Efficacy and safety of pharmacotherapy for Alzheimer's disease and for behavioural and psychological symptoms of dementia in older patients with moderate and severe functional impairments: a systematic review of controlled trials.

BACKGROUND: Many patients with Alzheimer's disease (AD) are physically frail or have substantial functional impairments. There is growing evidence that such patients are at higher risk for medication-induced adverse events. Furthermore, frailty seems to be more predictive of poor clinical outcomes than chronological age alone. To our knowledge, no systematic review of clinical trials examining drug therapy of AD or behavioural and psychological symptoms of dementia (BPSD) has specifically focused on the topic of physical frailty. Our objective was to evaluate the efficacy and safety of pharmacotherapy in AD patients with frailty or significant functional impairments. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled trials (RCTs) of drug therapy of AD and BPSD in patients with significant functional impairments according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Cochrane research criteria. Significant functionally impaired patient populations were identified using the recommendations of the Medication and Quality of Life in frail older persons (MedQoL) Research Group. Screening, selection of studies, data extraction and risk of bias assessment were performed independently by two reviewers. Outcomes including functional status, cognitive function, changes in BPSD symptoms, clinical global impression and quality of life were analysed. For assessing harm, we assessed adverse events, drop-outs as a proxy for treatment tolerability and death. Results were analysed according to Cochrane standards and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 45,045 search results, 38,447 abstracts and 187 full texts were screened, and finally, 10 RCTs were included in the systematic review. Selected articles evaluated pharmacotherapy with acetylcholinesterase-inhibitors (AChEI), anticonvulsants, antidepressants and antipsychotics. Studies of AChEIs suggested that patients with significant functional impairments had slight but significant improvements in cognition and that AChEIs were generally well tolerated. Studies of antidepressants did not show significant improvements in depressive symptoms. Antipsychotics and anticonvulsants showed small effects on some BPSD items but also higher rates of adverse events. However, due to the very small number of identified trials, the quality of evidence for all outcomes was low to very low. Overall, the small number of eligible studies demonstrates that significantly functional impaired older patients have not been adequately taken into consideration in most clinical trials investigating drug therapy of AD and BPSD. CONCLUSION: Due to lack of evidence, it is not possible to give specific recommendations for drug therapy of AD and BSPD in frail older patients or older patients with significant functional impairments. Therefore, clinical trials focussing on frail older adults are urgently required. A standardized approach to physical frailty in future clinical studies is highly desirable.

A multi-contrast MRI study of microstructural brain damage in patients with mild cognitive impairment.

OBJECTIVES: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI). METHODS: Forty-two MCI patients and 77 healthy controls (HC) underwent T1/T2* relaxometry as well as Magnetization Transfer (MT) MRI. Between-groups comparisons in MRI metrics were performed using permutation-based tests. Using MRI data, a generalized linear model (GLM) was computed to predict clinical performance and a support-vector machine (SVM) classification was used to classify MCI and HC subjects. RESULTS: Multi-parametric MRI data showed microstructural brain alterations in MCI patients vs HC that might be interpreted as: (i) a broad loss of myelin/cellular proteins and tissue microstructure in the hippocampus (p ≤ 0.01) and global white matter (p < 0.05); and (ii) iron accumulation in the pallidus nucleus (p ≤ 0.05). MRI metrics accurately predicted memory and executive performances in patients (p ≤ 0.005). SVM classification reached an accuracy of 75% to separate MCI and HC, and performed best using both volumes and T1/T2*/MT metrics. CONCLUSION: Multi-contrast MRI appears to be a promising approach to infer pathophysiological mechanisms leading to brain tissue alterations in MCI. Likewise, parametric MRI data provide powerful correlates of cognitive deficits and improve automatic disease classification based on morphometric features.

Differential effects of age on subcomponents of response inhibition.

