Kristian Steen Frederiksen

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity

An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer's Disease: A Randomized Controlled Trial

BACKGROUND Studies of physical exercise in patients with Alzheimers disease (AD) are few and results have been inconsistent. OBJECTIVE To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. METHODS In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. RESULTS The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: -3.5, 95% confidence interval (CI) -5.8 to -1.3, p = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p = 0.028), suggesting a dose-response relationship between exercise and cognition. CONCLUSIONS This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity.

Corpus Callosum Atrophy in Patients with Mild Alzheimer’s Disease

Background/Objectives: Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer’s disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as age-related white matter changes (ARWMC) and progression of the disease. Meth ods: Twenty-eight patients in the early stages of AD and 50 non-demented elderly subjects with varying degrees of ARWMC were investigated using MRI. The CC was assessed semi-automatically, and ARWMC were rated according to the Fazekas scale. Results: A significant difference in posterior CC size could be detected between non-demented elderly subjects and early stage AD patients. The sizes of the total CC, rostral body and splenium at baseline were correlated with change from baseline MMSE score after a 1-year follow-up in AD patients. There was no association between CC size and ARWMC. Conclusions: The present findings indicate that posterior CC atrophy is present in mild AD independently of ARWMC. Furthermore, CC atrophy may be associated with cognitive deterioration.

Lack of association between prior depressive episodes and cerebral [11C]PiB binding

Depressive symptoms are frequent in Alzheimers disease (AD), but it is controversial whether depression is a risk factor for AD. This study measured for the first time cortical amyloid-β (Aβ) levels using [(11)C] Pittsburgh Compound B (PiB) positron emission tomography (PET) in a group of nondemented patients with prior depressive episodes. Twenty-eight elderly patients (mean age 61 years, range 51-75, 18 women) with onset of first depressive episode more than 6 years ago but now remitted from depression and 18 healthy subjects (mean age 61 years, range 50-76, 12 women) were included. All subjects were investigated with cognitive testing, 3T magnetic resonance imaging (MRI) and [(11)C]PiB high resolution research tomography (HRRT) positron emission tomography scan. There was no between-groups difference in [(11)C]PiB binding (p = 0.5) and no associations to number of depressive episodes, cognitive performance, or antidepressant treatment. Patients with late onset of depression had increased severity of white matter lesions (p = 0.04). In this study depressive episodes were not associated with increased levels of [(11)C]PiB. Thus, our results do not support the notion that depressive episodes previously in life are a risk factor for developing AD.

Added Diagnostic Value of 11C-PiB-PET in Memory Clinic Patients with Uncertain Diagnosis

Introduction: The added diagnostic value of 11C-PiB-PET for the assessment of the accumulation of cortical beta-amyloid in memory clinic patients with uncertain diagnosis remains undetermined. Methods: All patients who underwent PiB-PET at the Copenhagen Memory Clinic between March 2008 and November 2011 were included in this uncontrolled, retrospective study. The standard diagnostic evaluation program included physical and neurological examination, cognitive and functional assessment, a cranial CT or MRI, functional imaging and cerebrospinal fluid sampling. Based on anonymized case reports, three experienced clinicians reached a consensus diagnosis and rated their confidence in the diagnosis before and after disclosure of PiB-PET ratings. PiB-PET scans were rated as either positive or negative. Results: A total of 57 patients (17 females, 30 males; age 65.7 years, range 44.2–82.6) were included in the study. Twenty-seven had a positive PiB-PET scan. At the first diagnostic evaluation, 16 patients were given a clinical Alheimer’s disease diagnosis (14 PiB positive). Of the 57 patients, 13 (23%) were diagnostically reclassified after PiB-PET ratings were disclosed. The clinicians’ overall confidence in their diagnosis increased in 28 (49%) patients. Conclusion: PiB-PET adds to the specialist clinical evaluation and other supplemental diagnostic investigations in the diagnostic classification of patients with uncertain diagnosis in a specialized memory clinic.

