Progressive Cortical Atrophy Research Articles

Rehabilitation of gesture imitation: A case study with fMRI

Acquired disorders of gesture imitation are amenable to treatment, but with poor generalisation toward gestures not included in the training program. We investigated the neural basis of this item-specific recovery in a patient with a slowly progressive posterior cortical atrophy, by means of an fMRI study comparing imitation of rehabilitated and not-rehabilitated gestures. Results suggested that in our patient gesture imitation recruited the mirror system and additional areas relevant to gesture analysis and preparation. Imitation of rehabilitated gestures activated the mirror neuron system, and also left dorsolateral prefrontal cortex and putamen, and the right anterior temporal cortex. This suggests that item-specific recovery was based on interaction of circuitry of imitation with neural systems involved in emotional and motivational processing.

Newly observed thalamic involvement and mutations of the HEXA gene in a Korean patient with juvenile GM2 gangliosidosis

Neuroimaging studies of patients with GM2 gangliosidosis are rare. The thalamus and basal ganglia are principally involved in patients affected by the infantile form of GM2 gangliosidosis. Unlike in the infantile form, in juvenile or adult type GM2 gangliosidosis, progressive cortical and cerebellar atrophy is the main abnormality seen on conventional magnetic resonance imaging (MRI); no basal ganglial or thalamic impairment were observed. This report is of a Korean girl with subacute onset, severe deficiency of hexosaminidase A activity and mutations (Arg137Term, Ala246Thr) of the HEXA gene. A 3.5-year-old girl who was previously in good health was evaluated for hypotonia and ataxia 3 months ago and showed progressive developmental deterioration, including cognitive decline. Serial brain MRI showed progressive overall volume decrease of the entire brain and thalamic atrophy. Fluorine-18 FDG PET scan showed severe decreased uptake in bilateral thalamus and diffuse cerebral cortex. We suggest, through our experience, that the thalamic involvement in MR imaging and FDG-PET can be observed in the juvenile form of GM2 gangliosidosis, and we suspect the association of mutations in the HEXA gene.

Induction of Oxidative Stress by Chronic and Acute Glutaric Acid Administration to Rats

: 1. Glutaric acidemia type I (GA I) is a neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which leads to tissue accumulation of predominantly glutaric acid (GA) and also 3-hydroxyglutaric acid to a lesser amount. Affected patients usually present progressive cortical atrophy and acute striatal degeneration attributed to the toxic accumulating metabolites.2. In the present study, we determined a number of oxidative stress parameters, namely chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total antioxidant reactivity (TAR), glutathione (GSH) levels, and the activities of catalase and glutathione peroxidase (GPx), in various tissues from rats chronically exposed to GA or to saline (controls). High GA concentrations, similar to those found in glutaric aciduria type I, were induced in the brain by three daily subcutaneous injections of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 5-22 days of life. The parameters were assessed 12 h after the last GA administration in different brain structures, skeletal muscle, heart, liver, erythrocytes, and plasma. The lipid peroxidation parameters chemiluminescence and/or TBA-RS measurements were found significantly increased in midbrain, liver, and erythrocytes of GA-injected rats. The activity of GPx was significantly reduced in midbrain and markedly increased in liver. TAR measurement was significantly reduced in midbrain and liver. Furthermore, GSH levels were reduced in liver and heart. We also investigated the acute in vivo effect of GA administration on the same oxidative stress parameters in cerebral structures and erythrocytes from 22-day-old rats. We found that TBA-RS values were significantly increased in erythrocytes, TAR levels were markedly decreased in midbrain and cerebellum, and GPx activity mildly reduced in the midbrain.3. These data showing an imbalance between antioxidant defences and oxidative damage, particularly in midbrain, liver, and erythrocytes from GA-injected rats, indicate that oxidative stress might be involved in GA toxicity and that the midbrain, where the striatum is located, is the brain structure more susceptible to GA chronic and acute exposition.

