Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease.

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

EFNS task force: the use of neuroimaging in the diagnosis of dementia.

BACKGROUND AND PURPOSE: The European Federation of the Neurological Societies (EFNS) guidelines on the use of neuroimaging in the diagnosis and management of dementia are designed to revise and expand previous EFNS recommendations for the diagnosis and management of patients with Alzheimer's disease (AD) and to provide an overview of the evidence for the use of neuroimaging techniques in non-AD dementias, as well as general recommendations that apply to all types of dementia in clinical practice. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published before April 2012. The evidence was classified, and consensus recommendations were given and graded according to the EFNS guidance regulations. RESULTS: Structural imaging, which should be performed at least once in the diagnostic work-up of patients with cognitive impairment, serves to exclude other potentially treatable diseases, to recognize vascular lesions and to identify specific findings to help distinguish different forms of neurodegenerative types of dementia. Although typical cases of dementia may not benefit from routine functional imaging, these tools are recommended in those cases where diagnosis remains in doubt after clinical and structural imaging work-up and in particular clinical settings. Amyloid imaging is likely to find clinical utility in several fields, including the stratification of patients with mild cognitive impairment into those with and without underlying AD and the evaluation of atypical AD presentations. CONCLUSIONS: A number of recommendations and good practice points are made to improve the diagnosis of AD and other dementias.

Frontotemporal dementia caused by CHMP2B mutations.

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.

Chromosome 3 linked frontotemporal dementia (FTD-3).

BACKGROUND: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. METHODS: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. RESULTS: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H2 15 O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. CONCLUSIONS: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Cerebral functional anatomy of voluntary contractions of ankle muscles in man.

1. Cerebral activation elicited by right-sided voluntary ankle muscle contraction was investigated by positron emission tomography measurements of regional cerebral blood flow. Two studies with eight subjects in each were carried out. Tonic isometric plantar and dorsiflexion and co-contraction of the antagonist muscles were investigated in study 1. Tonic contraction was compared with dynamic ramp-and-hold contractions in study 2. 2. All types of contraction elicited activation of the left primary motor cortex (M1). The distance between the M1 peak activation locations for tonic isometric dorsi- and plantar flexion was 17 mm. Co-contraction elicited activation of a larger area of M1 mainly located in between but partially overlapping the M1 areas activated during isolated dorsi-/plantar flexion. 3. A voxel-by-voxel correlation analysis corrected for subject covariance showed for dorsiflexion a significant correlation between tibialis anterior EMG level and cerebral blood flow activation in the cerebellum and the M1 of the medial frontal cortex. For plantar flexion a significant correlation was found between soleus EMG and cerebral activation in the left medial S1 and M1, left thalamus and right cerebellum. 4. The activation during dynamic isotonic and isometric dorsi- and plantar flexion was significantly more extensive than during tonic contractions. In addition to M1, activation was seen in the contralateral supplementary motor area and bilaterally in the premotor and parietal cortices. Isotonic and isometric contractions did not differ except in a small area in the primary somatosensory cortex. 5. One possible explanation of the different cerebral activation during co-contraction compared to that during plantar/dorsiflexion is that slightly different populations of cortical neurones are involved. The more extensive activation during dynamic compared with tonic contractions may reflect a larger cortical drive necessary to initiate and accelerate movements.

Dementia with impaired temporal glucose metabolism in late-onset metachromatic leukodystrophy.

An unusual case of very-late-onset metachromatic leukodystrophy (MLD) with dementia was studied. The patient was a 41-year-old male who presented with mild dementia and a single generalized tonic clonic seizure. Neuropsychological assessment demonstrated mild amnesia, visuospatial dysfunction and attention deficits with a slow psychomotor speed. MR brain imaging displayed confluent hyperintensities of periventricular and subcortical white matter. Low levels of arylsulfatase A confirmed the diagnosis. Impaired cortical glucose metabolism especially of the medial temporal and frontal cortices was observed using positron emission tomography and fluor-18-labeled fluorodesoxyglucose. The neuropsychological deficits are related to the location of deficits in glucose metabolism.

Cerebral activation during bicycle movements in man.

