Alzheimer Disease: Visser PJ

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Visser PJ. · Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands. · J Nutr Health Aging. · Pubmed #16554947 No free full text.

Abstract: Cognitive impairment is a key feature of Alzheimer's disease (AD). Cognitive performance will therefore be an important outcome measure in disease modifying drug trials. However, cognitive assessment also has several limitations such as a large inter and intra individual variability and floor and ceiling effects. To reduce the effect of these limitations on the accuracy with which drug-related changes can be detected, it is proposed to analyse cognitive change using a slope analysis. In addition, it is suggested to use as the main outcome measure for cognitive impairment a neuropsychological compound score that is based on a z-score transformation of a number of well-validated tests. The selection of these tests would depend on a number of study characteristics such as the inclusion criteria and the length of follow-up.

Visser PJ, Scheltens P, Verhey FR. · Department of Psychiatry, University Hospital Maastricht and Alzheimer Centre Limburg, Maastricht, Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16170074 links to  free full text

Abstract: BACKGROUND: Drugs effective in Alzheimer-type dementia have been tested in subjects with mild cognitive impairment (MCI) because these are supposed to have Alzheimer's disease in the predementia stage. OBJECTIVES: To investigate whether MCI criteria used in these drug trials can accurately diagnose subjects with predementia Alzheimer's disease. METHODS: MCI criteria of the Gal-Int 11 study, InDDEx study, ADCS memory impairment study, ampakine CX 516 study, piracetam study, and Merck rofecoxib study were applied retrospectively in a cohort of 150 non-demented subjects from a memory clinic. Forty two had progressed to Alzheimer type dementia during a five year follow up period and were considered to have predementia Alzheimer's disease at baseline. Outcome measures were the odds ratio, sensitivity, specificity, and positive and negative predictive value. RESULTS: The odds ratio of the MCI criteria for predementia Alzheimer's disease varied between 0.84 and 11. Sensitivity varied between 0.46 and 0.83 and positive predictive value between 0.43 and 0.76. None of the criteria combined a high sensitivity with a high positive predictive value. Exclusion criteria for depression led to an increase in positive predictive value and specificity at the cost of sensitivity. In subjects older than 65 years the positive predictive value was higher than in younger subjects. CONCLUSIONS: The diagnostic accuracy of MCI criteria used in trials for predementia Alzheimer's disease is low to moderate. Their use may lead to inclusion of many patients who do not have predementia Alzheimer's disease or to exclusion of many who do. Subjects with moderately severe depression should not be excluded from trials in order not to reduce the sensitivity.

Karas GB, Scheltens P, Rombouts SA, Visser PJ, van Schijndel RA, Fox NC, Barkhof F. · Department of Diagnostic Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · Neuroimage. · Pubmed #15488420 No free full text.

Abstract: PURPOSE: Mild cognitive impairment (MCI) is thought to be the prodromal phase to Alzheimer's disease (AD). We analyzed patterns of gray matter (GM) loss to examine what characterizes MCI and what determines the difference with AD. MATERIALS AND METHODS: Thirty-three subjects with AD, 14 normal elderly controls (NCLR), and 22 amnestic MCI subjects were included and underwent brain MR imaging. Global GM volume was assessed using segmentation and local GM volume was assessed using voxel-based morphometry (VBM); VBM was optimized for template mismatch and statistical mass. RESULTS: AD subjects had significantly (12.3%) lower mean global GM volume when compared to controls (517 +/- 58 vs. 590 +/- 52 ml; P < 0.001). Global GM volume in the MCI group (552 +/- 52) was intermediate between these two: 6.2% lower than AD and 6.5% higher than the controls but not significantly different from either group. VBM showed that subjects with MCI had significant local reductions in gray matter in the medial temporal lobe (MTL), the insula, and thalamus compared to NCLR subjects. By contrast, when compared to subjects with AD, MCI subjects had more GM in the parietal association areas and the anterior and the posterior cingulate. CONCLUSION: GM loss in the MTL characterizes MCI, while GM loss in the parietal and cingulate cortices might be a feature of AD.

Visser PJ, Verhey FR, Scheltens P, Cruts M, Ponds RW, Van Broeckhoven CL, Jolles J. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behaviour, University of Maastricht, The Netherlands. · J Neurol. · Pubmed #11993532 No free full text.

