Dissociation of body-centered and stimulus-centered representations in unilateral neglect.

BACKGROUND: Previous studies on unilateral neglect have shown that there are at least two types of neglect-i.e., body-centered and stimulus-centered neglect. These symptoms suggest that the human brain has at least two different reference frames for processing external space. It is unknown, however, whether these two frames are represented independently in the brain and if so, which areas (or networks) of the brain are responsible for each frame of reference. OBJECTIVE: To determine whether body-centered neglect and stimulus-centered neglect can be dissociated in patients with brain injury. METHODS: New figure discriminative cancellation tasks were designed to simultaneously assess body-centered neglect and stimulus-centered neglect. Two neglect patients with lesions located in different anatomic regions were required to circle every complete figure and to cross out every figure with a missing portion on a sheet of white (29.7 x 42 cm) paper. RESULTS: Patient 1 omitted leftward stimuli on the paper, but the stimuli he found were correctly circled or crossed out. On the other hand, Patient 2 marked stimuli across the paper although he mistakenly circled stimuli that were missing a portion of their left side. Neither patient manifested interaction between the two types of neglect. CONCLUSION: The results of this study clearly showed double dissociation between the two types of neglect. Furthermore, it not only provides evidence that there are two distinct systems of reference frame for external space in the human brain, but also adds new knowledge indicating that these two systems function independently, at least in part.

Transthyretin binds amyloid beta peptides, Abeta1-42 and Abeta1-40 to form complex in the autopsied human kidney - possible role of transthyretin for abeta sequestration.

The deposition of amyloid beta protein (Abeta), a proteolytic cleavage product of amyloid precursor protein (APP), is an invariable pathological feature of the Alzheimer's disease brain, while APP gene is widely expressed in all neuronal and non-neuronal tissues with the highest levels of expression in the brain, and kidney. To understand the role transthyretin (TTR) plays in the sequestration mechanism of Abeta in the kidney, we have investigated interactions of TTR with Abeta1-40 and Abeta1-42 molecules by an immunoprecipitation method, in vitro binding studies, and overlay assay. These in vivo and in vitro biochemical experiments showed that TTR bound Abeta1-42 preferentially, and Abeta1-40 only to a limited extent, to form TTR-monomer and -dimer-Abeta complexes in the normal human kidney. We provide new evidence supporting the hypothesis that TTR, an Abeta binding protein, plays an important role in the sequestration of Abeta and prevents amyloid formation in the kidney.

Retention of words in long-term memory: a functional neuroanatomical study with PET.

We used PET to identify brain regions associated with retention of verbal materials in long-term memory. During a PET scan, subjects repeated many sets of words one after another. In a retention condition, they were simultaneously required to retain 10 key words that were irrelevant to the repetition task. Significant increases in regional cerebral blood flow during the retention condition were found in bilateral parahippocampal regions, the left prefrontal and parietal association cortices, the supplementary motor area, the neostriatum and the cerebellum. We clearly demonstrated that retention of verbal materials was accompanied by neural activities in the medial temporal lobes. We also showed that, in the early phase, retention of words in long-term memory recruited left cortical areas surrounding those relevant to verbal short-term memory.

Proper name anomia after left temporal lobectomy: a patient study.

A patient with a selective deficit in retrieving proper names after left temporal lobectomy is reported. He showed proper name anomia in conversation, in response to photographs, and in verbal descriptions, despite being able to provide semantic information about the people he was unable to name. This report provides evidence that the rostral part of the left temporal lobe plays a crucial role in processing proper names without involvement of other verbal functions.

Eye-head coordination abnormalities and regional cerebral blood flow in Alzheimer's disease.

1. Three patients with Alzheimer's disease (AD) and three healthy controls (HC) were examined for eye-head coordination. Regional cerebral blood flow (rCBF) was measured in AD patients. 2. Eye-head coordination was analyzed using a Vision analyzer, and magnetic sensors. The authors measured the rCBF with 123I-IMP, and 99mTc-ECD SPECT. 3. AD reduced gaze accuracy and head movements, and prolonged the latency of saccade as compared to HC. AD patients had a tendency to focus on the target by using eye movements only. 4. AD reduced the rCBF in the inferior parietal part and the visual area, relative to the motor area. Damage of these areas may have caused the eye-head coordination disorders in the AD patients.

Disproportionate retrograde amnesia in a patient with herpes simplex encephalitis.

We describe a patient who developed a severe but temporally limited retrograde amnesia coupled with a relatively mild anterograde amnesia following herpes simplex encephalitis. The patient showed a profound retrograde amnesia for autobiographical events extending for about 10 years prior to the disease onset. Her knowledge about public events and famous persons was also impaired for this period. An MRI and SPECT demonstrated bilateral medial temporal pathology. This case represents a further instance of a relatively focal retrograde amnesia following brain damage. We review other reported cases with focal retrograde amnesia and consider theoretical and neuroanatomical accounts for the present case. Two factors may account for her amnesic patterns: a partial disruption of the store for premorbid binding codes (i.e., information that multimodal feature representations occurred synchronously); along with a relative preservation of the encoding process required to develop new synchronous codes.