Corticobasal degeneration as cause of progressive non‐fluent aphasia: Clinical, radiological and pathological study of an autopsy case

A Japanese male developed gradual loss of spontaneous speech at age 60. Three years later meaningful speech had deteriorated to the point that it had become restricted to monotonous utterances. Neuropsychological examination at age 62 showed that he had severe non-fluent aphasia. A brain MRI demonstrated mild cortical atrophy with ischemic lesions in the cerebral white matter. He was diagnosed as having primary progressive aphasia. At age 63, he was admitted to the hospital to reevaluate the neurological condition. Neurologic examination showed severe non-fluent aphasia, hyperreflexia, snout and sucking reflexes. No alien hand was observed. He was able to walk, dress, wash himself and use chopsticks as well as name real objects. At age 65, 99Tc-hexamethylpropyleneamine oxime single photon emission computed tomography (HMPAO-SPECT) revealed diffuse cerebral hypoperfusion that was particularly prominent in the left frontal lobe. An MRI showed progressive cortical atrophy with the definite atrophy of the left paracentral gyrus. The hippocampal formation and putamen were also atrophic. He died of pneumonia at age 67. The brain weighed 810 g with atrophy of the frontal lobe, globus pallidus, enlargement of the lateral ventricles and depigmentation of the substantia nigra. Microscopic examination showed severe neuronal loss and gliosis in the cerebral cortex, globus pallidus interna and substantia nigra. Ballooned neurons were observed in the cerebral cortex. Gallyas-Braak method revealed numerous astrocytic plaques and argentophilic threads in the cerebrum. Clinical diagnosis of corticobasal degeneration sometimes is difficult in individuals with atypical clinical presentations. More exact clinical and radiological criteria may warrant a diagnosis of corticobasal degeneration.

Putaminal involvement in Rasmussen encephalitis

Rasmussen encephalitis (RE) is a rare devastating disease of childhood causing progressive neurological deficits and intractable seizures, typically affecting one hemisphere. Characteristic MRI features include progressive unihemispheric focal cortical atrophy and grey- or white-matter high-signal changes and basal ganglion involvement, particularly of the caudate nucleus. To analyse the pattern of involvement of different brain structures in a series of patients with RE and to attempt clinical correlation. We reviewed the medical records and neuroimaging data of 12 patients diagnosed with RE satisfying the European Consensus Statement diagnostic criteria. The disease manifested as seizures in all patients and was refractory; epilepsia partialis continua was a notable feature (nine patients). Hemiparesis of varying grades was noted in all but one patient; none had extrapyramidal signs. Neuroimaging showed cortical involvement in the insular/periinsular regions in 11 patients. Caudate atrophy was noted in ten patients. Putaminal atrophy was seen in nine patients, six of whom had additional hyperintense signal changes. Our study highlights frequent putaminal atrophy and signal changes in RE, which suggests a more extensive basal ganglion involvement than emphasized previously. Recognition of putaminal changes may be a useful additional tool in the radiological diagnosis of RE.

The Correlation of Cognitive Decline with Frontotemporal Dementia Induced Annualized Gray Matter Loss Using Diffeomorphic Morphometry

This study uses large deformation medical image registration to analyze, in a disease-specific normalized space, the annual rate of gray matter atrophy caused by frontotemporal dementia (FTD) and its correlation with cognitive decline. The analysis consists of three parts. First, a labeled structural MRI atlas is deformed into the shape of an average FTD brain. Second, annualized FTD-related atrophy of gray matter structures is estimated for each patient in the database. Third, the group-wise annualized atrophy rate caused by FTD is correlated, for each gray matter voxel, with declining performance on cognitive tests. This study gives insight into the relationship between FTD-related progressive cortical atrophy and loss in cognitive function.

Malignant migrating partial seizures in infancy

Malignant migrating partial seizures in infancy is a rare, age-specific epileptic encephalopathy. It is characterized by onset before age 6 months, virtually continuous multifocal seizures with ictal electrical encephalographic activity shifting from one hemisphere to the other, no identifiable immediate or remote causes, intractability to antiepileptic drugs, and developmental arrest. This report adds two patients to the 21 previously described in the literature. One infant, microcephalic at birth, developed at age 4 months clusters of nearly continuous multifocal seizures with secondary generalization, refractory to antiepileptic drugs. By age 4.5 years she was seizure-free but remains without any cognitive or motor function. Patient 2, born with a normal head circumference, began seizures at age 3 months, never became seizure-free, and died at age 18 months. Electroencephalograms of both children were characteristic, and the neuroimaging finding was one of progressive cortical and subcortical atrophy. It has been hypothesized that neurotransmitter dysfunction with persistent, pronounced excitatory or cytotoxic mechanisms may explain the continuous, erratic epileptic activity. Awareness of malignant migrating partial seizures in infancy and research focused on its pathophysiologic mechanisms may reveal innovative treatments of this devastating, age-specific disorder.