Inhibitory deficits contribute to cognitive decline in the aging brain. Separating subcomponents of response inhibition may help to resolve contradictions in the existing literature. A total of 49 healthy participants underwent functional magnetic resonance imaging (fMRI) while performing a Go/no-go-, a Simon-, and a Stop-signal task. Regression analyses were conducted to identify correlations of age and activation patterns. Imaging results revealed a differential effect of age on subcomponents of response inhibition. In a simple Go/no-go task (no spatial discrimination), aging was associated with increased activation of the core inhibitory network and parietal areas. In the Simon task, which required spatial discrimination, increased activation in additional inhibitory control regions was present. However, in the Stop-signal task, the most demanding of the three tasks, aging was associated with decreased activation. This suggests that older adults increasingly recruit the inhibitory network and, with increasing load, additional inhibitory regions. However, if inhibitory load exceeds compensatory capacity, performance declines in concert with decreasing activation. Thus, the present findings may refine current theories of cognitive aging.

Disentangling common and specific neural subprocesses of response inhibition.

Response inhibition is disturbed in several disorders sharing impulse control deficits as a core symptom. Since response inhibition is a cognitively and neurally multifaceted function which has been shown to rely on differing neural subprocesses and neurotransmitter systems, further differentiation to define neurophysiological endophenotypes is essential. Response inhibition may involve at least three separable cognitive subcomponents, i.e. interference inhibition, action withholding, and action cancelation. Here, we introduce a novel paradigm - the Hybrid Response Inhibition task - to disentangle interference inhibition, action withholding and action cancelation and their neural subprocesses within one task setting during functional magnetic resonance imaging (fMRI). To validate the novel task, results were compared to a battery of separate, standard response inhibition tasks independently capturing these subcomponents and subprocesses. Across all subcomponents, mutual activation was present in the right inferior frontal cortex (rIFC), pre-supplementary motor area (pre-SMA) and parietal regions. Interference inhibition revealed stronger activation in pre-motor and parietal regions. Action cancelation resulted in stronger activation in fronto-striatal regions. Our results show that all subcomponents share a common neural network and thus all constitute different subprocesses of response inhibition. Subprocesses, however, differ to the degree of regional involvement: interference inhibition relies more pronouncedly on a fronto-parietal-pre-motor network suggesting its close relation to response selection processes. Action cancelation, in turn, is more strongly associated with the fronto-striatal pathway implicating it as a late subcomponent of response inhibition. The new paradigm reliably captures three putatively subsequent subprocesses of response inhibition and might be a promising tool to differentially assess disturbed neural networks in disorders showing impulse control deficits.

Frontostriatal activation in patients with obsessive-compulsive disorder before and after cognitive behavioral therapy.

BACKGROUND: Cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) is the psychotherapeutic treatment of choice for obsessive-compulsive disorder (OCD). However, little is known about the impact of CBT on frontostriatal dysfunctioning, known to be the neuronal correlate of OCD. METHOD: A probabilistic reversal learning (RL) task probing adaptive strategy switching capabilities was used in 10 unmedicated patients with OCD and 10 healthy controls during an event-related functional magnetic resonance imaging (fMRI) experiment. Patients were scanned before and after intensive CBT, controls twice at comparable intervals. RESULTS: Strategy change within the RL task involved activity in a broad frontal network in patients and controls. No significant differences between the groups or in group by time interactions were detected in a whole-brain analysis corrected for multiple comparisons. However, a reanalysis with a more lenient threshold revealed decreased responsiveness of the orbitofrontal cortex and right putamen during strategy change before treatment in patients compared with healthy subjects. A group by time effect was found in the caudate nucleus, demonstrating increased activity for patients over the course of time. Patients with greater clinical improvement, reflected by greater reductions in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores, showed more stable activation in the pallidum. CONCLUSIONS: Although these findings are preliminary and need to be replicated in larger samples, they indicate a possible influence of psychotherapy on brain activity in core regions that have been shown to be directly involved both in acquisition of behavioral rules and stereotypes and in the pathophysiology of OCD, the caudate nucleus and the pallidum.

[New possibilities for automated diagnosis of dementia]. / Neue Möglichkeiten der automatisierten Demenzdiagnostik.

Dementia is underdiagnosed and undertreated in Germany. Automatic diagnosing of dementia based on standard magnetic resonance imaging has the capacity to reduce diagnostic uncertainties. The algorithm learns a disease specific pattern of atrophy from training samples. It is independent from radiological expertise which may be scarce outside specialised centres and can be installed on MRT-machines or desktop PCs. It can also play its part in planning and conducting treatment trials by recruiting a sample with predicted fast future decline. Extension, based e.g. on resting state functional imaging are possible but are further away from clinical routine.