Participation of the prefrontal cortices in prospective memory: evidence from a PET study in humans.

Prospective memory is a memory feature in humans which involves activities for remembering to do something in the future. The present study provides functional neuroanatomy of prospective memory for the first time. We used positron emission tomography (PET) and found several localized brain activations in relation to a prospective memory task required to retain and remember a planned action while performing an ongoing routine activity. Activations were identified in the right dorsolateral and ventrolateral prefrontal cortices, the left frontal pole and anterior cingulate gyrus, the left parahippocampal gyrus, and midline medial frontal lobe. We attributed these activations to several cognitive processes involved in prospective memory, such as holding an intention toward future behavior, checking target items within presented stimuli, and dividing attention between the planned action and the routine activity.

Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases.

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.

Pure somaesthetic alexia: somaesthetic-verbal disconnection for letters.

We studied a patient who manifested a bilateral reading disorder through the somaesthetic modality, without deficit of elementary tactile sensation or tactile object naming, due to a left parietal infarct. Detailed investigation established the following points. (i) The patient showed normal function on elementary somaesthetic examination, normal function on high level tactile perception, except for minimal impairment of the right hand on the two-point discrimination test, and normal latencies on the somatosensory evoked potential in both hands. (ii) The patient had difficulty in reading letters using any somaesthetic strategy (graphaesthesia, directional joint kinaesthesia and active touch) with either hand. (iii) On a same-different judgement task, the patient's performance with the right hand was slightly defective on graphaesthesia and active touch, but performance with the left hand was within the normal range for all of the strategies. The patient's disorder was highly category specific and modality specific, indicating that somaesthetic letter reading can be disrupted not only independent of other high level somaesthetic functions, like object recognition, but also independent of other modes of reading functions, such as visual reading. A lesion involving the intraparietal sulcus, the upper part of the inferior parietal lobule and the adjacent white matter in the left hemisphere may be capable of compromising the pathways for somaesthetic letter reading with both hands.

Evidence for presenilin-1 involvement in amyloid angiopathy in the Alzheimer's disease-affected brain.

Presenilin-1 (PS-1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). The role PS-1 plays in the pathogenesis of Alzheimer's disease (AD) remains unclear. Using a set of antibodies raised against PS-1 synthetic peptides, polyclonal antibody to amyloid beta protein (Abeta) and end-specific antibodies against Abeta40, and Abeta42, immunohistochemical studies were performed on brain sections obtained from AD cases and controls. The PS-1 antibodies clearly stained amyloid angiopathies in AD-affected brains, but no recognizable immunoreactions were observed in any other vessels free from amyloid involvement in either AD-affected brains or controls. Abeta antibodies and the end-specific antibody against Abeta40 also decorated amyloid angiopathies, showing localization similar to that of PS-1. Western blot analyses predominantly detected protein band polypeptide species of a 50 kDa, band, presumably full-length PS-1 protein with N-terminus antisera, since these antibodies turned out to recognize a 50-kDa full-length band in cell lysate of transfected HeLa cell overexpressing PS-1. In addition, we recognized 30, 27 and 25 kDa proteins in both AD and control brain homogenate with these antibodies. In microvessel fractions extracted from brain homogenates, the 50, and 27 kDa fragments were observed in AD-affected brains but not in those of controls. C-terminus rabbit antisera reacted strongly with the 33 and 27 kDa bands, and additionally detected a small amount of full-length PS-1 protein in extracts from AD and control brains. Our present data indicate that PS-1 might be involved in the pathogenesis of amyloid angiopathy in the AD brain.

Impaired recall and preserved encoding in prominent amnesic syndrome: a case of basal forebrain amnesia.

We describe a patient who developed amnesia following extensive basal forebrain infarct. He completely recovered from the infarct 32 days postonset. He had poor spontaneous recall and preserved recognition of recent as well as more remote events. Surprisingly, he could recall events in sequence during the postictal amnesic period after recovery. We speculate that encoding and recall may employ different neural systems.

Amino-terminus truncated apolipoprotein E is the major species in amyloid deposits in Alzheimer's disease-affected brains: a possible role for apolipoprotein E in Alzheimer's disease.