Early epilepsy surgery.

Uncontrolled epilepsy is associated with progressive cortical and hippocampal atrophy, substantial cognitive and psychosocial morbidity, and increased mortality. Seizure freedom is required to reverse such morbidity and mortality. Surgery is vastly superior to medical therapy for patients with chronic, refractory temporal lobe seizures, and is now the standard of care for these patients. On the other hand, the concept of early surgery requires further exploration and definition. Although there is no robust, direct evidence to support early epilepsy surgery, case series and cohort studies report an association between earlier surgery and better outcomes. The evidence for earlier epilepsy surgery is reviewed.

P2-210 Regional MR brain volumes in the prediction of cognitive decline in ad

P2-210 Regional MR brain volumes in the prediction of cognitive decline in ad

TBP, a polyglutamine tract containing protein, accumulates in Alzheimer's disease

Alzheimer's disease (AD) is characterised by extra cellular β-amyloid (βA) deposition, Tau-containing neurofibrillary tangles (NFTs) and progressive cortical atrophy. Abnormal protein accumulation is also a common feature of other late onset neurodegenerative diseases, including the heritable polyglutamine (polyQ) disorders such as Huntington disease (HD) and the spinocerebellar ataxias (SCAs). One of this family of disorders, SCA17, is caused by an expansion of a polymorphic polyQ repeat in TATA binding protein (TBP), an essential transcription factor. Surprisingly, the wild type TBP repeat length ranges from 25 to 42, and in Caucasian populations the most common allele is 38, a size large enough to cause HD if within the huntingtin protein. Wild type length TBP accumulates in HD and in at least some of the SCAs, and consequently we hypothesised that it may contribute to AD. Here we provide evidence that TBP accumulates in AD brain, localising to neurofibrillary tangle structures. A proportion of TBP present in AD brain is insoluble; a signature of the polyQ diseases. TBP is present differentially between patients and its amount and distribution is not directly proportional to that of Tau or β-amyloid positive structures. We present this as evidence for the hypothesis that the accumulation or misfolding of this polyQ containing protein may be a contributing factor in Alzheimer's disease.

Causes of Nursery Death beyond the Neonatal Period

To investigate causes of death in infants who died after 28 days, beyond the neonatal period but before discharge from the nursery, to establish their clinical courses and causes of death and to attempt to find criteria for earlier identification of these infants. We identified 30 such infants (12% of nursery deaths) from 1993 through 1998 and conducted a retrospective review of their records including placental pathology and autopsy reports when available. In all, 14 infants who weighed <or = 860 g at birth were matched with survivors. The 30 infants divided almost equally into two groups. Of them 15 infants weighing >or = 880 g died of diverse congenital anomalies, including five with nonhemolytic hydrops and four with pulmonary hypoplasia. One infant without congenital anomaly weighed 3290 g. Support for this severely asphyxiated infant was withdrawn after 103 days because of progressive cortical atrophy. The remaining 14, the largest of which weighed 860 g, died of complications of prematurity, which we termed postponed neonatal deaths (PND). They followed a typical course of progressive multiple organ failure. All received assisted ventilation and postnatal steroids, developed chronic lung disease, and were on ventilation at the time of death. Renal insufficiency occurred late in the course. Acute infections and renal failure were the major proximal causes of death. When compared with surviving controls the PND were less likely to have received antenatal steroids and received more inotropic agents for cardiovascular support and more amphotericin for fungal infection; surgery for perforated bowel was confined to the PND. The incidence of postneonatal nursery deaths has not changed in more than 20 years remaining at 11 to 12% of nursery deaths. Congenital anomaly was a prominent cause of death (50%). When infants without congenital anomalies (PND) were compared to surviving controls, no differences were found, which could reliably identify PND early in their course. The only potentially preventable factor was lack of antenatal steroid exposure in the PND.