Physical activity in the elderly is associated with improved executive function and processing speed: the LADIS Study

Physical activity reduces the risk of cognitive decline but may affect cognitive domains differently. We examined whether physical activity modifies processing speed, executive function and memory in a population of non‐dementia elderly subjects with age‐related white matter changes (ARWMC).

Corpus Callosum Tissue Loss and Development of Motor and Global Cognitive Impairment: The LADIS Study

Objective: To examine the impact of corpus callosum (CC) tissue loss on the development of global cognitive and motor impairment in the elderly. Methods: This study was based on the Leukoaraiosis and Disability (LADIS) study. Assessment of cognitive and motor functions and magnetic resonance imaging (MRI) were done at baseline and at a 3-year follow-up in nondemented elderly subjects. Results: 328 of 639 LADIS subjects had MRIs at baseline and at the 3-year follow-up, which allowed for assessment of CC. Logistic regression revealed differential tissue loss rates in posterior CC in subjects converting to dementia, compared to nonconverters (p < 0.05). Anterior and posterior CC tissue loss was significantly correlated with self-perceived memory impairment in nonconverters (p < 0.05). CC tissue loss was also significantly associated with impaired single leg stance time (p < 0.01). Conclusion: The present longitudinal study on CC supports the role of callosal tissue loss in the development of global cognitive as well as motor impairment.

Callosal tissue loss parallels subtle decline in psychomotor speed. A longitudinal quantitative MRI study. The LADIS Study

Cross-sectional studies have suggested that corpus callosum (CC) atrophy is related to impairment in global cognitive function, mental speed, and executive functions in the elderly. Longitudinal studies confirming these findings have been lacking. We investigated whether CC tissue loss is associated with change in cognitive performance over time in subjects with age-related white matter lesions (WML). Two-hundred-fifty-three subjects, aged 65-84 years, were evaluated by using repeated MRI and neuropsychological evaluation at baseline and after 3 years. The effect of overall and regional CC tissue loss on cognitive decline was analyzed with hierarchical linear regression models. After controlling for age, sex, education, and baseline cognitive performance, the rates of tissue loss in the total CC area, and in rostrum/genu and midbody subregions were significantly associated with decline in a compound measure of cognitive speed and motor control, but not in those of executive functions, memory, or global cognitive function. Total CC area and midbody remained significant predictors of speed also after adjusting for baseline WML volume, WML progression, and global brain atrophy. However, the relationship between anterior CC and speed performance was mediated by WML volume. In conclusion, the overall and regional rate of CC tissue loss parallels longitudinal slowing of psychomotor performance. The adverse effect of CC tissue loss on psychomotor function may be driven by altered interhemispheric information transfer between homologous cortical areas.

Effect of aerobic exercise on physical performance in patients with Alzheimer's disease

Knowledge about the feasibility and effects of exercise programs to persons with Alzheimers disease is lacking. This study investigated the effect of aerobic exercise on physical performance in community‐dwelling persons with mild Alzheimers disease.

Application of the PredictAD Software Tool to Predict Progression in Patients with Mild Cognitive Impairment

Background: The PredictAD tool integrates heterogeneous data such as imaging, cerebrospinal fluid biomarkers and results from neuropsychological tests for compact visualization in an interactive user interface. This study investigated whether the software tool could assist physicians in the early diagnosis of Alzheimer’s disease. Methods: Baseline data from 140 patients with mild cognitive impairment were selected from the Alzheimer’s Disease Neuroimaging Study. Three clinical raters classified patients into 6 categories of confidence in the prediction of early Alzheimer’s disease, in 4 phases of incremental data presentation using the software tool. A 5th phase was done with all available patient data presented on paper charts. Classifications by the clinical raters were compared to the clinical diagnoses made by the Alzheimer’s Disease Neuroimaging Initiative investigators. Results: A statistical significant trend (p < 0.05) towards better classification accuracy (from 62.6 to 70.0%) was found when using the PredictAD tool during the stepwise procedure. When the same data were presented on paper, classification accuracy of the raters dropped significantly from 70.0 to 63.2%. Conclusion: Best classification accuracy was achieved by the clinical raters when using the tool for decision support, suggesting that the tool can add value in diagnostic classification when large amounts of heterogeneous data are presented.