Abstract: The Preclinical AD Scale (PAS) is a newly developed scale for the diagnosis of preclinical Alzheimer's disease (AD). The PAS combines six markers of preclinical AD, namely age, MMSE score, functional impairment, cognitive test performance, medial temporal lobe atrophy, and the apolipoprotein E (APOE) genotype. The aim of the study was to investigate whether the PAS can accurately identify subjects with preclinical AD who become demented during a 2 or 5 year follow-up from among subjects with mild cognitive impairment for other reasons. We also investigated whether a step-wise scoring of the PAS could reduce the number of elaborate or expensive diagnostic procedures. The PAS was scored retrospectively in two independent samples of non-demented subjects with mild cognitive impairment older than 55 years (average age 65.6 years), who were selected from a memory clinic population. In the first sample, the follow-up was 5 years (5-year follow-up sample; n=69). In the second sample, the follow-up was 2 years (2-year follow-up sample; n=23). The PAS item medial temporal lobe atrophy was not scored in the 5-year follow-up sample. A PAS cut-off score of 4/5 could best identify subjects with AD-type dementia at follow-up (n=25) in the 5-year follow-up sample with a sensitivity of 80% and a positive predictive value of 77%. A PAS cut-off score of 5/6 could best identify subjects with AD-type dementia at follow-up (n=8) in the 2-year follow-up sample with a sensitivity of 88% and a positive predictive value of 70%. The positive predictive value could be increased to 94% in the 5-year follow-up sample and to 80% in the 2-year follow-up sample by using higher cut-off scores, but this reduced the sensitivity. Step-wise scoring of the PAS had the same diagnostic accuracy as the total PAS score and reduced the number of cognitive assessments by 22 to 38%, the number of assessments of medial temporal lobe atrophy by 57 to 74%, and the number of APOE genotypings by 74%. It is concluded that the PAS is a useful scale to identify subjects with preclinical AD who will become demented during the next 2 or 5 years. Step-wise scoring of the PAS can reduce the number of elaborate or expensive diagnostic procedures considerably.

Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. · Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. · JAMA. · Pubmed #19622817 No free full text.

Abstract: CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, Minthon L, Wallin AK, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert MO, Verbeek MM, Spiru L, Blennow K. · Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, 6200 MD Maastricht, Netherlands. · Lancet Neurol. · Pubmed #19523877 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS: Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS: The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION: AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING: European Commission; Ana Aslan International Foundation.

Winblad B, Frisoni GB, Frolich L, Johannsen P, Johansson G, Kehoe P, Lovestone S, Olde-Rikkert M, Reynish E, Visser PJ, Vellas B. · B. Winblad, Karolinska Institute - Alzheimer Disease Research Center, Stockholm, Sweden. · J Nutr Health Aging. · Pubmed #19043641 No free full text.

This publication has no abstract.

Nobili F, Frisoni GB, Portet F, Verhey F, Rodriguez G, Caroli A, Touchon J, Calvini P, Morbelli S, De Carli F, Guerra UP, Van de Pol LA, Visser PJ. · Clinical Neurophysiology Unit, Dept. of Endocrinological and Medical Sciences, University of Genoa, Viale Benedetto XV, 6, 16132, Genoa, Italy. · J Neurol. · Pubmed #18958573 No free full text.

Abstract: The Development of Screening Guidelines and Clinical Criteria of Predementia Alzheimer's Disease (DESCRIPA) multicenter study enrolled patients with MCI or subjective cognitive complaints (SUBJ), a part of whom underwent optional brain perfusion SPECT. These patients were classified as SUBJ (n = 23), nonamnestic MCI (naMCI; n = 17) and amnestic MCI (aMCI; n = 40) based on neuropsychology. Twenty healthy subjects formed the control (CTR) group. Volumetric regions of interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures, corrected for age and center, showed significant differences between groups (p = 0.01) and VROI (p < 0.0001) with a significant group-region interaction (p = 0.029). In the post hoc comparison, SUBJ did not differ from CTR. aMCI disclosed reduced uptake in the left hippocampus and bilateral temporal cortex (compared with CTR) or in the left hippocampus and bilateral parietal cortex (compared with SUBJ). In the naMCI group, reduced VROI values were found in the bilateral temporal cortex and right frontal cortex. In the comparison between aMCI and naMCI, the former had lower values in the left parietal cortex and precuneus. Discriminant analysis between SUBJ/CTR versus all MCI patients allowed correct allocations in 73 % of cases. Mean VROI values were highly correlated (p < 0.0001) with the learning measure of a verbal memory test, especially in the bilateral precunei and parietal cortex and in the left hippocampus. In a subset of 70 patients, mean VROI values showed a significant correlation (p < 0.05) with the white matter hyperintensities score on MRI. In conclusion, MCI subtypes have different perfusion patterns. The aMCI group exhibited a pattern that is typical of early Alzheimer's disease, while the naMCI group showed a more anterior pattern of hypoperfusion. Instead, a homogeneous group effect was lacking in SUBJ.

Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, Jolles J, Verhey FR. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behaviour, Maastricht University, Maastricht, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #18617739 No free full text.

Abstract: BACKGROUND: Memory problems are a main feature of mild cognitive impairment (MCI) and may be related to the apolipoprotein E (APOE) epsilon4 allele. We investigated whether the effect of the APOE genotype on memory in subjects with MCI was dependent on age and underlying Alzheimer disease (AD) pathology. METHODS: Subjects with MCI (n = 180) were selected from a memory clinic setting. Subjects with at least one APOE epsilon4 allele (n = 83) were compared to non-carriers on several memory measures. Subjects were reassessed 5-10 years later in order to identify those who developed AD. RESULTS: In the middle-aged subgroup, the APOE epsilon4 allele was most strongly related to decreased subjective organization and in the old subgroup to a decreased delayed recall. After excluding subjects with incipient AD (n = 33), results remained similar in the middle-aged subgroup, but in the old subgroup the APOE genotype was no longer associated with memory dysfunction. CONCLUSION: The presence of the APOE epsilon4 allele is associated with impaired memory functioning in both middle-aged and old subjects with MCI, although the memory function affected varies with age. Its effect on memory function may be dependent on underlying AD pathology in elderly subjects, but not in middle-aged subjects.

Visser PJ, Verhey FR, Boada M, Bullock R, De Deyn PP, Frisoni GB, Frolich L, Hampel H, Jolles J, Jones R, Minthon L, Nobili F, Olde Rikkert M, Ousset PJ, Rigaud AS, Scheltens P, Soininen H, Spiru L, Touchon J, Tsolaki M, Vellas B, Wahlund LO, Wilcock G, Winblad B. · Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands. · Neuroepidemiology. · Pubmed #18515975 No free full text.

Abstract: BACKGROUND: There is an urgent need to identify subjects with Alzheimer's disease (AD) in the predementia phase, but validated diagnostic approaches are currently lacking. In this paper, we present the background, design and methods of a study, which aims to develop clinical criteria for predementia AD. We also present baseline characteristics of the subjects included. The study was part of the multicentre DESCRIPA project, which is being conducted within the network of the European Alzheimer's Disease Consortium. METHODS: Clinical criteria will be based on a prospective cohort study of non-demented subjects older than 55 years and referred to a memory clinic. At baseline, a number of markers and risk factors for AD were collected, including demographic variables, measures of performance in activities of daily living, cognitive, neuroimaging and genetic markers, and serum and cerebrospinal fluid markers. Subjects will be reassessed annually for 2-3 years, and we will evaluate which combination of variables best predicts AD-type dementia at follow-up. RESULTS: Between 2003 and 2005, 881 subjects were included from 20 memory clinics. Subjects were on average 70.3 years old, and had 10.4 years of education. The average score on the Mini-Mental State Examination was 27.4.

Reynish E, Cortes F, Andrieu S, Cantet C, Olde Rikkert M, Melis R, Froelich L, Frisoni GB, Jönsson L, Visser PJ, Ousset PJ, Vellas B, Anonymous00177. · Inserm, U558, Toulouse, France. · Neuroepidemiology. · Pubmed #17898521 No free full text.

Abstract: The long-term objective of the ICTUS study is to identify milestones in Alzheimer's disease (AD) progression and to develop a model to predict disease course in individual AD patients in Europe. The secondary objectives are to describe the patterns of prescribing, and the socioeconomic impact of AD in Europe. Between 2003 and 2005 1,380 patients with probable AD were recruited in specialised (secondary care) clinics in 12 European countries. Their mean age was 76 years and they had a mean of 8.0 +/- (SD) 4.6 years of education. Thirty-five percent were male. The mean MMSE score was 20.4 +/- (SD) 4.0. Forty-three percent had very mild dementia (CDR 0.5) and 44% had mild dementia (CDR 1). All patients completed baseline evaluation and biannual follow-up is ongoing. The goals of the current study are to describe the specific methods for recruitment in this crosscultural setting and the characteristics of the inception ICTUS cohort, including clinical features, co-morbidity, neuropsychological performance, neuropsychiatric symptoms, functional impairment and social burden.