The cerebral activation during bicycle movements was investigated by oxygen-15-labelled H2O positron emission tomography (PET) in seven healthy human subjects. Compared to rest active bicycling significantly activated sites bilaterally in the primary sensory cortex, primary motor cortex (M1) and supplementary motor cortex (SMA) as well as the anterior part of cerebellum. Comparing passive bicycling movements with rest, an almost equal activation was observed. Subtracting passive from active bicycle movements, significant activation was only observed in the leg area of the primary motor cortex and the precuneus, but not in the primary sensory cortex (S1). The M1 activation was positively correlated (alpha=0.75-0.85, t=6.4, P<10(-5)) with the rate of the active bicycle movements. Imagination of bicycle movements compared to rest activated bilaterally sites in the SMA. It is suggested that the higher motor centres, including the primary and supplementary motor cortices as well as the cerebellum, take an active part in the generation and control of rhythmic motor tasks such as bicycling.

Statistical maps of cerebral blood flow deficits in Alzheimer's disease.

Images of cerebral blood flow or metabolism are useful as adjunct to the differential diagnosis of cortical dementia. The aim of this study was to create statistical objective voxel maps of significant differences in regional cerebral blood flow between patients with Alzheimer's disease and age-matched healthy volunteers. Maps of significantly reduced cerebral blood flow were created based on a spatially normalized distribution of cerebral blood flow, measured with O-15-water and positron emission tomography in 16 Alzheimer's patients, compared to 16 healthy age-matched volunteers. After spatial normalization of voxel counts, the t-statistic of the cerebral blood flow deficit was determined from the local voxel-SDs. In the patients, significant reduction (P < 0.05) of the flow distribution was present in regions near the hippocampus, extending rostrally to the temporo-parietal region in both hemispheres, including the medial parietal cortex plus smaller frontal areas. The maximum reduction occurred in the left tapetum/hippocampus (53%, P = 0.061). In conclusion, statistical maps of cerebral blood flow deficits objectively reveal the location of deficits, identifying areas that are difficult to identify by subjective visual inspection of conventional sections of cerebral blood flow maps. This is particularly well illustrated by the pronounced flow reduction of the medial parietal cortices.

Cerebral blood flow in volunteers measured by PET and Xe CT/CBF. A comparison.

Aim of this study was to compare two quantitative CBF methods. Seven young, healthy volunteers were studied with PET (15-0 labelled water) and afterwards with Xe CT/CBF (30% xenon in oxygen, 3 minutes wash-in, 5 minutes washout protocol). Xe CT/CBF showed greater differences between high and low flow areas than PET CBF. Correlation was found within subjects between ROI's, but no agreement or correlation between the methods could be demonstrated. The disagreement in this study could be due to changes in PCO2.

Cortical centres underlying auditory temporal processing in humans: a PET study.

We have used positron emission tomography (PET) to test a specific hypothesis of a neural system subserving auditory temporal processing (acoustical stimulus duration discrimination). Maps of the cerebral blood flow distribution during specific stimulations were obtained from five normally-hearing and otherwise healthy subjects. The auditory stimuli consisted of sounds of varying duration and of auditorily presented words in which the duration of the initial phoneme was manipulated. All stimuli alternated with conditions of silence in a subtraction paradigm. The blood flow distribution was mapped with O-15-labelled water. The results demonstrated that stimuli requiring recognizing, memorizing, or attending to specific target sounds during temporal processing generally resulted in significant activation of both frontal lobes and the parietal lobe in the right hemisphere. Based on these results, we hypothesise that a network consisting of anterior and posterior auditory attention and short-term memory sites subserves acoustical stimulus duration perception and analysis (auditory temporal processing).

Stimulus-dependent central processing of auditory stimuli: a PET study.

Positron emission tomography (PET) was used to investigate the neural systems involved in the central processing of different auditory stimuli. Noise, pure tone and pure-tone pulses, music and speech were presented monaurally. O-15-water PET scans were obtained in relation to these stimulations presented to five normal hearing and healthy subjects. All stimuli were related to a basic scan in silence. Processing of simple auditory stimuli, such as pure tones and noise, predominantly activate the left transverse temporal gyrus (Brodmann area [BA] 41), whereas sounds with discontinued acoustic patterns, such as pure-tone pulse trains, activated parts of the auditory association area in the superior temporal gyri (BA 42) in both hemispheres. Moreover, sounds with complex spectral, intensity, and temporal structures (words, speech, music) activated spatially even more extensive associative auditory areas in both hemispheres (BA 21, 22). PET has revealed a remarkable potential to investigate early central auditory processing, and has provided evidence of the coexistence of functionally linked, but individually active parallel and serial auditory networks.

Cortical responses to sustained and divided attention in Alzheimer's disease.

