Background and objectives: In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of ...Alzheimer’s disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non‐Alzheimer dementias are not included in this guideline.
Methods: The task force working group reviewed evidence from original research articles, meta‐analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided.
Results: The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline.
Conclusion: A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non‐evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD.
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Functional MRI (fMRI) can be applied to study the functional connectivity of the human brain. It has been suggested that fluctuations in the blood oxygenation level-dependent (BOLD) signal during ...rest reflect the neuronal baseline activity of the brain, representing the state of the human brain in the absence of goal-directed neuronal action and external input, and that these slow fluctuations correspond to functionally relevant resting-state networks. Several studies on resting fMRI have been conducted, reporting an apparent similarity between the identified patterns. The spatial consistency of these resting patterns, however, has not yet been evaluated and quantified. In this study, we apply a data analysis approach called tensor probabilistic independent component analysis to resting-state fMRI data to find coherencies that are consistent across subjects and sessions. We characterize and quantify the consistency of these effects by using a bootstrapping approach, and we estimate the BOLD amplitude modulation as well as the voxel-wise cross-subject variation. The analysis found 10 patterns with potential functional relevance, consisting of regions known to be involved in motor function, visual processing, executive functioning, auditory processing, memory, and the socalled default-mode network, each with BOLD signal changes up to 3%. In general, areas with a high mean percentage BOLD signal are consistent and show the least variation around the mean. These findings show that the baseline activity of the brain is consistent across subjects exhibiting significant temporal dynamics, with percentage BOLD signal change comparable with the signal changes found in task-related experiments.
The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this ...study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67±9, 6 females, MMSE 23±5) and 18 healthy controls (age 66±9, 11 females, MMSE 29±1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.
► Network analysis applied to MEG data to study functional sub-networks (modules). ► In Alzheimer's disease, altered modular organization relates to cognitive symptoms. ► Intermodular connectivity is damaged most, parietal region has highest local damage.
In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph ...theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a ‘Targeted Attack’ model than by a ‘Random Failure’ model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network ‘hubs’ may be especially at risk in Alzheimer's disease.
We investigated whether functional brain networks are abnormally organized in Alzheimer's disease (AD). To this end, graph theoretical analysis was applied to matrices of functional connectivity of ...beta band–filtered electroencephalography (EEG) channels, in 15 Alzheimer patients and 13 control subjects. Correlations between all pairwise combinations of EEG channels were determined with the synchronization likelihood. The resulting synchronization matrices were converted to graphs by applying a threshold, and cluster coefficients and path lengths were computed as a function of threshold or as a function of degree K. For a wide range of thresholds, the characteristic path length L was significantly longer in the Alzheimer patients, whereas the cluster coefficient C showed no significant changes. This pattern was still present when L and C were computed as a function of K. A longer path length with a relatively preserved cluster coefficient suggests a loss of complexity and a less optimal organization. The present study provides further support for the presence of “small-world” features in functional brain networks and demonstrates that AD is characterized by a loss of small-world network characteristics. Graph theoretical analysis may be a useful approach to study the complexity of patterns of interrelations between EEG channels.
Cerebral microbleeds (MBs) are commonly observed in memory clinic patients. Little is known about occurrence of and risk factors for developing new MBs in this population.
To investigate incidence of ...lobar and nonlobar MBs in a memory clinic population. Furthermore, to assess risk factors for the development of new MBs and their associations with other MRI changes.
A total of 254 patients visiting our memory clinic, with repeat gradient-recalled echo T2*-weighted MRI, were included (scan interval 1.9 +/- 0.9 years). Baseline and incident MBs were regionally counted. White matter hyperintensities (WMH) and progression of WMH were assessed using visual rating scales. Baseline brain volume and whole-brain atrophy rate were estimated automatically. In a subset, APOE was determined.
Thirty-one (12%) patients developed new MBs (range 1-19). Both multiple strictly lobar and nonlobar MBs at baseline predicted incident MBs (odds ratio OR 8.4; 95% confidence interval CI 2.2-33.2, and OR 33.8; 95% CI 8.1-140.8). Furthermore, baseline WMH grade (OR 1.2; 1.1-1.3), lacunar infarcts (OR 2.8; 1.3-6.0), and APOE epsilon2 carriership (OR 4.2; 1.4-12.5) predicted MB incidence. Incident MB patients had more progression of WMH (p < 0.01) and incident lacunar infarcts (p < 0.05). These relations were most prominent for incident nonlobar MBs. Incident strictly lobar MBs were associated with smoking.
In addition to APOE genotype, presence and progression of small-vessel disease and vascular risk factors were predictors of new MBs. The latter are potentially modifiable, suggesting the possibility of preventing incident MBs, hopefully resulting in slower clinical decline.
To investigate whether concomitant Alzheimer's disease (AD) pathology, reflected by cerebrospinal fluid (CSF) biomarkers, has an impact on dementia with Lewy bodies (DLB) in terms of clinical ...presentation, cognitive decline, nursing home admittance and survival.
We selected 111 patients with probable DLB and CSF available from the Amsterdam Dementia Cohort. On the basis of the AD biomarker profile (CSF tau/amyloid-β 1-42 (Aβ42) ratio >0.52), we divided patients into a DLB/AD+ and DLB/AD- group. Of the 111 patients, 42 (38%) had an AD CSF biomarker profile. We investigated differences between groups in memory, attention, executive functions, language and visuospatial functions. Difference in global cognitive decline (repeated Mini-Mental State Examination (MMSE)) was investigated using linear mixed models. Cox proportional hazard analyses were used to investigate the effects of the AD biomarker profile on time to nursing home admittance and time to death.
Memory performance was worse in DLB/AD+ patients compared with DLB/AD- patients (p<0.01), also after correction for age and sex. Hallucinations were more frequent in DLB/AD+ (OR=3.34, 95% CI 1.22-9.18). There was no significant difference in the rate of cognitive decline. DLB/AD+ patients had a higher mortality risk (HR=3.13, 95% CI 1.57 to 6.24) and nursing home admittance risk (HR=11.70, 95% CI 3.74 to 36.55) compared with DLB/AD- patients.
DLB-patients with a CSF AD profile have a more severe manifestation of the disease and a higher risk of institutionalisation and mortality. In clinical practice, CSF biomarkers may aid in predicting prognosis in DLB. In addition, DLB-patients with positive AD biomarkers could benefit from future treatment targeting AD pathology.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of ...acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available—including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, “head to head” studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches–including those more closely targeted to the pathogenesis of the disease–will also be reviewed. These potentially disease modifying treatments include amyloid-β-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents
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