Visser PJ, Verhey FR. · Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands. · Psychol Med. · Pubmed #17451628 No free full text.

Abstract: BACKGROUND: We investigated whether the predictive accuracy of mild cognitive impairment (MCI) for Alzheimer-type dementia (AD) in a clinical setting is dependent on age and the definition of MCI used. METHOD: Non-demented subjects older than 40 (n=320) who attended a memory clinic of a university hospital were reassessed 5 years later for the presence of AD. MCI was diagnosed according to the criteria of amnestic MCI, mild functional impairment (MFI), ageing-associated cognitive decline (AACD), and age-associated memory impairment (AAMI). The main outcome measure was the area under the curve (AUC) of a receiver operating characteristic (ROC) curve. Analyses were conducted on the entire sample and on subgroups of subjects aged 40-54, 55-69 and 70-85 years. RESULTS: A diagnosis of AD at follow-up was made in 58 subjects. Four of them were in the 40-54 age group, 29 in the 55-69 age group and 25 in the 70-85 age group. The diagnostic accuracy in the entire sample was low to moderately high with AUCs ranging from 0.56 (AACD) to 0.75 (amnestic MCI). A good predictive accuracy with an AUC >0.80 was only observed in subjects aged 70-85 using the criteria of amnestic MCI (AUC=0.84). CONCLUSIONS: The predictive accuracy of MCI for AD is dependent on age and the definition of MCI used. The predictive accuracy is good only for amnestic MCI in subjects 70-85 years. As subjects with prodromal AD are often younger than 70, the usefulness of MCI as predictor of AD in clinical practice is limited.

Visser PJ, Brodaty H. · Department of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands. · Int Psychogeriatr. · Pubmed #17001760 No free full text.

This publication has no abstract.

van de Pol LA, Hensel A, van der Flier WM, Visser PJ, Pijnenburg YA, Barkhof F, Gertz HJ, Scheltens P. · VUMC, Department of Neurology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #16306153 links to  free full text

Abstract: BACKGROUND: Hippocampal atrophy on magnetic resonance imaging (MRI) is an early characteristic of Alzheimer's disease. However, hippocampal atrophy may also occur in other dementias, such as frontotemporal lobar degeneration (FTLD). OBJECTIVE: To investigate hippocampal atrophy on MRI in FTLD and its three clinical subtypes, in comparison with Alzheimer's disease, using volumetry and a visual rating scale. METHODS: 42 patients with FTLD (17 frontotemporal dementia, 13 semantic dementia, and 12 progressive non-fluent aphasia), 103 patients with Alzheimer's disease, and 73 controls were included. Hippocampal volumetry and the easily applicable medial temporal lobe atrophy (MTA) rating scale were applied to assess hippocampal atrophy. RESULTS: Multivariate analysis of variance for repeated measures showed an effect of diagnostic group on hippocampal volume. There was a significant diagnosis by side (left v right) interaction. Both FTLD and Alzheimer's disease showed hippocampal atrophy compared with controls. Results of the visual MTA rating scale confirmed these findings. Within the FTLD subtypes there were marked differences in hippocampal atrophy. Frontotemporal dementia and semantic dementia showed bilateral hippocampal atrophy, and in semantic dementia the left hippocampus was smaller than in Alzheimer's disease. No significant hippocampal atrophy was detected in non-fluent progressive aphasia. CONCLUSIONS: Hippocampal atrophy is not only a characteristic of Alzheimer's disease but also occurs in FTLD. The three clinical subtypes of FTLD show different patterns of hippocampal atrophy.

Schoonenboom SN, Visser PJ, Mulder C, Lindeboom J, Van Elk EJ, Van Kamp GJ, Scheltens PH. · Department of Neurology Alzheimer Centre, VU University Medical Centre, Amsterdam, the Netherlands. · Neurocase. · Pubmed #15804919 No free full text.

Abstract: The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer's disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Abeta42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Abeta32 or high CSF tau (intermediate-risk) and 20% a normal CSF Abeta42 and tau (low-risk). Both high-and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS),which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Abeta42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.