A longitudinal MRI study in children with Rasmussen syndrome

The aim of this study was to identify the presence of any neuroimaging patterns of Rasmussen syndrome using magnetic resonance imaging (MRI). This was a prospective study evaluating brain MRIs in seven children with neuropathologically proven Rasmussen syndrome. All patients were unresponsive to conventional antiepileptics; five patients subsequently underwent functional hemispherectomy, and two patients underwent cortical resection. Three to eight (mean = 4.7) MRIs per patient were performed, and neuropathologic examination of the brain was available. Serial MRIs were obtained between 12 months before and 9 months after the onset of epilepsia partialis continua. The most common region of initial MRI signal change was the frontocentral region (six patients). Three patterns of neuroimaging abnormalities were observed as follows: (1) normal MRI followed by increased signal intensity with progressive cortical atrophy over time, (2) initial increased focal signal intensity followed by decrease in spatial extent and degree of signal intensity; (3) initially increased signal intensity without further changes on follow-up scans. This observation suggests three possible distinct patterns of MRI changes in patients with Rasmussen syndrome and that the differences in these neuroimaging patterns may reflect inherent differences in the pathogenesis of Rasmussen syndrome.

Hypertension and cerebrovascular diseases: a specific role of vascular protection for the prevention of dementia.

Despite the use of antihypertensive drugs, mortality (but not morbidity) from cerebrovascular diseases has been reduced significantly. As a consequence, an increasing number of patients suffer from recurring strokes and from the debilitating consequences of cerebrovascular diseases and develop progressive cognitive impairment. Its pathological substrates are regional alteration of cerebral perfusion, lacunae, white matter lesions, progressive cortical atrophy, even in the asymptomatic patient and in the absence of extracranial carotid artery stenosis. Lacunar infarction and white matter lesions are particularly frequent in the hypertensive diabetic patient. Lacunae and white matter lesions sometimes coexist and may favour the development of dementia in the hypertensive patient, through focal ischaemia, perivascular oedema, disruption of the blood-brain barrier, cerebral diaschisis and cortical deafferentation. Treatment with calcium channel blockers, angiotensin converting enzyme inhibitors and diuretics smooth the patchy hypoperfusion despite the fall in pressure. However, the time course and the extent of this effect vary according to the drug administered. In particular, only a calcium channel blocker increased perfusion of both cortical and subcortical areas, while diuretic treatment increased perfusion only after prolonged treatment, and this effect was limited to the cortical areas. Such differences may explain the discrepant results on risk reduction for dementia observed in large intervention trials.

Progressive cortical atrophy after forebrain ischemia in diabetic rats.

The morphological changes in the brain of diabetic rats were examined up to 8 weeks after transient forebrain ischemia produced by transient occlusion of both carotid arteries. Using histochemistry, we also examined the extent and rate of development of atrophic changes in the brain, appearance of astrocytes, activated microglia, and glucose transporter 1 (GLUT1) in streptozotocin-treated rat brains after forebrain ischemia. Atrophic changes appeared in the hippocampus in both non-diabetic-- and diabetic--ischemic groups 4 weeks after ischemia. In diabetic--ischemic rats, the atrophic changes were more severe and progressed more rapidly in the hippocampus, and were also observed in the frontal, temporal and parietal cortices, but not in any cortical areas of the non-diabetic--ischemic rats and non-ischemic--diabetic rats. We observed reduced density of GLUT1 in all cortical regions and hippocampus in ischemic-diabetic rats at 4--8 weeks, when the number of activated microglias and astroglias increased in all cortical regions. Although severe atrophic changes were observed in the gray matter, no serious injury was noted in the white matter in the diabetic-ischemic group. Our results indicate that brain ischemia in the presence of diabetes causes more severe late-onset damage culminating in brain atrophy, compared with non-diabetics.

