Effects of physical activity training in patients with Alzheimer's dementia: results of a pilot RCT study.

BACKGROUND: There is evidence that physical activity (PA) is of cognitive benefit to the ageing brain, but little is known on the effect in patients with Alzheimer's disease (AD). The present pilot study assessed the effect of a home-based PA training on clinical symptoms, functional abilities, and caregiver burden after 12 and 24 weeks. METHODS: In an RCT thirty patients (aged 72.4±4.3 years) with AD (MMSE: 20.6±6.5 points) and their family caregivers were allocated to a home-based 12-week PA intervention program or the usual care group. The program changed between passive, motor-assisted or active resistive leg training and changes in direction on a movement trainer in order to combine physical and cognitive stimuli. RESULTS: Analysis of activities of daily living in the patients (ADCS ADL total score) revealed a significant group × time interaction effect (95% CI of the difference between both groups at T2: 5.01-10.51). The control group experienced decreases in ADL performance at week 12 and 24 whereas patients in the intervention group remained stable. Analyses of executive function and language ability revealed considerable effects for semantic word fluency with a group × time interaction (95% CI of the difference between both groups at T2: 0.18-4.02). Patients in the intervention group improved during the intervention and returned to initial performance at week 12 whereas the controls revealed continuous worsening. Analyses of reaction time, hand-eye quickness and attention revealed improvement only in the intervention group. Caregiver burden remained stable in the intervention group but worsened in the control group. CONCLUSIONS: This study suggests that PA in a home-based setting might be an effective and intrinsically attractive way to promote PA training in AD and modulate caregiver burden. The results demonstrate transfer benefits to ADL, cognitive and physical skill in patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02196545.

Cardiovascular risk and hippocampal thickness in Alzheimer's disease.

Cardiovascular risk factors influence onset and progression of Alzheimer's disease. Among cognitively healthy people, changes in brain structure and function associated with high blood pressure, diabetes, or other vascular risks suggest differential regional susceptibility to neuronal damage. In patients with Alzheimer's disease, hippocampal and medial temporal lobe atrophy indicate early neuronal loss preferentially in key areas for learning and memory. We wanted to investigate whether this regional cortical thinning would be modulated by cardiovascular risk factors. We utilized high-resolution magnetic resonance imaging and a cortical unfolding technique to determine the cortical thickness of medial temporal subregions in 30 patients with Alzheimer's disease. Cardiovascular risk was assessed using a sex-specific multivariable risk score. Greater cardiovascular risk was associated with cortical thinning in the hippocampus CA2/3/dentate gyrus area but not other hippocampal and medial temporal subregions. APOE genotype, a family history of Alzheimer's disease, and age did not influence cortical thickness. Alzheimer's disease-related atrophy could mask the influence of genetic risk factors or age on regional cortical thickness in medial temporal lobe regions, whereas the impact of vascular risk factors remains detectable. This highlights the importance of cardiovascular disease prevention and treatment in patients with Alzheimer's disease.

APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer's disease.

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer's disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer's disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer's disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer's disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.

Memantine effects measured with the Relevant Outcome Scale for Alzheimer's disease in an open-label, single-arm, multicenter clinical study.

