Anders Gade

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

Awareness of Deficits in Mild Cognitive Impairment and Alzheimer’s Disease: Do MCI Patients Have Impaired Insight?

In this study we investigated impaired awareness of cognitive deficits in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Very few studies have addressed this topic, and methodological inconsistencies make the comparison of previous studies difficult. From a prospective research program 36 consecutive patients with mild AD (MMSE above 19), 30 with amnesic MCI and 33 matched controls were examined. Using three methods for awareness assessment we found no significant differences in the level of awareness between MCI and AD. Both groups had impaired awareness and significant heterogeneity in the clinical presentation of awareness. The results demonstrate that subjective memory problems should not be a mandatory prerequisite in suspected dementia or MCI, which makes reports from informants together with thorough clinical interview and observation central when assessing suspected dementia disorders.

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli : A 15O-PET study

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.

Evidence for diabetic encephalopathy.

Auditory brain stem responses were recorded in 20 normoacoustic long‐duration Type 1 diabetic patients (duration of diabetes 26 (range 13–46) years, age 44 (25–66) years) with peripheral neuropathy and retinopathy and in 19 sex‐matched normoacoustic short‐duration Type 1 diabetic patients (duration of diabetes 2 (0–6) years, age 23 (18–50) years) without clinical signs of neuropathy or microangiopathy. Abnormal brain stem auditory evoked responses were demonstrated in 40% of the long‐duration and in 5.3% of the short‐duration diabetic patients (p < 0.01). Interpeak latencies Jv—JI and JIII‐JI were significantly prolonged in both patient groups compared with the non‐diabetic control group (p < 0.01). Magnetic resonance imaging was performed in 16 of the long‐duration patients and in 40 age‐matched healthy volunteers on a whole body MR‐scanner. Subcortical and/or brain stem lesions with abnormally high signals were seen in 69% of the long‐duration Type 1 patients and in 12% of the healthy volunteers (p < 0.02). Neuropsychological examination including 17 tests for intelligence and cognition were performed in the 20 long‐duration Type 1 diabetic patients. The results indicated a performance close to that seen in a control group of healthy age‐matched control subjects. Our study demonstrates that a considerable proportion of long‐duration Type 1 diabetic patients suffering from retinopathy and peripheral neuropathy additionally have signs but no symptoms of central nervous system affection, diabetic encephalopathy.

Amnesia after operations on aneurysms of the anterior communicating artery

All patients with ruptured aneurysms admitted to neurosurgical departments in Denmark after April, 1978, are the subjects in the prospective study that includes neuropsychological examinations. Data from 48 patients with aneurysms of the anterior communicating artery have been analyzed. Trapping of the aneurysm was done in 11 patients and resulted in an amnesic syndrome in 9. Thirty-seven patients were operated upon by ligation of the neck of the aneurysm or similar procedures, resulting in 6 cases of amnesia. Trapping invariably disrupts blood supply through newly described dorsal perforating branches from the anterior communicating artery. These perforating branches may supply areas of vital importance to memory function.

Effects of attention on dichotic listening: an 15O-PET study.

The present study investigated the effect of attention on brain activation in a dichotic listening situation. Dichotic listening is a technique to study laterality effects in the auditory sensory modality. Two different stimuli were presented simultaneously, one in each ear. Twelve subjects listened to lists of consonant‐vowel syllables, or short musical instrument passages, with the task of detecting a “target” syllable or musical instrument by pressing a button. The target stimulus appeared an equal number of times in the left and right ear. The subjects were instructed to either concentrate on the stimuli presented in both ears, or only on the left or right ear stimulus. Brain activation was measured with 15O‐PET, and significant changes in regional normalized counts (rNC) were evaluated using statistical parametric mapping (SPM96) software. Concentrating on either the right or left ear stimulus significantly decreased activity bilaterally in the temporal lobes compared to concentrating on both ear stimuli, at the expense of an increased activation in the right posterior and inferior superior parietal lobe. The CV‐syllables activated areas corresponding to the classic language areas of Broca and Wernicke. The musical instrument stimuli mainly activated areas in visual association cortex, cerebellum, and the hippocampus. An interpretation of the findings is that attention has a facilitating effect for auditory processing, causing reduced activation in the primary auditory cortex when attention is explicitly recruited. The observed activations in the parietal lobe during the focused attention conditions could be part of a modality non‐specific “attentional network”. Hum. Brain Mapping 10:87–97, 2000.

Categorization and category effects in normal object recognition A PET Study

To investigate the neural correlates of the structural and semantic stages of visual object recognition and to see whether any effects of category could be found at these stages, we compared the rCBF associated with two categorization tasks (subjects decided whether pictures represented artefacts or natural objects), and two object decision tasks (subjects decided whether pictures represented real objects or nonobjects). The categorization tasks differed from each other in that the items presented in the critical scan window were drawn primarily from the category of artefacts in the one task and from the category of natural objects in the other. The same was true for the object decision tasks. The experiment thus comprised a two-by-two factorial design. The factors were Task Type with two levels (object decision vs. categorization) and Category also with two levels (natural objects vs. artefacts). The object decision tasks were associated with activation of areas involved in structural processing (fusiform gyri, right inferior frontal gyrus). In contrast, the categorization tasks were associated with activation of the left inferior temporal gyrus, a structure believed to be involved in semantic processing. In addition, activation of the left premotor cortex was found during the categorization of artefacts compared with both the categorization of natural objects and object decision to artefacts. These findings suggest that the structural and semantic stages are dissociable and that the categorization of artefacts, as opposed to the categorization of natural objects, is based, in part, on action knowledge mediated by the left premotor cortex. However, because artefacts and natural objects often caused activation in the same regions within tasks, processing of these categories is not totally segregated. Rather, the categories differ in their weight on different forms of knowledge in particular tasks.

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; H215O-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.

Semantic Memory Impairment in the Earliest Phases of Alzheimer’s Disease

The presence and the nature of semantic memory dysfunction in Alzheimer’s disease (AD) have been widely debated. This study aimed to determine the frequency of impaired semantic test performances in mild AD and to study whether incipient semantic impairments could be identified in predementia AD. Five short neuropsychological tests sensitive to semantic memory and easily applicable in routine practice were administered to 102 patients with mild AD (Mini-Mental State Examination score above 19), 22 predementia AD patients and 58 healthy subjects. ‘Category fluency’ and ‘naming of famous faces’ were the most frequently impaired tests in both patient groups. The study demonstrated that impairments on semantically related tests are common in mild AD and may exist prior to the clinical diagnosis. The results imply that assessment of semantic memory is relevant in the evaluation of patients with suspected AD.

Spontaneous alternation in rats with lesions in the frontal lobes: An extension of the frontal lobe syndrome

Bilateral lesions in the anteromedial neocortex or the associated part of the neostriatum abolished spontaneous alternation in rats; removal of the suprarhinal strip did not. The classical deficit of spatial choice following frontal-lobe injury is not an artifact of the learning paradigm, but can be extended to unconditioned behavior. Furthermore, the impairment is not restricted to food-reinforced or massed responses. The response-guiding role of the frontal lobe is of such wide generality in the laboratory that it can be expected to operate in the animal’s usual environment as well.