Pitfalls in the use of voxel-based morphometry as a biomarker: examples from huntington disease.

BACKGROUND AND PURPOSE: VBM is increasingly used in the study of neurodegeneration, and recently there has been interest in its potential as a biomarker. However, although it is largely "automated," VBM is rarely implemented consistently across studies, and changing user-specified options can alter the results in a way similar to the very biologic differences under investigation. MATERIALS AND METHODS: This work uses data from patients with HD to demonstrate the effects of several user-specified VBM parameters and analyses: type and level of statistical correction, modulation, smoothing kernel size, adjustment for brain size, subgroup analysis, and software version. RESULTS: The results demonstrate that changing these options can alter results in a way similar to the biologic differences under investigation. CONCLUSIONS: If VBM is to be useful clinically or considered for use as a biomarker, there is a need for greater recognition of these issues and more uniformity in its application for the method to be both reproducible and valid.

Magnetic resonance imaging of Huntington's disease: preparing for clinical trials.

The known genetic mutation causing Huntington's disease (HD) makes this disease an important model to study links between gene and brain function. An autosomal dominant family history and the availability of a sensitive and specific genetic test allow pre-clinical diagnosis many years before the onset of any typical clinical signs. This review summarizes recent magnetic resonance imaging (MRI)-based findings in HD with a focus on the requirements if imaging is to be used in treatment trials. Despite its monogenetic cause, HD presents with a range of clinical manifestations, not explained by variation in the number of CAG repeats in the affected population. Neuroimaging studies have revealed a complex pattern of structural and functional changes affecting widespread cortical and subcortical regions far beyond the confines of the striatal degeneration that characterizes this disorder. Besides striatal dysfunction, functional imaging studies have reported a variable pattern of increased and decreased activation in cortical regions in both pre-clinical and clinically manifest HD-gene mutation carriers. Beyond regional brain activation changes, evidence from functional and diffusion-weighted MRI further suggests disrupted connectivity between corticocortical and corticostriatal areas. However, substantial inconsistencies with respect to structural and functional changes have been reported in a number of studies. Possible explanations include methodological factors and differences in study samples. There may also be biological explanations but these are poorly characterized and understood at present. Additional insights into this phenotypic variability derived from study of mouse models are presented to explore this phenomenon.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Automatic detection of preclinical neurodegeneration: presymptomatic Huntington disease.

BACKGROUND: Treatment of neurodegenerative diseases is likely to be most beneficial in the very early, possibly preclinical stages of degeneration. We explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. The availability of a definitive genetic test for Huntington disease (HD) provides an excellent metric for judging the performance of such methods in gene mutation carriers who are free of symptoms. METHODS: Using the gray matter segment of MRI scans, this study explored the usefulness of a multivariate support vector machine to automatically identify presymptomatic HD gene mutation carriers (PSCs) in the absence of any a priori information. A multicenter data set of 96 PSCs and 95 age- and sex-matched controls was studied. The PSC group was subclassified into three groups based on time from predicted clinical onset, an estimate that is a function of DNA mutation size and age. RESULTS: Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned to the PSC group 69% of the time. Accuracy improved to 83% when regions affected by the disease were selected a priori for analysis. Performance was at chance when the probability of developing symptoms in 5 years was less than 10%. CONCLUSIONS: Presymptomatic Huntington disease gene mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic scans, without additional a priori information. Prior information is required to allow separation when degenerative changes are either subtle or variable.

Laterality of interhemispheric inhibition depends on handedness.

There is some evidence that handedness is related to lateralisation of excitability in the motor system. We investigated lateralisation of interhemispheric inhibition (IHI), motor thresholds and short interval intracortical inhibition (SICI) and facilitation (SICF) in relation to handedness in 12 right (RH) and 13 left handed (LH) subjects. Because there is some controversy as to the optimal localisation to produce IHI we also compared IHI induced by conditioning the dorsal premotor cortex (dPM) versus primary motor cortex (M1) in ten RH. IHI was stronger following conditioning the motor dominant as compared to the motor non-dominant hemisphere in RH and LH. Motor thresholds were higher when elicited over the right hemisphere than over the left in both RH and LH, while SICI and SICF showed no differences between hemispheres or dependency from handedness. We hypothesize that IHI is a function of handedness perhaps reflecting predominant usage of the dominant hand, while lateralisation of thresholds and intracortical excitability are determined by other factors.