OBJECTIVE: The Relevant Outcome Scale for Alzheimer's disease (ROSA) is a novel, valid, and reliable instrument for multidimensional assessment of Alzheimer's disease (AD) symptoms across all severity stages. The ROSA and four standard instruments -- the Alzheimer's disease Assessment Scale-cognitive (ADAS-cog), Severe Impairment Battery (SIB), Disability Assessment for Dementia (DAD), and the Neuropsychiatric Inventory (NPI) -- were used in an open-label, multicenter, single-arm clinical study to assess treatment-induced changes in cognitive, functional, and behavioral symptoms in patients with AD at different severity stages. METHODS: A total of 451 patients were treated with memantine (initiated at 5 mg/day and up-titrated with 5 mg weekly to a final dose of 20 mg/day) for 12 weeks. The study endpoints comprised changes from baseline in the scores of the ROSA, ADAS-cog, SIB, DAD, and NPI as well as global changes on the Clinical Global Impression of Change (CGI-C). Analyses were performed for the overall population and by AD severity stage (early, middle, late). RESULTS: The ROSA scores increased significantly after a 12-week treatment in all study groups except for early stage. Mean changes in the ADAS-cog score indicated a trend towards worsening in early and middle stages. Non-significant changes were shown by the SIB, NPI, and DAD assessments at week 12. The CGI-C demonstrated 'minimal improvement' or 'no change' for most of the patients. Overall, memantine treatment was safe and well tolerated. CONCLUSION: The results demonstrated the ROSA feasibility in daily practice for assessment of memantine effects over time in patients with moderate and late AD.

Functional imaging during recognition of personally familiar faces and places in Alzheimer's disease.

Alzheimer's disease (AD) patients show better everyday functioning in a familiar setting, but they have a reduced ability to access contextual details and episodes associated with a familiar person or environment. This suggests a dysfunction in the neural networks associated with stimulus identification. Using functional magnetic resonance imaging, we investigated the neural activity during the recognition of personally familiar and unfamiliar faces and places among AD patients and elderly controls. We did not find a group difference in the neural activity within brain areas important for perceptual familiarity recognition. Patients showed reduced activation for familiar stimuli in prefrontal brain areas known to be important for retrieving contextual information for a stimulus when compared with controls. These changes may contribute to how AD patients experience a personally familiar face or place.

Interview for Deterioration in Daily Living Activities in Dementia: construct and concurrent validity in patients with mild to moderate dementia.

BACKGROUND: The purpose of the study was to translate the Interview for Deterioration in Daily Living Activities in Dementia (IDDD) into German and to evaluate the construct and concurrent validity in people with mild to moderate dementia. METHODS: IDDD data of two pooled samples (n = 301) were analyzed regarding ceiling and bottom effects, internal consistency, factor reliability and correlations with corresponding scales on cognition and activities of daily living. RESULTS: We found minimal bottom (< 5%) and ceiling (≤ 2%) effects, good internal consistency (Cronbach's α > 0.7) and moderate to good factor reliability (0.66-0.87). Low correlations with cognition (Pearson coefficient: < 0.17) confirmed the differences between cognitive testing and activities of daily living (ADL). Minor correlations with other ADL scores (r < 0.2) indicated that different scores cover a different range of ADLs. The original two factor model could not be confirmed. A suggested four factor model distinguishing initiative and performance of basic and instrumental ADL demonstrated better indices of fit and higher correlations with corresponding scales. CONCLUSION: A four factor model of the IDDD can be used in dementia research for assessing initiative in and performance of basic and household activities of daily living. The findings suggest that ADL scales correlate only poorly and that further development of the IDDD is needed to cover a broader range of ADLs.

Validation of the relevant outcome scale for Alzheimer's disease: a novel multidomain assessment for daily medical practice.