Neuropsychological data suggests that divided attention is more impaired than sustained attention during the early phases of Alzheimer's disease. The purpose of the present study was to compare cerebral activation patterns during sustained and divided attention between Alzheimer patients and healthy elderly. The O-15-water PET activation method was used to map sustained and divided attention in 16 patients with Alzheimer's disease (mean age +/- SD: 68 +/- 5 years; MMSE: 11-25, mean +/- SD = 19.5 +/- 4.9) and in 16 healthy age-matched control subjects. After stereotactical normalization, voxel-by-voxel t statistics was used to assess the significance of activated brain areas and to compare activations between patients and control subjects. In the healthy elderly, sustained and divided attention both elicited activation of the right inferior parietal lobule, and the right middle frontal gyrus, whereas the anterior cingulate gyrus was activated during sustained attention only. Only medial frontal structures (Brodmann Area (BA) 32/34) were activated in Alzheimer patients, and both frontal (BA-10), posterior cingulate (BA-23/31), and subcortical sites were deactivated. Compared to the healthy elderly, the activations in the patients of the right medial (BA-11) superior (BA-10) and inferior (BA-47) frontal gyri, the right middle temporal (BA-20), and the left lingual (BA-17) gyri were significantly reduced. More cortical sites differed statistically between Alzheimer patients and control subjects during divided than during sustained attention. The activation pattern elicited by attention supports the neuropsychological data that divided attention is more impaired than sustained attention in early Alzheimer's disease.

Positron emission tomography of cortical centers of tinnitus.

Tinnitus is associated with a wide variety of disorders in the auditory system. Whether generated peripherally or centrally, tinnitus is believed to be associated with activity in specific cortical regions. The present study tested the hypothesis that these cortical centers subserve the generation, perception and processing of the tinnitus stimulus and that these processes are suppressed by lidocaine and masking. Positron emission tomography was used to map the tinnitus-specific central activity. By subtracting positron emission tomography images of regional cerebral blood flow distribution obtained during suppression of the tinnitus from positron emission tomography images obtained during the habitual tinnitus sensation, we were able to identify brain areas concerned with the cerebral representation of tinnitus. Increased neuronal activity caused by tinnitus occurred predominantly in the right hemisphere with significant foci in the middle frontal and middle temporal gyri, in addition to lateral and mesial posterior sites. The results are consistent with the hypothesis that the sensation of tinnitus is associated with activity in cortical regions functionally linked to subserve attention, emotion and memory. For the first time, the functional anatomy of conditions with and without the habitual tinnitus sensation was obtained and compared in the same subjects.

Activation of human extrageniculostriate pathways after damage to area V1.

We have used positron emission tomography (PET) to specify the cortical and subcortical structures activated following visual stimulation of the scotomatous field in a patient with an asymmetric bilateral developmental anomaly of the visual cortex. Computerized perimetry indicated a left visual field defect only although MRI and 18FDG-PET scans showed abnormalities in both occipital lobes. The visual stimuli were semicircular gratings moving in opposite directions on a dynamic random-dot background. They were specifically constructed to eliminate intra- and extraocular light scatter and to optimize the activation of extra-striate cortical areas and their projecting subcortical relays. For anatomical localization PET images were coregistered to the subject's MRI in Talairach coordinates. After subtraction of the baseline conditions from the stimulation conditions, a t-statistic map was created on a voxel-by-voxel basis. Stimulation of the scotomatous hemifield yielded significant activations of Brodmann cortical areas 18-19 and 47 as well as the pulvinar thalami of the left hemisphere, in addition to a less prominent activation in the right hemisphere. Stimulation of the intact hemifield produced significant activation of Brodmann cortical areas 30 and 47 of the left hemisphere. These results suggest that in the absence of area V1, residual vision observed in the blind hemifield could be mediated by a retinofugal pathway to extrastriate cortex via the pulvinar.

Cerebral blood flow measurements by magnetic resonance imaging bolus tracking: comparison with [(15)O]H2O positron emission tomography in humans.

In six young, healthy volunteers, a novel method to determine cerebral blood flow (CBF) using magnetic resonance (MR) bolus tracking was compared with [(15)O]H2O positron emission tomography (PET). The method yielded parametric CBF images with tissue contrast in good agreement with parametric PET CBF images. Introducing a common conversion factor, MR CBF values could be converted into absolute flow rates, allowing comparison of CBF values among normal subjects.

Origin of human motor readiness field linked to left middle frontal gyrus by MEG and PET.