Amyloid deposits in Alzheimer's disease (AD) are composed of amyloid beta protein (A beta) and many other components called amyloid-associated proteins. Apolipoprotein E (apoE) is one of the most important amyloid-associated proteins. The role apoE plays in AD, however, is yet to be determined. In this study, we present the biochemical and histochemical nature of apoE in AD-affected brains using four monoclonal antibodies (mAbs) against apoE and newly established antibodies against the amino-terminal (anti-apoE-N), and carboxyl-terminal regions (anti-apoE-C) of apoE. Competitive ELISA and Western-blot analysis combined with thrombolytic digestion of apoE indicated that our four mAbs recognized at least two different epitopes within a 22-kDa amino-terminal domain of apoE. Using these mAbs and an anti-A beta mAb, double immunostaining showed that the majority of amyloid deposits were stained by both anti-apoE and anti-A beta mAbs, but the minority of them were detected only by either anti-apoE or anti-A beta mAbs. Differences in staining properties between anti-apoE-N and anti-apoE-C were that anti-apoE-C recognized both amyloid deposits and astrocytes similar to anti-apoE mAbs, but anti-apoE-N strongly stained only astrocytes. Preliminary semi-quantitative determinations of apoE in CSF and brain homogenate showed that the amount of apoE increased in AD and Creutzfeldt-Jakob disease brains compared to normal samples. Our immunological data, using antibodies specific for the amino and carboxyl termini of apoE, suggest that apoE may, in some circumstances, initiate plaque formation, and that apoE in amyloid deposits has at least part of its amino termini cleaved out.

Amyloid precursor protein, A beta and amyloid-associated proteins involved in chloroquine retinopathy in rats--immunopathological studies.

To understand the retinal changes in Alzheimer disease (AD) patients, pathological and immunocytochemical studies were performed on retinal cells in the chloroquine-treated rats at 0, 4, 8, 12, 16, 20, and 24 weeks after the initial injection, using anti-amyloid precursor protein (APP), -amyloid beta protein (A beta), -apolipoprotein E (apoE), -ubiquitin, and -cathepsin D antibodies. Pathological alterations consistent with chloroquine retinopathy were recognized in the ganglion cells of the ganglion cell layer (GCL) and the inner plexiform layer (IPL) 4 weeks after initial chloroquine injection. Rat retinal changes appear to have a direct relationship to the duration of chloroquine administration. Intense immunoreactivities for anti-APP, A beta, apoE (an associated protein), and ubiquitin co-localized in the swollen ganglion cells and Muller cells by 20-24 weeks together with the lysosomal enzyme cathepsin D. The present data indicate that the endosomal/lysosomal pathway plays an important role in the processing of APP in rat retina. This experimental model is considered to be a suitable neural model to understand retinal pathology and the processing of APP in terms of the pathogenesis of AD, whereas chloroquine-induced myopathy is a useful extra neuronal model.

[Chronic neuropathy, a high level of protein in cerebrospinal fluid, and vitamin B1 and folate deficiency in a patient with normal-pressure hydrocephalus].

A 67-year-old woman presented with a 1-year history of gradual weight loss, reduced mental activity, muscle weakness, and urinary dysfunction. Neurological examination revealed mild lethargy, severe muscular atrophy, and diminished deep tendon reflexes in the extremities. The levels of vitamin B1 and folate in blood were low: 1.9 micrograms/dl (normal range 2.0-7.2) and 0.7 ng/ml (normal range 4.0-12.0). respectively. A lumbar puncture was done. The pressure of the cerebrospinal fluid was within normal limits, the level of protein was very high (467 mg/dl), and only a few lymphocytes were seen. A nerve-conduction study showed low amplitudes of action potentials and slow conduction velocities in both the motor and sensory nerves. Myelin irregularity, "onion bulb formation", and axonal atrophy were seen in a specimen obtained by sural nerve biopsy. A T2-weighted magnetic resonance image of the brain showed ventricular dilatation, high-intensity signals around the lateral ventricles, and a flow-void sign of the cerebral aqueduct. Radioisotope cisternography (111In-DTPA) disclosed ventricular reflux and slow clearance of the tracer from the ventricles. These findings indicated the presence of chronic inflammatory demyelinating polyneuropathy, nutritional polyneuropathy, vitamin B1 deficiency, folate deficiency, and normal pressure hydrocephalus. In this patient, the high level of protein in the cerebrospinal fluid may have caused the hydrocephalus.

Different roles of the left and right parahippocampal regions in verbal recognition: a PET study.

We examined the role of the parahippocampal regions in humans during two types of verbal recognition process, i.e. delayed matching and non-matching, by measuring regional cerebral blood flow (rCBF) using PET. The results showed differential activation of each parahippocampal region during verbal memory tasks in which the side activated shifted depending on the nature of the task employed; an increase in rCBF in the left parahippocampal gyrus was associated with retrieval strategy of non-matching, and an increase in rCBF in the right parahippocampal gyrus was associated with retrieval strategy of matching. We conclude that lateralized parahippocampal activation may depend on the type of response required.