Visser PJ, Scheltens P, Pelgrim E, Verhey FR, Anonymous00317. · Department of Neurology, Alzheimer Centre, VU Medisch Centrum, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #15627759 No free full text.

Abstract: BACKGROUND: Only a subgroup of subjects with probable AD shows cognitive improvement after treatment with cholinesterase inhibitors. OBJECTIVES: To investigate whether atrophy of the medial temporal lobe and the apolipoprotein E (APOE) genotype could predict cognitive improvement in subjects with probable AD treated with rivastigmine. METHODS: 121 subjects with mild to moderate probable AD were treated for 26 weeks with escalating doses of rivastigmine. Outcome measures were change on the MMSE and the ADAS-Cog between baseline and follow-up and treatment response defined as at least 2 points improvement on the MMSE or at least 4 points improvement on the ADAS-Cog. The study was an open-label multi-centre study in The Netherlands. RESULTS: Subjects with medial temporal lobe atrophy (MTLA) tended to show more decline on the MMSE after correction for age, sex, education, baseline cognitive score, and dosage at week 26 compared with subjects without MTLA (p = 0.08). A significant interaction between MTLA and dosage at week 26 existed for change on the MMSE and ADAS-Cog: subjects with MTLA showed more cognitive decline than subjects without MTLA only in the group of patients who received a low dosage at week 26. MTLA was not associated with treatment response. The APOE genotype was not associated with change on the MMSE or ADAS-Cog or with treatment response. CONCLUSIONS: MTLA and the APOE genotype are not clinically useful predictors of cognitive response in subjects with probable AD who are treated with rivastigmine.

Rasquin SM, Lodder J, Visser PJ, Lousberg R, Verhey FR. · Research Institute Brain and Behavior, Department of Psychiatry and Neuropsychology, University of Maastricht, University Hospital Maastricht, Maastricht, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #15591801 No free full text.

Abstract: AIM: The aim of this study was to investigate the prognostic accuracy of different subtypes of mild cognitive impairment (MCI): amnestic MCI, multiple domain MCI, and single non-memory domain MCI, for the development of Alzheimer's dementia (AD) and vascular dementia (VaD). PATIENTS: Nondemented patients from a memory clinic cohort (n = 118), and a stroke cohort (n = 80, older than 55 years and with a cognitive impairment). RESULTS: 'Multiple domain MCI' had the highest sensitivity for both AD (80.8%) and VaD (100%), and 'amnestic MCI' had the highest specificity (85.9% for AD, 100% for VaD). The positive predictive value was low for all subtypes (0.0-32.7%), whereas the negative predictive value was high (72.8-100%). DISCUSSION: The subtype 'multiple domain MCI' has high sensitivity in identifying people at risk for developing AD or VaD. The predictive accuracy of the MCI subtypes was similar for both AD and VaD.

Korf ES, Wahlund LO, Visser PJ, Scheltens P. · Department of Neurology and Alzheimer Center, Vrije Universiteit Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #15249617 No free full text.

Abstract: BACKGROUND: Although detailed volumetric MRI assessment of medial temporal lobe atrophy (MTA) can predict dementia in patients with mild cognitive impairment (MCI), it is not easily applied to routine clinical practice. OBJECTIVE: To test the predictive accuracy of visually assessed MTA in MCI patients using a standardized visual rating scale. METHODS: Seventy-five MCI patients (mean age 63 years) underwent a coronal three-dimensional magnetization-prepared rapid gradient echo brain MRI sequence. MTA was rated visually using a 5-point rating scale. RESULTS: The mean follow-up period for the cohort was 34 months. At follow-up, 49% of the enrolled MCI patients fulfilled criteria for dementia. MTA assessed using a standardized visual rating scale was significantly associated with dementia at follow-up, with a hazard ratio of 1.5 for every point increase in atrophy score (p < 0.001) and of 3.1 for the presence of atrophy based on the dichotomized atrophy score (p = 0.003). The predictive accuracy of visually assessed MTA was independent of age, gender, education, Mini-Mental State Examination score, Clinical Dementia Rating Sum of Boxes score, Verbal Delayed Recall, and the presence of hypertension, depression, the APOE epsilon4 allele, and white matter hyperintensities. CONCLUSIONS: Visual assessment of MTA on brain MRI using a standardized rating scale is a powerful and independent predictor of conversion to dementia in relatively young MCI patients. As overlap existed in MTA scores between patients with and without dementia at follow-up, the results should be interpreted in the light of the odds for the individual patient.

