Yolande A.L. Pijnenburg

Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30–50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2–21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.

EEG synchronization in mild cognitive impairment and Alzheimer's disease

Objectives – To compute the synchronization likelihood of multichannel electroencephalogram (EEG) data in Alzheimer (AD) patients, subjects with mild cognitive impairment (MCI) and subjects with subjective memory complaints (SC).

Early-Versus Late-Onset Alzheimer's Disease: More than Age Alone

Alzheimers disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD ( 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 +/- 5 years and 74 +/- 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia.

The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.

There is increasing evidence that frontotemporal dementia and amyotrophic lateral sclerosis are part of a disease continuum. Recently, a hexanucleotide repeat expansion in C9orf72 was identified as a major cause of both sporadic and familial frontotemporal dementia and amyotrophic lateral sclerosis. The aim of this study was to investigate clinical and neuropathological characteristics of hexanucleotide repeat expansions in C9orf72 in a large cohort of Dutch patients with frontotemporal dementia. Repeat expansions were successfully determined in a cohort of 353 patients with sporadic or familial frontotemporal dementia with or without amyotrophic lateral sclerosis, and 522 neurologically normal controls. Immunohistochemistry was performed in a series of 10 brains from patients carrying expanded repeats using a panel of antibodies. In addition, the presence of RNA containing GGGGCC repeats in paraffin-embedded sections of post-mortem brain tissue was investigated using fluorescence in situ hybridization with a locked nucleic acid probe targeting the GGGGCC repeat. Hexanucleotide repeat expansions in C9orf72 were found in 37 patients with familial (28.7%) and five with sporadic frontotemporal dementia (2.2%). The mean age at onset was 56.9 ± 8.3 years (range 39-76), and disease duration 7.6 ± 4.6 years (range 1-22). The clinical phenotype of these patients varied between the behavioural variant of frontotemporal dementia (n = 34) and primary progressive aphasia (n = 8), with concomitant amyotrophic lateral sclerosis in seven patients. Predominant temporal atrophy on neuroimaging was present in 13 of 32 patients. Pathological examination of the 10 brains from patients carrying expanded repeats revealed frontotemporal lobar degeneration with neuronal transactive response DNA binding protein-positive inclusions of variable type, size and morphology in all brains. Fluorescence in situ hybridization analysis of brain material from patients with the repeat expansion, a microtubule-associated protein tau or a progranulin mutation, and controls did not show RNA-positive inclusions specific for brains with the GGGGCC repeat expansion. The hexanucleotide repeat expansion in C9orf72 is an important cause of frontotemporal dementia with and without amyotrophic lateral sclerosis, and is sometimes associated with primary progressive aphasia. Neuropathological hallmarks include neuronal and glial inclusions, and dystrophic neurites containing transactive response DNA binding protein. Future studies are needed to explain the wide variation in clinical presentation.

EEG synchronization likelihood in mild cognitive impairment and Alzheimer's disease during a working memory task

OBJECTIVE Synchronization likelihood analysis of resting state EEG has shown that cognitive dysfunction in Alzheimers disease (AD) and its precursor mild cognitive impairment (MCI) are associated with a loss of functional connectivity in high (upper alpha and beta) frequency bands. Working memory tasks are known to change functional connectivity, but it is unknown whether this increases the differences between AD, MCI and healthy controls. Our objective was to investigate the behavior of synchronization likelihood of multichannel EEG in AD, MCI and cognitively healthy controls, both at rest and during a working memory task. METHODS EEGs (200 Hz sample frequency, 21 channels, average reference) were recorded at rest as well as during a visual working memory task in 14 patients with AD according to the NINCDS-ADRDA criteria (mean age 76.4; SD 13.6), 11 patients with MCI according to the criteria of Petersen (mean age 78.4; SD 6.4) and 14 with subjective memory complaints but no demonstrable memory disturbance (mean age 61.6; SD 26.6). The synchronization likelihood was computed over 19 channels, comparing each channel with all the other channels for the 0.5-4, 4-8, 8-10, 10-12, 12-30, 30-50 Hz frequency bands. RESULTS The synchronization likelihood was significantly decreased in the upper alpha (10-12) and beta (12-30) bands in AD compared to persons with subjective memory complaints. The working memory task scores strongly correlated with Mini-Mental State Examination scores. During the working memory task the synchronization likelihood was significantly higher in MCI compared to the control subjects in the lower alpha band (8-10 Hz). CONCLUSIONS Decrease of beta band synchronization occurs in mild AD, both in a resting condition and during a working memory task. SIGNIFICANCE Decrease of beta band synchronization in mild AD is a robust finding. The present study confirms our findings in a different cohort of patients, using alternative frequency bands. The diagnostic value of the synchronization likelihood in AD and MCI needs to be further established.

Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

Objective: To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. Methods: Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients. Results: A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%. Conclusion: CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

Disturbed fluctuations of resting state EEG synchronization in Alzheimer's disease.

OBJECTIVE We examined the hypothesis that cognitive dysfunction in Alzheimers disease is associated with abnormal spontaneous fluctuations of EEG synchronization levels during an eyes-closed resting state. METHODS EEGs were recorded during an eyes-closed resting state in Alzheimer patients (N=24; 9 males; mean age 76.3 years; SD 7.8; range 59-86) and non-demented subjects with subjective memory complaints (N=19; 9 males; mean age 76.1 years; SD 6.7; range: 67-89). The mean level of synchronization was determined in different frequency bands with the synchronization likelihood and fluctuations of the synchronization level were analysed with detrended fluctuation analysis (DFA). RESULTS The mean level of EEG synchronization was lower in Alzheimer patients in the upper alpha (10-13Hz) and beta (13-30Hz) band. Spontaneous fluctuations of synchronization were diminished in Alzheimer patients in the lower alpha (8-10Hz) and beta bands. In patients as well as controls the synchronization fluctuations showed a scale-free pattern. CONCLUSIONS Alzheimers disease is characterized both by a lower mean level of functional connectivity as well as by diminished fluctuations in the level of synchronization. The dynamics of these fluctuations in patients and controls was scale-free which might point to self-organized criticality of neural networks in the brain. SIGNIFICANCE Impaired functional connectivity can manifest itself not only in decreased levels of synchronization but also in disturbed fluctuations of synchronization levels.

Generalized synchronization of MEG recordings in Alzheimer's Disease: evidence for involvement of the gamma band.

Summary The purpose of this study was to investigate interdependencies in whole-head magnetoencephalography (MEG) of Alzheimer patients and healthy control subjects. Magnetoencephalograms were recorded in 20 Alzheimer patients (11 men; mean age, 69.0 years [standard deviation, 8.2 years]); Mini-Mental State Examination score, 21.3 points; range, 15 to 27 points) and 20 healthy control subjects (9 men; mean age, 66.4 years [standard deviation, 9.0 years]) during a no-task eyes-closed condition with a 151 channel whole-head MEG system. Synchronization likelihood (a new measure for linear as well as nonlinear interdependencies between signals) and coherence were computed for each channel in different frequency bands (2 to 6, 6 to 10, 10 to 14, 14 to 18, 18 to 22, 22 to 40 Hz). Synchronization was lower in Alzheimer patients in the upper &agr; band (10 to 14 Hz), the upper &bgr; band (18 to 22 Hz), and the &ggr; band (22 to 40 Hz). In contrast, coherence did not show significant group differences at the p<0.05 level. The synchronization likelihood showed a spatial pattern (high synchronization central, parietal and right frontal; low synchronization, occipital and temporal). This study confirms a widespread loss of functional interactions in the &agr; and &bgr; bands, and provides the first evidence for loss of &ggr; band synchronization in Alzheimer’s disease. Synchronization likelihood may be more sensitive to detect such changes than the commonly used coherence analysis.

Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele

Some patients with early-onset Alzheimers disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE ɛ4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, theAPOE ɛ4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE ɛ4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.

A systematic review of Instrumental Activities of Daily Living scales in dementia: room for improvement

Background: Instrumental Activities of Daily Living (IADL) questionnaires can be helpful in diagnosing dementia and are often used for clinical follow-up and treatment evaluation in dementia patients. Despite the large number of questionnaires, their quality has received little attention. Objective: To systematically review the measurement properties of all available structured informant-based (I)ADL questionnaires, developed or validated for use in demented patients. Methods: A systematic literature search was conducted in MEDLINE, PsycINFO and EMBASE for psychometric articles on (I)ADL questionnaires. In addition, reference lists of all retrieved articles were screened. Standardised criteria were used to assess the quality of the measurement properties. When possible, investigators were contacted to obtain missing information. Two authors independently extracted studies and performed the quality assessment of the questionnaires. Findings: Thirty-two articles were selected, covering 12 (I)ADL questionnaires. Information on 52.3% of the quality aspects was not available, 32.4% of the ratings were indeterminate, 8.1% were positive, and 7.2% were negative. Out of eight measurement properties, two scales (the DAD and the Bristol ADL) received two positive ratings and were classified as of moderate quality. Five scales (ADL-PI, ADL-IS, B-ADL, CSADL and Lawton IADL) received one positive rating. Interpretation: The findings indicate that improvements in and more data on psychometric properties of (I)ADL questionnaires for dementia patients are necessary in order to justify their use.