Combined magnetoencephalography and positron emission tomography identified a prior source of activity in the left middle frontal gyrus during uncued movements of the right index finger. Voluntary movements gave rise to a change in the cortical electrical potential known as the Bereitschaftspotential or Readiness Potential, recorded as early as 1500 ms before the onset of movement. The Readiness Field is the magnetic field counterpart to the Bereitschaftspotential. In the present study, magnetoencephalography identified four successively active sources of fluctuation in the Readiness Field in the period from 900 ms before, to 100 ms after, the onset of the movement. The first source to be active was registered between 900 and 200 ms prior to the onset of the movement. This source of initial activity was mapped by positron emission tomography to the middle frontal gyrus, Brodmann area 9. The three sources subsequently to be active were mapped to the supplementary motor area, premotor cortex, and motor cortex (M1), all in the left hemisphere.

Cerebral blood-flow changes evoked by two levels of painful heat stimulation: a positron emission tomography study in humans.

Positron emission tomography (PET) and accumulation of H(2)(15)O as a marker of neuronal activity were used to create maps of cerebral blood-flow changes evoked by painful heat stimulation in 10 subjects. Two levels of painful tonic and phasic heat stimuli were applied with use of a newly developed contact heat thermode on the volar surface of the dominant (right) arm. The subjects participated in two separate PET sessions. Maps reflecting low and high levels of painful tonic heat were obtained in the first session, and low and high levels of painful phasic heat in the second session. The subjects scored their peak pain intensity and unpleasantness on 10-cm visual analogue scales. For each subject, PET images were aligned to nuclear magnetic resonance (NMR) images and remapped into the standardized co-ordinate system of Talairach. After normalization of the PET volumes, subtraction images were formed voxel-by-voxel and converted to a t-statistic volume. The perceived pain intensity and unpleasantness were identical with painful tonic and phasic heat stimulation. Directed searches revealed significant blood-flow increases in the contralateral primary sensorimotor cortex (MI/SI), SII, insular cortex and cingulate cortex when the low tonic heat map was subtracted from the high. A similar, but not identical, pain-processing network was observed for the maps representing the subtraction of low and high phasic heat. In this subtraction, the blood-flow increases in MSI/SI did not reach statistical significance, and significant blood flow decreases were found in the contralateral middle temporal gyrus. Finally, the location of the activation site in the cingulate cortex was different from that observed during tonic heat pain. This study has provided more evidence for the existence of a common pain-processing network engaged during the perception of different levels of toxic and phasic heat pain. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Cortical sites of sustained and divided attention in normal elderly humans.

Human brain mechanisms subserving attention have been assigned to prefrontal, midfrontal, and posterior parietal cortices, as well as to the anterior cingulate and the thalamus. To map these mechanisms in the brain, most studies have used selective attention tasks; few studies have mapped the brain under sustained or divided attention. The present study was designed to create maps of regional activity associated with sustained and divided attention using two different sensory modalities: visual checkerboard stimulation and vibrotactile stimulation of the right hand. Five cerebral PE-tomograms of 15O-labeled water uptake were acquired from 16 elderly healthy subjects during sustained or divided attention to the frequency of stimulation. To locate active brain regions, the t-statistic map of relative changes in cerebral blood flow was coregistered to the subjects' averaged brain MR images and to the standard Talairach brain coordinate system. Attention was associated with activity in two sites, the right middle frontal gyrus (Brodmann area 46) and the right inferior parietal lobule (Brodmann area 40). The frontal site was more active when the subjects attended to the visual stimulus and when the attention was divided, while the parietal site was more active during attention to the vibrotactile stimulus and during simple sustained attention. Our observations are consistent with the hypotheses (1) that the right posterior parietal attention center subserves attention to several sensory modalities and (2) that a cortical network of specific neuronal sites subserves both sustained and divided attention. These hypotheses must be tested in further studies.

[Alzheimer's disease and genes]. / Alzheimers sygdom og generne.

Alzheimer's disease is genetically heterogeneous. The rare familial early-onset form of the disease is caused by dominant mutations in at least four different genes. Three of these genes have now been identified and the gene for presenilin 1 (PS1) on chromosome 14 is mutated in about 75% of the families. By contrast, the common form of Alzheimer's disease has late onset and may occur as sporadic cases in the families. This form is multifactorial and the most important genetic risk factor is the E4 allele of the polymorphic apolipoprotein E gene (APOE) on chromosome 19. The E4 allele is associated with moderately or strongly increased lifetime risk of Alzheimer's disease in persons with respectively one or two copies of the gene variant. Apolipoprotein E genotyping may serve as an adjunct in the diagnostic evaluation of Alzheimer's disease, but predictive genotyping of asymptomatic persons is premature and should not be done.