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.

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.

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.

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.

Functional imaging of vegetative state applying single photon emission tomography and positron emission tomography.

Nuclear medicine techniques, such as single photon emission tomography (SPECT) and positron emission tomography (PET) have been applied in patients in a vegetative state to investigate brain function in a non-invasive manner. Parameters investigated include glucose metabolism, perfusion at rest, variations of regional perfusion after stimulation, and benzodiazepine receptor density. Compared to controls, patients in a vegetative state show a substantial reduction of glucose metabolism and perfusion. While patients post-anoxia exhibit a rather homogenous cortical reduction of glucose metabolism, patients after head trauma often show severe cortical and sub-cortical reductions at the site of primary trauma. To distinguish reduced glucose metabolism due to neuronal inactivation from neuronal loss, flumazenil-PET, an indicator of benzodiazepine receptor density, could add valuable information on the extent of brain damage. Activation studies focus on the evaluation of residual brain network, looking for processing in secondary projection fields. So far the predictive strength concerning possible recovery for the individual patient is limited, and PET and SPECT are not routine procedures in the assessment of patients in a vegetative state.

Regional cerebral metabolism in early Alzheimer's disease with clinically significant apathy or depression.

BACKGROUND: Alzheimer's disease (AD) is clinically characterized by cognitive impairment and behavioral disturbances. The aim of the study was to identify regional alterations in brain function associated with neuropsychiatric symptoms in early AD. METHODS: Patients underwent measures of cerebral glucose metabolism applying positron emission tomography (PET) and (18)F-fluorodeoxyglucose. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI). Positron emission tomography images of patients suffering a neuropsychiatric symptom of clinical significance (NPI subscore for a specific item >/=4 points) were compared with the images of patients without the specific symptom under study (NPI subscore for a specific item = 0 points). RESULTS: A total of 53 patients with AD (Mini-Mental State Examination [MMSE] 22.5 +/- 2.94 points) entered the study. Of all symptoms, apathy and depression were most frequently encountered. The patient group with apathy (n = 17) revealed significant decreases in left orbitofrontal regions when compared with patients free of apathy. Depression of clinical significance (n = 10) was associated with hypometabolism in dorsolateral prefrontal regions. CONCLUSIONS: These findings support the notion that different functional circuits underlie apathy and depression in early AD.