Snake coiled fibres in rat soleus muscle in chloroquine induced myopathy share immunohistochemical characteristics with amyloid depositions in Alzheimer's disease brain tissue.

Pathological and immunopathological studies were carried out on snake coiled fibres (SCF) which occurred in affected soleus muscle in chloroquine treated rats. The SCF began to appear in denervated soleus muscle by 8 days after chloroquine injection. By day 14, typical SCF were observed with an unusual swirling pattern of the myofibrils, presenting a bizarre appearance. By day 21 or later, the SCF became less remarkable, and were fragmented and broken apart to form large vacuoles. Immunopathological studies demonstrated that the amyloid beta (A beta) and N and C-terminal regions of amyloid precursor protein (APP), and the amyloid associated proteins tested, apolipoprotein E (apoE), SP-40,40, alpha 1-antichymotrypsin (alpha 1-ACT), and ubiquitin, which are known to be components of amyloid depositions found in Alzheimer's disease (AD) affected brains, were present in the SCF. ApoE, SP-40,40, alpha 1-ACT, and ubiquitin are induced following certain cell challenges (e.g. heat shock, various drugs and injury). The significance of APP, A beta, and amyloid associated proteins are discussed in respect to snake coiled fibre formations in chloroquine rat myopathy and in the amyloidogenesis of AD.

Amyloid beta protein and transthyretin, sequestrating protein colocalize in normal human kidney.

The localization of amyloid beta protein (A beta), A beta 40, A beta 42, and transthyretin (TTR) was investigated immunohistochemically in the autopsied human kidney, using polyclonal antibodies against TTR, A beta and C-terminal end-specific antibodies against A beta 40 and 42. Immunoreactivities of A beta and A beta 40 were found both in the proximal and distal tubular epithelial cells. But the immunolocalization of A beta 40 was observed predominantly in the distal tubules whereas that of A beta 42 was predominantly recognized in the proximal tubules. TTR, sequestrating protein for A beta, was present in the proximal tubules. The mechanism by which A beta does not form amyloid in Alzheimer's disease outside the brain remains unknown. The tubular epithelial cells in the kidney may provide a useful system to shed light on this issue.

Persisting childish behavior after bilateral thalamic infarcts.

We report a case with bilateral paramedian thalamic infarcts. The patient showed a dramatic personality change characterized by childish behavior and euphoria; which remained unchanged for 2 years after the onset. 'Vorbeireden' characterized by approximate answers was also observed. Anterograde amnesia had quite improved after 2 years, while retrograde amnesia for 1 year prior to the stroke onset and vertical gaze palsy remained unchanged. An MRI scan demonstrated bilateral medial thalamic and right midbrain infarcts without other lesions in the brain. A position emission tomography study showed that cerebral metabolic rate for glucose was markedly decreased in both thalami and in the cerebellum, and only slightly decreased in the parietal and occipital cortical regions. Cerebral metabolic rates of glucose in the frontal and temporal cortices were within normal range. The paramedian thalamic lesions per se may be responsible for the patient's personality change, 'Vorbeireden', and amnesia.

[The disturbance of reversible operation in space in the early stage of Alzheimer's disease].

Constructional apraxia is one of the neuropsychological findings frequently observed in the early stage of the Alzheimer's disease, which may result from the visuo-spatial disturbances. The visual space consists of a variety of visual information processing, viewer-centered coordinate system, objects-centered coordinate system, integration of both coordinate systems, and verifying visual representation with the knowledge in the memory. The reversible operation in space, or mental rotation appears to play an important role in visuo-spatial functions, which refers to the operation of the visual representation at one orientation in viewer-centered coordinate system to construct the representation in object-centered coordinate system so that one can look like if it were presented at another orientation. To the present, little is known about reversible operation or mental rotation in patients with Alzheimer's disease. In this present paper, we attempted to investigate the ability of reversible operations in space so as to understand the mechanisms underlying constructional apraxia, or visuo-spatial disturbances in the early stage of Alzheimer's disease. The subjects were 12 patients with Alzheimer's disease in early stage (AD group), 12 patients with multi-infarcts dementia as disease control (MID group), 12 age matched persons as healthy control (HC group). In perspective taking tasks, that requires the subjects to imagine the spatial arrangement of the objects at the different view points from the subjects' one, AD group showed more severe deficits than MID group and HC group. Moreover, in a task that the subjects were asked to assume the photo-angle of the photograph taken of the model which was in front of them, AD group was imparied compared to the control groups. These disturbances were closely associated with deficits in Block Design test of WAIS. These results clearly demonstrate that the patients with Alzheimer's disease have disturbance in reversible operation in space and that the disturbance may be responsible for visuo-spatial dysfunctions, not only the constructional apraxia, but also a variety of performance deficits in the early stage of Alzheimer's disease.