MRI Patterns of Leigh Syndrome

To emphasize the varied clinical, neuroradiological and biochemical/genetic features of Leigh syndrome (LS). 3 cases with different metabolic anomalies and a family with 5 members affected by the same biochemical/genetic abnormality had 2 to 4 years follow-up with a 1.5 unit. Cases 1 and 2 had respectively pyruvate dehydrogenase (PDH) and activated Complex I defect; both presented at birth with seizures and brainstem involvement and developed microcephaly and quadriparesis. MRI showed rapid, progressive cortical atrophy with transient subdural fluid collections (case 1), and haemorrhagic necrosis of both thalami and central mesencephalon (case 2). Case 3 started at the 5th month of life with seizures, hypotonia, brainstem signs, and was found to have a defect of Complex II of the mitochondrial respiratory chain; MRI disclosed transient subdural fluid collections, necrosis of the basal ganglia at first, and of brainstem and subcortical white matter soon afterwards. Of the five members of a family with the so called NARP mutation only two had symptoms of brain involvement: an infant who developed at four months of age hypotonia, epilepsy, mental/motor regression and retinitis pigmentosa, had MRI pictures of putaminal, cerebellar, brainstem necrosis along with hypomyelination of the cerebral hemispheric white matter. His aunt of 28 who, after presenting when 1 year old with a Lennox- Gastaut syndrome, suffered from mental delay, ataxia, pigmentary retinopathy, displayed a severe brain atrophy, mostly cerebellar, at MRI. The peculiar variability of Leigh syndrome is stressed and confirmed, with emphasis on case 2.

Cortical atrophy in Alzheimer's disease unmasks electrically silent sulci and lowers EEG dipolarity.

Alzheimer's disease (AD) patients show lower dipolarity (goodness-of-fit) for dipole localizations of alpha or other dominant electroencephalography (EEG) frequency components in the occipital cortex. In the present study, we performed computer simulations to discover which of distributions of dipole activity lower dipolarity in a manner similar to that seen in severe AD. Dipolarity was estimated from simulations of various electric dipole generator configurations within the occipital cortex under conditions of widened cortical sulci (a severely demented AD case) or no sulcal widening (a normal subject). The cortical and scalp surfaces, derived from the subjects' MRI's, were assumed to be uniformly electrically conducting. Randomly placed, nonoverlapping lesions ranging from 1 to 4 mm2 per lesion were used in both the normal and AD models to simulate the electrical effect of neuropathological AD lesions. In both models, dipolarity decreased as total lesion size increased. However, the AD model showed lower dipolarity than the normal model for both individual lesion sizes and for larger total lesion sizes. The larger decline in dipolarity in the AD model appears to be due to sulcal widening which unmasks the effect of lesions buried within sulci. These simulations identify a possible mechanism explaining why sulcally-located neuropathological changes plus progressive cortical atrophy in AD brains (and presumably other cortical disorders producing atrophy) alter EEG patterns and dipolarity differently from normal cortex damaged by similar lesions.

Infant rat model of the shaken baby syndrome: preliminary characterization and evidence for the role of free radicals in cortical hemorrhaging and progressive neuronal degeneration.

Infants subjected to repeated episodes of violent shaking develop brain damage characterized by intracranial hemorrhage and progressive cortical atrophy. We have developed an animal model that mimics this pathological state and investigated its etiology and treatment. Anesthetized male rats, 6 days of age, were subjected to one episode of shaking per day for 3 consecutive days. Separate groups of rats were sacrificed 1 h postinjury on the third day of shaking for HPLC quantification of cortical .OH and vitamin E levels, and histological assessment of cortical hemorrhaging. Additional groups were sacrificed 7 or 14 days postinjury to demonstrate progressive neuronal degeneration via cortical wet weight comparisons. In comparison to noninjured shams, the results indicated that cortical vitamin E and .OH levels rose 53.7% (p < 0.005) and 457.1% (p < 0.001), respectively, in shaken infant rats. Brain histologies revealed a moderate-to-severe degree of cortical hemorrhaging in these animals 1 h postinjury. By 7 and 14 days postinjury, there was a 13.3% and 28.7% (p < 0.0001 vs. sham) loss of cortical tissue in shaken infants, respectively, indicating progressive neuronal degeneration. Treatment with 10 mg/kg (ip) of the 21-aminosteroid antioxidant, tirilazad mesylate, 10 min before and 2 h after each episode of shaking, resulted in a 53.1% attenuation of cortical .OH levels and a 34.9% decrease in brain hemorrhaging (p < 0.05 vs. vehicle). Tirilazad treatment did not, however, significantly effect cortical vitamin E concentrations at 1 h postinjury or the extent of progressive neuronal degeneration at either 7 or 14 days postinjury. The present animal model mimics the brain pathology seen in abused children. Our observation that tirilazad mesylate, an antioxidant-lipid peroxidation inhibitor, significantly reduces cortical .OH levels and brain hemorrhaging in shaken infant rats supports a role for oxygen radicals in the pathophysiology of this type of CNS injury. The failure of tirilazad to block progressive cortical degeneration suggests that mechanisms other than free radicals may be of prime importance in the mediation of this aspect of the pathology.

