keywords: Alzheimer's disease, amyloid-β, APOEε4, cerebrospinal fluid, hyperphosphorylated tau, normal aging

DOI: 10.3233/JAD-2010-100561

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 459-468, 2010

Authors: Lewczuk, Piotr | Popp, Julius | Lelental, Natalia | Kölsch, Heike | Maier, Wolfgang | Kornhuber, Johannes | Jessen, Frank

Article Type: Research Article

Abstract: In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical …dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biomarkers, cerebrospinal fluid

DOI: 10.3233/JAD-2011-110857

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 119-125, 2012

Authors: Müller, Theresa | Payton, Nicola M. | Kalpouzos, Grégoria | Jessen, Frank | Grande, Giulia | Bäckman, Lars | Laukka, Erika J.

Article Type: Research Article

Abstract: Background: Although associated with dementia and cognitive impairment, microstructural white matter integrity is a rarely used marker of preclinical dementia. Objective: We aimed to evaluate the individual and combined effects of multiple markers, with special focus on microstructural white matter integrity, in detecting individuals with increased dementia risk. Methods: A dementia-free subsample (n  = 212, mean age = 71.33 years) included in the population-based Swedish National Study on Aging and Care (SNAC-K) underwent magnetic resonance imaging (T1-weighted, fluid-attenuated inversion recovery, diffusion tensor imaging), neuropsychological testing (perceptual speed, episodic memory, semantic memory, letter and category fluency), and genotyping (APOE ). Incident dementia was assessed …during six years of follow-up. Results: A global model (global cognition, APOE , total brain tissue volume: AUC = 0.920) rendered the highest predictive value for future dementia. Of the models based on specific markers, white matter integrity of the forceps major tract was included in the most predictive model, in combination with perceptual speed and hippocampal volume (AUC = 0.911). Conclusion: Assessment of microstructural white matter integrity may improve the early detection of dementia, although the added benefit in this study was relatively small. Show more

Keywords: APOE, cognition, diffusion tensor imaging, magnetic resonance imaging, preclinical dementia, white matter

DOI: 10.3233/JAD-200445

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1443-1453, 2020

Authors: Koppara, Alexander | Frommann, Ingo | Polcher, Alexandra | Parra, Mario A. | Maier, Wolfgang | Jessen, Frank | Klockgether, Thomas | Wagner, Michael

Article Type: Research Article

Abstract: Background: Feature binding is a sensitive and specific cognitive marker for Alzheimer’s disease (AD). Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are clinical categories associated with an increased risk for AD. Objective: To investigate whether the SCD and MCI group are impaired with regard to feature binding. Methods: The feature binding test was administered to memory clinic patients with either SCD (n  = 19, mean MMSE: 29.2) or with MCI (n  = 23, mean MMSE: 26.5), and to a group of healthy controls (HC, n  = 23, mean MMSE: 29.0). Participants were assessed with the CERAD Plus neuropsychological test battery. Cognitive …performance of the three groups was compared by ANCOVA with age, gender and education as covariates and planned contrasts. Results: Groups differed in the binding condition. Planned contrasts showed significant differences in adjusted means between HC and SCD (p  = 0.003), as well as between HC and MCI (p  <  0.0001). Discussion: The feature binding task detects subtle cognitive impairments in participants with SCD, who are unimpaired in traditional neuropsychological testing. This corroborates the use of feature binding tests in preclinical AD studies and suggests that specific cognitive deficits can be found in SCD. Future studies incorporating AD biomarkers and longitudinal follow-up are needed to further establish the clinical utility of feature binding. Show more

Keywords: Alzheimer’s disease, early detection, feature binding, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-150105

Citation: Journal of Alzheimer's Disease, vol. 48, no. s1, pp. S161-S170, 2015

Authors: Arlt, Sönke | Schwedhelm, Edzard | Kölsch, Heike | Jahn, Holger | Linnebank, Michael | Smulders, Yvo | Jessen, Frank | Böger, Rainer H. | Popp, Julius

Article Type: Research Article

Abstract: Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42 ), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as …CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis. Show more

Keywords: Alzheimer's disease, asymmetric dimethylarginine, cerebrospinal fluid, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine

DOI: 10.3233/JAD-2012-112138

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 751-758, 2012

Authors: Popp, Julius | Lewczuk, Piotr | Linnebank, Michael | Cvetanovska, Gabriela | Smulders, Yvo | Kölsch, Heike | Frommann, Ingo | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Aβ1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β = 0.490; p < 0.001), 5-MTHF (β …= -0.273; p = 0.010) levels, and SAM/SAH ratio (β = -0.319; p = 0.013) in controls, and with SAH (β = 0.529; p = 0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, homocysteine, phosphorylated tau

DOI: 10.3233/JAD-2009-1187

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 819-828, 2009