INTRODUCTION: The Relevant Outcome Scale for Alzheimer's Disease (ROSA) is a new observer rating instrument recently developed for routine medical practice. The validity and reliability of ROSA as well as sensitivity to changes due to intervention were examined in an open-label, single-arm, multicenter clinical study in patients with Alzheimer's disease (AD). METHODS: The study enrolled 471 patients with a diagnosis of AD consistent with the criteria of the National Institute of Neurological and Communicative Disease and Stroke/Alzheimer's Disease and Related Disorders Association or with the Diagnostic and Statistical Manual Disorders criteria for dementia of Alzheimer's type. Following assessments of the ROSA and other standard assessments (Alzheimer's Disease Assessment Scale - cognitive subscale, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia), patients were treated with memantine for 12 weeks. Factor analysis of the baseline ROSA total scores was performed based on the principal components method using the varimax orthogonal rotational procedure. The psychometric analyses of the ROSA included internal consistency, test-retest reliability, inter-rater reliability, construct validity, and responsiveness to changes over time. RESULTS: All items showed adequate factor loadings and were retained in the final ROSA as Factor 1 (all items related to cognition, communication, function, quality of life and caregiver burden) and Factor 2 (all behavior items). The ROSA demonstrated high internal consistency (Cronbach's α = 0.93), test-retest reliability (intraclass correlation coefficient = 0.93), and inter-rater reliability (intraclass correlation coefficient = 0.91). The correlation coefficients between the ROSA and each of the validated scales ranged between 0.4 and 0.7, confirming the ROSA construct validity. Nonsubstantial floor and ceiling effects were found in middle and late disease stages, whereas a small ceiling effect was observed in the early stage. The ROSA responsiveness to change was high (responsiveness index ≥0.8) for all severity stages. CONCLUSIONS: The ROSA is a valid and reliable instrument to aid medical practitioners in sensitively assessing AD-relevant symptoms over time in their clinical practice.

Visual personal familiarity in amnestic mild cognitive impairment.

BACKGROUND: Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general concept or helps to identify an object or a person. METHODOLOGY/PRINCIPAL FINDINGS: Using functional magnetic resonance imaging, we investigated the neural networks associated with the perception of personal familiar faces and places in patients with amnestic mild cognitive impairment and healthy control subjects. Irrespective of stimulus type, patients compared to control subjects showed lower activity in right prefrontal brain regions when perceiving personally familiar versus unfamiliar faces and places. Both groups did not show different neural activity when perceiving faces or places irrespective of familiarity. CONCLUSIONS/SIGNIFICANCE: Our data highlight changes in a frontal cortical network associated with knowledge-based personal familiarity among patients with amnestic mild cognitive impairment. These changes could contribute to deficits in social cognition and may reduce the patients' ability to transition from basic to complex situations and tasks.

Age-dependent differences in the neural mechanisms supporting long-term declarative memories.

Autobiographical memories enable us to mentally reconstruct and relive past events, which is essential for one's personal identity. Unfortunately, this complex memory system is susceptible to age-related deterioration, possibly changing the way episodic information is being processed in older adults. The aim of this study was to investigate whether age influences the neural activity associated with content (episodic versus semantic) and remoteness (recent versus remote) of memories. Using functional magnetic resonance imaging in healthy older and young adults, we found significant age-dependent differences in the neural networks underlying memory content but not remoteness. Our data suggest an age-associated functional reorganization in the neural networks underlying long-term declarative memory. Relative increase in activity of posterior brain regions could reflect changes in visuospatial processing during episodic memory retrieval in older adults.

Age and the neural network of personal familiarity.

BACKGROUND: Accessing information that defines personally familiar context in real-world situations is essential for the social interactions and the independent functioning of an individual. Personal familiarity is associated with the availability of semantic and episodic information as well as the emotional meaningfulness surrounding a stimulus. These features are known to be associated with neural activity in distinct brain regions across different stimulus conditions (e.g., when perceiving faces, voices, places, objects), which may reflect a shared neural basis. Although perceiving context-rich personal familiarity may appear unchanged in aging on the behavioral level, it has not yet been studied whether this can be supported by neuroimaging data. METHODOLOGY/PRINCIPAL FINDINGS: We used functional magnetic resonance imaging to investigate the neural network associated with personal familiarity during the perception of personally familiar faces and places. Twelve young and twelve elderly cognitively healthy subjects participated in the study. Both age groups showed a similar activation pattern underlying personal familiarity, predominantly in anterior cingulate and posterior cingulate cortices, irrespective of the stimulus type. The young subjects, but not the elderly subjects demonstrated an additional anterior cingulate deactivation when perceiving unfamiliar stimuli. CONCLUSIONS/SIGNIFICANCE: Although we found evidence for an age-dependent reduction in frontal cortical deactivation, our data show that there is a stimulus-independent neural network associated with personal familiarity of faces and places, which is less susceptible to aging-related changes.