Slowly progressive anarthria with late anterior opercular syndrome: a variant form of frontal cortical atrophy syndromes

We describe eight patients with slowly progressive speech production deficit combining speech apraxia, dysarthria, dysprosody and orofacial apraxia, and initially no other deficit in other language and non-language neuropsychological domains. Long-term follow-up (6–10 years) in 4 cases showed an evolution to muteness, bilateral suprabulbar paresis with automatic-voluntary dissociation and frontal lobe cognitive slowing without generalised intellectual deterioration. Most disabled patients presented with an anterior opercular syndrome (Foix-Chavany-Marie syndrome), and pyramidal or extrapyramidal signs. CT and MRI findings disclosed asymmetric (left > right) progressive cortical atrophy of the frontal lobes predominating in the posterior inferior frontal region, notably the operculum. SPECT and PET revealed a decreased cerebral blood flow and metabolism, prominent in the left posterior-inferior frontal gyrus and premotor cortex, extending bilaterally in the most advanced cases. Pathological study of two cases showed non-specific neuronal loss, gliosis, and spongiosis of superficial cortical layers, mainly confined to the frontal lobes, with no significant abnormalities in the basal ganglia, thalamus, cerebellum, brain stem (except severe neuronal loss in the substantia nigra in one case), and spinal cord. We propose to call this peculiar syndrome Slowly Progressive Anarthria (SPA), based on its specific clinical presentation, and its metabolic and pathological correlates. SPA represents another clinical expression of focal cortical degeneration syndromes, that may overlap with other similar syndromes, specially primary progressive aphasia and the various frontal lobe dementias.

CNS Changes in DRPLA with Dementia and Personality Changes: CT, MR and SPECT Findings

CNS changes in a case of DRPLA associated with dementia and personality changes were observed by CT, MR and SPECT. Brain CT and MR of the patient revealed progressive cortical atrophy which was recognized in parallel with the clinical course of the progression of dementia and personality changes. SPECT using 123I-iodoamphetamine (IMP) disclosed a diffuse low perfusion of the cerebral cortex, especially in the frontal and temporal lobes. These findings suggest that the dementia and personality changes in this case might be concerned with a dysfunction of the cerebral cortex.

Paradoxical increase in striatal neuropeptide gene expression following ischemic lesions of the cerebral cortex.

Ischemic lesions of the cerebral cortex occur frequently in humans as a result of stroke. One major consequence of the death of cortical neurons is the loss of excitatory cortical projections to subcortical regions. Little is known, however, about the transsynaptic effect of such lesions on neurotransmitter expression in subcortical structures. We have examined the effects of ischemic cortical lesions on the peptidergic neurotransmitters enkephalin and tachykinins in the striatum, a brain region massively innervated by glutamatergic cortical inputs. The levels of enkephalin and tachykinin mRNAs increased in the striatum of adult rats after thermocoagulation of pial vessels. The effects were more pronounced in the striatal region most heavily innervated by the lesioned cortex but were also observed in other striatal regions and on the contralateral side. Increased gene expression was accompanied by increased immunoreactivity for the two peptides. Elevated levels of enkephalin mRNA were observed up to 3 months after surgery in the ipsilateral striatum. Whereas results of previous studies of acute cortical ablations suggested that excitatory corticostriatal neurons were necessary to maintain normal peptide levels in striatal efferent neurons, the present data indicate that lesions of the same corticostriatal neurons secondary to local ischemia result in a paradoxical transsynaptic activation of neuropeptide synthesis in subcortical structures. This effect may play a role in the functional consequences of cortical strokes and progressive cortical atrophy in humans and may have critical bearing for their treatment and prognosis.