Beta-CIT SPECT demonstrates reduced availability of serotonin transporters in patients with Fatal Familial Insomnia.

Fatal familial insomnia (FFI) is a rare hereditary human prion disease with unique clinical features including progressive sleep impairment and autonomic dysfunction. The serotonergic system is considered to be involved in the regulation of the sleep-wake cycle. In this study we demonstrate a reduced availability of serotonin transporters of 57% and 73% respectively in a thalamus-hypothalamus region of two FFI patients examined with beta-CIT SPECT as compared to age-expected control values.

Prominent stress response of Purkinje cells in Creutzfeldt-Jakob disease.

To examine the role of stress-related 70-kDa heat shock proteins (Hsp-s) in Creutzfeldt-Jakob disease (CJD), we performed immunocytochemistry to detect Hsp-72 and Hsp-73, together with the abnormal (PrP(Sc)) and the presumed cellular form (PrP(C)) of the prion protein, and TUNEL method to measure cellular vulnerability in different brain regions in CJD and control cases. While Hsp-73 showed uniform distribution in all the examined samples, an increase in the number of Purkinje cells with prominent accumulation of Hsp-72 in the CJD group was observed. These neurons also showed intense PrP(C) staining, but TUNEL-positive nuclei were only detected in the granular (Hsp-72-negative) cell layer. Fewer cells of the inferior olivary nucleus were immunoreactive for Hsp-72 in CJD than in control cases, and regions showing severe spongiform change and gliosis exhibited fewer Hsp-72-immunoreactive neurons. Our results indicate that accumulation of the inducible Hsp-72 in certain cell types may be part of a cytoprotective mechanism, which includes preservation of proteins like PrP(C).

Marked increase of neuronal prion protein immunoreactivity in Alzheimer's disease and human prion diseases.

In neurodegenerative disorders including Alzheimer's disease (AD), free radical damage to lipids, carbohydrates, proteins and DNA has been demonstrated to play a key pathogenetic role. In vitro studies have suggested a function of the cellular prion protein (PrPc) in the defense against oxidative stress. Therefore, we investigated the distribution of PrPc immunoreactivity in hippocampus (sectors CA4-CA1), subiculum (Sub), entorhinal (EC), and temporal cortex (TC) in sections from AD, human transmissible spongiform encephalopathy (TSE) and control brains. Compared to control cases, AD brains revealed an increase in the proportion of PrPc-immunoreactive neurons, which was statistically significant in CA2, Sub, and TC. In TSEs, a statistically significant increase of PrPc-immunoreactive neurons was observed in CA2, CA1, Sub, EC, and TC. In conclusion, our data show a striking up-regulation of PrPc in neurodegeneration and provide additional support for the concept that PrPc may be involved in the defense against oxidative stress.

Serotonergic nuclei of the raphe are not affected in human ageing.

Sleep disorders increase with ageing. The serotonergic system has been linked with sleep regulation. In fatal familial insomnia, a prion disease with insomnia as one major clinical feature, we recently observed a disturbance in the serotonergic system as likely substrate of typical symptoms. Using immunohistochemistry for the serotonin synthesizing enzyme, tryptophan hydroxylase, we investigated the serotonergic median raphe nuclei (dorsal raphe nucleus, superior central nucleus, and raphe obscurus nucleus) in brains of an older (n = 12; age range 62-84 years) and a younger group (n = 10; age range 5-29 years). We found no significant difference between age groups in the percentage of neurons able to synthesize serotonin. Other changes might relate to sleep disturbances in the elderly.

Alteration of the serotonergic nervous system in fatal familial insomnia.

Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep. We studied the serotonergic system in 8 FFI-affected subjects by immunohistochemistry for the serotonin-synthesizing enzyme, tryptophan hydroxylase (TH). Quantification of neurons in median raphe nuclei showed no total neuronal loss in FFI but a substantial increase of TH+ neurons (approximately 62%) in FFI subjects compared with controls. Our data indicate an alteration of the serotonergic system that might represent the functional substrate of some typical symptoms of FFI.