Overgenerality of autobiographical memory in people with amnestic mild cognitive impairment and early Alzheimer's disease.

Episodic autobiographical memory (ABM) is important for social functioning. Loss of specificity in ABM retrieval has been observed in people with mild to moderate Alzheimer's disease (AD). Our aim was to extend these findings to subjects with amnestic mild cognitive impairment (aMCI) and very early AD. We performed a cued ABM task with both subject groups and healthy elderly controls. Although aMCI participants performed better than early AD subjects both showed reduced specificity of ABM retrieval when compared with controls. We conclude that qualitative memory retrieval deficits could contribute to social functioning impairment in people with aMCI and early AD, and highlight the complexity of symptoms already present in early stages of cognitive impairment.

Altered neural network supporting declarative long-term memory in mild cognitive impairment.

Autobiographical episodic memory represents a subsystem of declarative long-term memory and largely depends on combining information from multiple sources. The purpose of this study was to assess neural correlates of declarative long-term memory in patients with amnestic mild cognitive impairment (MCI) and controls using fMRI and a task requiring autobiographical and semantic memory retrieval. Comparison of the network supporting episodic autobiographical and semantic memory irrespective of remoteness (recent and remote) revealed significant activations in right parietal cortex and precuneus bilaterally in the patients. Autobiographical episodic versus semantic memory retrieval in the controls led to significant bilateral activations of the parietal-temporal junction, left temporal pole, anterior cingulate, retrosplenial cortex and cerebellum. In contrast, MCI patients activated left supplementary motor area, left premotor and superior temporal cortex. In MCI patients compared to controls a dysfunction of the retrosplenial cortex during memory retrieval was revealed by a lack of differential activation in relation to recency of memories and memory type. Our data suggest that MCI leads to a loss of specificity in the neural network supporting declarative long-term memory.

On the multivariate nature of brain metabolic impairment in Alzheimer's disease.

We used principal component analysis to decompose functional images of patients with AD in orthogonal ensembles of brain regions with maximal metabolic covariance. Three principal components explained 38% of the total variance in a large sample of FDG-PET images obtained in 225 AD patients. One functional ensemble (PC2) included limbic structures from Papez's circuit (medial temporal regions, posterior and anterior cingulate cortex, thalamus); its disruption in AD patients was related to episodic memory impairment. Another principal component (PC1) illustrated major metabolic variance in posterior cerebral cortices, and patients' scores were correlated to instrumental functions (language and visuospatial abilities). PC3 comprised frontal, parietal, temporal and posteromedial (posterior cingulate and precuneus) cortices, and patients' scores were related to executive dysfunction and global cognitive impairment. The three main metabolic covariance networks converged in the posterior cingulate area that showed complex relationships with medial temporal structures within each PC. Individual AD scores were distributed as a continuum along PC axes: an individual combination of scores would determine specific clinical symptoms in each patient.

A method for the detection of amyloid-beta1-40, amyloid-beta1-42 and amyloid-beta oligomers in blood using magnetic beads in combination with Flow cytometry and its application in the diagnostics of Alzheimer's disease.

A method for simultaneous quantification of amyloid-beta1-40, amyloid-beta1-42 and amyloid-beta oligomers in human plasma is described. The method consists of a combination of immunoprecipitation using specific antibodies against the different forms of amyloid-beta, and immobilization of the immunocomplexes to magnetic beads. Addition of fluorescence-labelled antibodies which recognize the specific antibodies to the amyloid-beta subsets allows the peptide/associates detection in the sample by flow cytometry. The clinical assay performance was tested using blood samples from Alzheimer disease's patients and control donors. A sensitivity of 70% and a specificity of 81% was achieved.

Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias.

