Anke Hensel

Mild cognitive impairment: Long-term course of four clinical subtypes.

Objective: To empirically validate the expanded concept of mild cognitive impairment (MCI), which differentiates between four clinical subtypes—amnestic MCI–single domain, amnestic MCI–multiple domains, nonamnestic MCI–single domain, and nonamnestic MCI–multiple domains—and to examine the prevalence, course, and outcome of these four clinical MCI subtypes. Methods: We studied a community sample of 980 dementia-free individuals aged 75 years or older who participated in the Leipzig Longitudinal Study of the Aged (LEILA 75+). All participants were examined by neuropsychological testing based on 6 years of observation. The diagnoses of the four clinical MCI subtypes were made according to the original and to slightly modified criteria by Petersen et al. (2001) (both with a cutoff of 1.0 SD and with a cutoff of 1.5 SD). The complete range of outcome types (dementia, death, improvement, stable diagnosis, unstable diagnosis) was described for all subtypes. The relative predictive power of stable MCI for dementia onset was determined. Results: MCI–single domain is more frequent than MCI–multiple domains, and the nonamnestic MCI type is as frequent as the amnestic MCI type. The “MCI modified, 1.0 SD” criteria have the highest relative predictive power for the development of dementia (sensitivity = 74%, specificity = 73%). Alzheimer disease (AD) was the most common type of dementia at follow-up in all but one MCI subtype. Participants with nonamnestic MCI–multiple domains were more likely to progress to a non-AD dementia. Conclusions: It has been assumed that each MCI subtype is associated with an increased risk for a particular type of dementia. We can only partially agree with this.

Hippocampal volume discriminates between normal cognition; questionable and mild dementia in the elderly

The sensitivity of MRI volumetric measures to detect cognitive dysfunction is examined in 39 participants of an epidemiological field study (age 75-85, MMSE 19-30). According to Clinical dementia rating (CDR), 17 subjects had normal cognition (CDR 0), 12 had questionable (CDR 0.5) and 10 mild dementia (CDR 1). Discriminant analysis based on four hippocampal measures resulted in a correct classification of 76.9% of all subjects. Left-sided and posterior hippocampal measures were more responsible for group discrimination than right-sided and anterior measures. In CDR 0.5, a significant hippocampal volume reduction of 14.3% vs.11.3% (left vs. right) relative to normal was found. The right hippocampus was significantly greater than the left in CDR 0 and CDR 0.5, but not in CDR 1. The magnitude of non-directional hippocampal asymmetry increased with decreasing cognitive state. We conclude that hippocampal atrophy is sensitive to detect cognitive dysfunction and subjects at risk for Alzheimers disease in the elderly population.

Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer’s disease

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.

Reduced α4β2*–Nicotinic Acetylcholine Receptor Binding and Its Relationship to Mild Cognitive and Depressive Symptoms in Parkinson Disease

CONTEXT Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs). OBJECTIVE To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD. DESIGN Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography. SETTING Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany. PARTICIPANTS Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers. MAIN OUTCOME MEASURES Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed. RESULTS In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum. CONCLUSIONS There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.

Hippocampal atrophy in Alzheimer disease: Age matters

Hippocampal atrophy is a marker of Alzheimer disease (AD). It remains unclear whether this holds true for younger patients as well. Hippocampal volume was measured on MRI scans of 103 clinically diagnosed AD patients and 73 controls (aged 51 to 85 years). Aging and AD were independently associated with smaller hippocampal volume. Both young and old AD patients have hippocampal atrophy abnormal for age. Age-dependent criteria for hippocampal atrophy, suggestive of AD, are needed.

Measuring cognitive change in older adults: reliable change indices for the Mini-Mental State Examination

Background: In clinical and research settings, the Mini-Mental State Examination (MMSE) is commonly used to measure cognitive change over time. The interpretation of changes in MMSE is often difficult. They do not necessarily result from true clinical change. Their interpretation requires comparison with normative data for change. However, MMSE change norms are lacking for long intervals. Objective: To examine what is a reliable change in MMSE for long follow-up periods commonly used in clinic. To provide normative data for change. Methods: A sample of 119 cognitively normal individuals, aged 75 years and over, who participated in the Leipzig Longitudinal Study of the Aged (LEILA 75+). All participants were tested six times at 1.5 year intervals with the MMSE over a mean period of 7.1 years. Reliable change indices were computed for a common confidence interval (90%). Results: In repeated assessments with 1.5 year intervals, a change in MMSE of at least 2–4 points indicated a reliable change at the 90% confidence level. Conclusion: Small changes in MMSE can be interpreted only with great uncertainty. They have a reasonable probability of being caused by measurement error, regression to the mean or practice.

Structural correlates of mild cognitive impairment

The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.

Correlation between cortical theta activity and hippocampal volumes in health, mild cognitive impairment, and mild dementia

Summary Cognitive decline is known to be associated with bothincreased &thgr; power over frontal regions and hippocampal atrophy. The aimof this study was to reveal the relation between these parameters in groupswith mild dementia, mild cognitive impairment, and healthy control subjects.The authors examined a preliminary randomly selected sample of 39 right-handedsubjects joining the Leipzig Longitudinal Study of the Aged, consisting of 17normal elderly subjects, 12 patients with mild cognitive impairment, and 10patients with mild dementia assessed by Clinical Dementia Rating. All subjectswere between 75 and 85 years old (mean age, 78 years; standard deviation, 2.78years) and underwent EEG and brain MRI. Mean spectral power densities werecalculated, and hippocampal body volume was measured. Significant negativelinear correlations between &thgr; power over frontal regions and hippocampalvolumes were found. The results support the assumption about a relationshipbetween hippocampal atrophy and &thgr; power, and may be helpful for a betterunderstanding of the course of Alzheimer’sdisease.

Serum Lipids and Hippocampal Volume: The Link to Alzheimer's Disease?

The association between hippocampal volume (as a presumed index of Alzheimers disease pathology) with serum total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High‐density lipoprotein cholesterol, but not low‐density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high‐density lipoprotein cholesterol on hippocampal atrophy and Alzheimers disease. Ann Neurol 2004;56:745–749

The relationship between head size and intracranial volume in elderly subjects

OBJECTIVE To study the relationship between parenchymal head volume (PHV) and intracranial volume (ICV), and to compare the ability of these two measurements to reflect the association between maximum mature brain volume and late-life cognition. METHODS An elderly sample of humans with a range of cognitive functions from normality, via mild cognitive impairment (MCI) to dementia (mean age 78.6, S.D. 2.8; mean MMSE 25.4, S.D. 4.2) was examined. Head-to-head measurements of ICV and parenchymal head volume (PHV) were obtained from three-dimensional T1 weighted magnetic resonance images using automated procedures. Analyses of cognitive functions were based on continuous and categorial variables. RESULTS PHV explained 55% of the variance in ICV. The ratio between PHV and ICV remained constant with increasing age and cognitive impairment. Measurements of PHV and ICV yielded comparable correlations with global cognitive performance. Group differences over gender and cognitive states were equally present in ICV and PHV. The relative risks of cognitive impairment that were associated with either small ICV or PHV were comparable. CONCLUSIONS Measures of PHV can be considered as useful estimates of ICV and cerebral volume reserve.