Visser PJ, Verhey FR, Ponds RW, Jolles J. · Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands. · Int Psychogeriatr. · Pubmed #12003248 No free full text.

Abstract: INTRODUCTION: The aim of the study was to investigate whether the preclinical stage of Alzheimer's disease (AD) can be diagnosed in a clinical setting. To this end we investigated whether subjects with preclinical AD could be differentiated from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. METHODS: Twenty-three subjects with preclinical AD, 44 subjects with nonprogressive mild cognitive impairment, and 25 subjects with very mild AD-type dementia were selected from a memory clinic population. Variables that were used to differentiate the groups were demographic variables, the Mini-Mental State Examination score, performance on cognitive tests, measures of functional impairment, and measures of noncognitive symptomatology. RESULTS: Age and the scores for the delayed recall task could best discriminate between subjects with preclinical AD and subjects with nonprogressive mild cognitive impairment. The overall accuracy was 87%. The score on the Global Deterioration Scale and a measure of intelligence could best discriminate between subjects with preclinical AD and subjects with very mild AD-type dementia. The overall accuracy was 85%. CONCLUSIONS: Subjects with preclinical AD can be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. This means that preclinical AD is a diagnostic entity for which clinical criteria should be developed.

Visser PJ, Verhey FR, Hofman PA, Scheltens P, Jolles J. · Institute of Brain and Behavior, Department of Psychiatry, University of Maastricht, Maastricht, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #11909909 links to  free full text

Abstract: OBJECTIVES: To investigate whether medial temporal lobe atrophy predicted outcome in patients with minor cognitive impairment and whether assessment of the medial temporal lobe could increase the predictive accuracy of age and delayed recall for outcome. Quantitative and qualitative methods of assessing the medial temporal lobe were also compared. METHODS: Patients with minor cognitive impairment older than 50 years (n=31) were selected from a memory clinic and were followed up for on average 1.9 years. The medial temporal lobe was assessed in three different ways: volumetry of the hippocampus, volumetry of the parahippocampal gyrus, and qualitative rating of medial temporal lobe atrophy (MTA). Outcome measures were Alzheimer type dementia or cognitive decline at follow up. Delayed recall was tested with a verbal learning test. RESULTS: Ten patients had experienced cognitive decline at follow up, of whom seven had probable Alzheimer type dementia. All medial temporal lobe measurements were associated with cognitive decline at follow up (p trend analysis between 0.001 (hippocampus) and 0.05 (parahippocampal gyrus)). Only the hippocampal volume and MTA score were associated with Alzheimer type dementia at follow up (p trend analysis respectively 0.003 and 0.01). All medial temporal lobe measurements increased the predictive accuracy of age and the delayed recall score for cognitive decline (p increase in predictive accuracy varied between <0.001 (hippocampus) and 0.02 (parahippocampal gyrus and MTA score)) and the hippocampal volume and the MTA score increased the predictive accuracy of age and the delayed recall score for Alzheimer type dementia (p= 0.02). CONCLUSIONS: The ability to detect patients at high risk for Alzheimer type dementia among those with minor cognitive impairment increases when data on age and memory function are combined with measures of medial temporal lobe atrophy. Volumetry of the hippocampus is preferred, but qualitative rating of medial temporal lobe atrophy is a good alternative.

Visser PJ, Verhey FR, Ponds RW, Kester A, Jolles J. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behavior, University of Maastricht, The Netherlands. · J Am Geriatr Soc. · Pubmed #10811539 No free full text.

Abstract: OBJECTIVE: To assess the prevalence of depression in subjects with preclinical Alzheimer's disease (AD) and to investigate the possibility of differentiating subjects with preclinical AD and depression from subjects with depression-related cognitive impairment. DESIGN: A prospective, observational cohort study. SETTING: An outpatient memory clinic of a university-affiliated hospital. PARTICIPANTS: Nondemented subjects with cognitive impairment older than 55 years (n = 111) without neurological or somatic causes for the cognitive impairment. MEASUREMENTS: At baseline, data were collected on patient characteristics, the severity of depression, and cognitive functioning. The course of the cognitive impairment and the presence of dementia were assessed after 2 and 5 years. RESULTS: Twenty-five subjects had preclinical dementia with Alzheimer's type dementia at follow-up. Sixty percent of these subjects (n = 15) were depressed at baseline. Subjects with depression and preclinical AD had at baseline a poorer performance on the cognitive tasks and were older than the subjects with depression-related cognitive impairment. Logistic regression with backward step selection selected age and memory performance as the best predictors for Alzheimer's type dementia in the depressed subjects. The specificity of these predictors for the diagnosis of future Alzheimer's type dementia in depressed subjects was 94%, sensitivity was 90%, positive predictive value was 90%, and negative predictive value was 94%. CONCLUSIONS: Depression is common in preclinical AD. Depressed subjects with preclinical AD can be accurately differentiated from subjects with depression-related cognitive impairment by age and the severity of the memory impairment. Research that aims to investigate preclinical AD should not exclude a priori subjects with depression inasmuch as preclinical AD is often accompanied by depression.

Visser PJ, Verhey FR, Ponds RW, Cruts M, Van Broeckhoven CL, Jolles J. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behavior, University of Maastricht, Maastricht, The Netherlands. · Int J Geriatr Psychiatry. · Pubmed #10767737 No free full text.

Abstract: The aim of the study was to investigate the course of objective memory impairment in non-demented subjects who attended a memory clinic and to test predictors of outcome. Non-demented subjects (N=74) were included when they were older than 40 years and had a baseline score on the delayed recall of a word learning test below the tenth percentile. Subjects with memory impairment due to known somatic or neurological causes were excluded. The subjects were reassessed after 2 and 5 years. At the 5-year follow-up, 42% of the subjects had no memory impairment, 19% of the subjects had memory impairment without dementia, and 39% of the subjects had Alzheimer type dementia (AD). Predictors at baseline of reversible memory impairment in a multivariate analysis were age, scores on the MMSE and delayed recall, and the degree of functional impairment. Predictors at baseline of AD in a multivariate analysis were age and the score on the MMSE. The apolipoprotein E genotype and the presence of depression at baseline were not predictors of outcome. The positive predictive value was 72% for reversible memory impairment and 81% for AD. Memory impairment is often reversible and therefore its presence alone is not sufficient to consider subjects as preclinically demented. Predictive accuracy can be increased by including simple measures such as age, the scores on the MMSE and delayed recall, and the degree of functional impairment.

Visser PJ, Scheltens P, Verhey FR, Schmand B, Launer LJ, Jolles J, Jonker C. · Department of Psychiatry and Neuropsychology, Institute of Brain and Behavior, University of Maastricht, The Netherlands. · J Neurol. · Pubmed #10431775 No free full text.

Abstract: To determine whether the medial temporal lobe is atrophic in subjects with mild cognitive impairment, and whether atrophy of this structure is a better predictor of dementia than memory dysfunction. Forty-five noninstitutionalized subjects aged 65-85 years were randomly selected from a population based study to obtain a sample with Alzheimer's disease (AD; n = 7), and a clinically nondemented sample (n = 38). Twenty of the latter subjects displayed some cognitive impairment and fulfilled CAMDEX criteria for "minimal dementia." Coronal T1-weighted magnetic resonance imaging was used to visualize the medial temporal lobe. The volume of the parahippocampal gyrus and hippocampus was measured, and medial temporal lobe atrophy was assessed qualitatively. The memory subscore from the CAMCOG was used as a measure of memory functioning. The follow-up period was 3 years. Nine subjects who were diagnosed as being minimally demented at baseline met the criteria for AD during follow-up. At baseline the volume of the parahippocampal gyrus of these subjects was smaller than that of the other subjects with minimal dementia. The memory score was the best predictor of clinical outcome. All medial temporal lobe measures increased the accuracy of prediction compared with only the memory score, by reducing the number of false-negative classifications of dementia. Severe medial temporal lobe atrophy is present even in some subjects with mild cognitive impairment and is an indicator of subsequent AD. The absence of medial temporal lobe atrophy, however, does not exclude the development of dementia. In the majority of subjects memory impairment was a better predictor of dementia than atrophy of the medial temporal lobe. The combination of the two increased predictive accuracy. Nondemented subjects with severe atrophy of the medial temporal lobe could be enrolled in drug trials aimed at slowing the progression of AD.

Visser PJ. · No affiliation provided · J Am Geriatr Soc. · Pubmed #17198525 No free full text.

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