UNLABELLED: This multicenter study examined (18)F-FDG PET measures in the differential diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). METHODS: We examined the (18)F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals ("normals" or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal (18)F-FDG uptake that were then applied to characterize MCI. RESULTS: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. (18)F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. CONCLUSION: Standardized automated analysis of (18)F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

Nonfluent aphasia in a patient with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is an uncommon low-grade lymphoma. Cognitive impairment due to central nervous system infiltration by lymphoplasmocytoid cells (Bing-Neel syndrome) has been rarely reported. We describe a 54-year-old man who was referred to a memory disorder clinic with a 9-month history of clinically obvious nonfluent aphasia and WM. He underwent extensive neuropsychological testing, clinical examination and structural and functional brain imaging. The diagnosis of the diffuse form of the Bing-Neel syndrome was supported by abnormal lymphoid cells found in the cerebrospinal fluid. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and subsequent functional deficits mimicking the neuropsychological syndrome encountered in progressive nonfluent aphasia. The diffuse form of Bing-Neel syndrome and neurological deficits are assumed to be the result of leptomeningeal infiltration by malignant cells and/or neoplastic vascular obstruction.

Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes.

Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction.

Severe chemotherapy-induced parosmia.

BACKGROUND: Smell and taste disorders are among the side effects of chemo- and radiotherapy. Although direct radionecrosis of the salivary glands and the taste buds might explain the chemosensory problems after radiotherapy, the olfactory and gustatory complaints seen after chemotherapy remain unexplained. The patients reporting olfactory symptoms rarely complain about qualitative olfactory disorders such as parosmia or phantosmia. Quantitative olfactory loss such as anosmia and hyposmia seem to be more frequent. METHODS: We present the case of a 63-year-old woman with chemotherapy-induced parosmia leading to severe nutrition and appetite problems resulting in a life-threatening weight loss. RESULTS: With the aid of a simple nose clip the parosmia could be abolished and oral food intake became possible again. Parosmia resolved gradually over an observation period of 9 months, in parallel to an increase of olfactory sensitivity. The patient progressively gained appetite and weight. CONCLUSION: Parosmia can occur as a severe and potentially life-threatening complication of chemotherapy. This rare presentation of parosmia illustrates the importance of olfactory testing with an adequate recognition of the underlying problem and a consecutive treatment.

18FDG PET in vascular dementia: differentiation from Alzheimer's disease using voxel-based multivariate analysis.

The brain metabolic pattern of vascular dementia (VaD) remains poorly characterized. Univariate voxel-based analysis ignores the functional correlations among structures and may lack sensitivity and specificity. Here, we applied a novel voxel-based multivariate technique to a large ((18)F)2-fluoro-2-deoxy-D-glucose positron emission tomography data set. The sample consisted of 153 subjects, one-third each being probable subcortical VaD, probable Alzheimer disease (AD) (matched for Mini-Mental-State examination (MMSE) and age), and normal controls (NCs). We first applied principal component (PC) analysis and removed PCs significantly correlated to age. The remainders were used as feature vectors in a canonical variate analysis to generate canonical variates (CVs), that is, linear combinations of PC-scores. The first two CVs efficiently separated the groups. CV(1) separated VaD from AD with 100% accuracy, whereas CV(2) separated NC from demented subjects with 72% sensitivity and 96% specificity. Images depicting CV(1) and CV(2) showed that lower metabolism differentiating VaD from AD mainly concerned the deep gray nuclei, cerebellum, primary cortices, middle temporal gyrus, and anterior cingulate gyrus, whereas lower metabolism in AD versus VaD concerned mainly the hippocampal region and orbitofrontal, posterior cingulate, and posterior parietal cortices. The hypometabolic pattern common to VaD and AD mainly concerned the posterior parietal, precuneus, posterior cingulate, prefrontal, and anterior hippocampal regions, and linearly correlated with the MMSE. This study shows the potential of voxel-based multivariate methods to highlight independent functional networks in dementing diseases. By maximizing the separation between groups, this method extracted a metabolic pattern that efficiently differentiated VaD and AD.

Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia.

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, -24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, -22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD.