Progressive lenticular degeneration

Summary Two cases of Wilson's disease (progressive lenticular degeneration) are described from a clinical and pathologic point of view. In addition, the clinical features of a third case are reported. The first case showed the typical clinicopathologic picture of the disease, while the second case, although exhibiting characteristic clinical features and the peculiar lenticular pathology, showed no liver involvement. On the base of these findings, the problem of the relationship of liver damage to brain pathology in Wilson's disease is briefly discussed.     

Progressive language disorder associated with frontal lobe degeneration

Abstract

We report a patient KC who presented with a profound disorder of propositional language in association with progressive frontal lobe degeneration. The salient clinical feature was her marked difficulty in responding to open-ended questions, contrasting with the relative preservation of performance on more closed, structured language tasks. Experimental investigations of her language skills revealed significant temporal organizational difficulties. She could generate sentences in sentence completion tasks, although there were errors in thematic role assignment and temporal ordering. She had profound difficulty rearranging written words to form a sentence, despite producing the sentence orally. She was unable to conjoin sentences with an appropriate conjunction. The nature of her language disorder is discussed with reference to traditional categories of aphasia. The case is important in drawing attention to the role of the frontal lobes in language functioning and the potential contribution of processes outside the traditional psycholinguistic categories of phonology, morphology, syntax and semantics. Moreover, KC's clinical presentation falls between that of ‘frontal-lobe’ dementia and ‘progressive aphasia‘, reinforcing the link between those clinical disorders.     

Progressive degeneration of the cerebral cortex in infancy

Summary The clinical and pathological features of a case with primary progressive degeneration of the cerebral cortex are presented. Two siblings had nearly identical clinical histories. All three children were born microcephalic and they died at the age of 7, 10 and 18 months, respectively. All showed progressive mental and motor deterioration. Myoclonus and attacks of opisthotonus were prominent features. Postmortem examination was performed in the third child, who died at the age of 10 months. The brain weight was 310 g. The cerebral cortex was severely atrophic, with extensive laminar neuronal loss. The cerebellum was normal. The optic tracts were atrophic. Neuronal loss was observed also in a few other systems but their relation to the primary disease is uncertain. The basal ganglia were normal and the hippocampus showed only slight nerve cell loss.The case is considered to belong to a small group of cases with primary progressive cortical degeneration described by Laurence and Cavanagh (1968). This group should be distinguished from cases with secondary cortical degeneration caused by anoxic damage from recurrent epileptic attacks. The primary cortical degeneration may start shortly before birth, or after a brief periood of normal postnatal development. A positive family history has been reported in most cases, suggesting an inherited metabolic defect as cause of the disease.     

Progressive medullary failure associated with neurofibrillary degeneration.

A clinicopathological report is presented of a British male, aged 59 years, who died after an illness of 10 years, manifested by progressive respiratory failure, ptosis, and dysphagia. At no time was there evidence of ophthalmoplegia, Parkinsonism or dementia. At necropsy the main finding was of neurofibrillary tangles in the neurons of the pontine and medullary reticular formation, with particularly severe involvement of the nucleus ambiguus, dorsal motor nucleus of the vagus and nucleus tractus solitarius. Morphologically, by light and electron microscopy and immunostaining, the tangles were similar to those of other neurofibrillary degenerative diseases. Although similar in some respects to progressive supranuclear palsy and amyotrophic lateral sclerosis of the Guam type, the combination of clinical and neuropathological features suggest that this is a distinct disease entity.     

Progressive centripetal degeneration in polyneuropathies (author's transl)

This is a clinicopathologic report on three patients with sensory polyneuropathies of different origin. Sensory loss involved all four limbs reaching the upper third of the thighs and the elbow level or higher, in all three patients. In addition to the limbs the central region of the anterior aspect of the trunk, from lower abdomen up to level T2, and on the top of the scalp were involved. There was minimal weakness. This pattern of sensory deficit can best be explained by a length dependent degeneration of fibers. Familial amyloidosis, Portugese type, was responsible for the neuropathy in the first patient, diabetes mellitus in the second and alcoholism in the third one. On teased nerve fiber study, single regenerating fibers were isolated on sural nerve biopsy specimens from patients 1 and 2. Segmental demyelination and/or remyelination occurred in 11 per cent of the fibres in patient 1, in 36 per cent in patient 2 and in 4 of the 19 fibres isolated in patient 3. On cross sections of nerve specimens embedded in Epon there was a striking loss of myelinated fibres which was less important and predominated on smaller fibres in patients 1 and 2. On electron microscopic examination loss of unmyelinated fibres was conspicuous in all three patients. On single fiber studies as well as on sections of embedded specimens, myelinated fibres occasionally showed demyelination in contact to amyloid deposits. The present study demonstrates that in this pattern of neuropathy degeneration of myelinated fibers begins in the distal part of longest axons and may be associated with axonal sprouting in more proximal parts of degenerating axons. As the neuropathy progresses axons of shorter and shorter length become involved.     

Chameleons and mimics: Progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that show parkinsonism as their main symptom. Both PSP and CBD are sporadic tauopathies associated with hyperphosphorylated four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and the appearance of tufted astrocytes and globose-type neurofibrillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar dentate nuclei. Conversely, the characteristic pathologies of CBD are cortical atrophy and the appearance of astrocytic plaques and argyrophilic threads. CBD is associated with severe degeneration in the cerebral white matter, substantia nigra, and globus pallidus. Clinical symptoms depend on the topographical distribution and severity of degeneration rather than on the type of aggregated protein or inclusions. PSP and CBD present clinically differential diagnostic difficulties because of their overlapping pathological distributions.     

Progressive anomia revisited: focal degeneration associated with progranulin gene mutation

In 2003 we reported a case study of a patient, Newton who presented with a progressive circumscribed anomia in association with focal left hemisphere atrophy. Remarkably, he could spell aloud the names of objects that he could not name, indicating dissociated access to phonology and orthography. We now present follow-up clinical data, post-mortem histopathological findings, and results of molecular genetic analysis. Newton showed tau-negative ubiquitin-positive histology consistent with frontotemporal lobar degeneration (FTLD) and a mutation in the progranulin (PGRN) gene. The case exemplifies the heterogeneity of clinical expression of FTLD and contributes to understanding of primary progressive aphasia.     

Progressive prosopagnosia at a very early stage of frontotemporal lobar degeneration

Background: The present paper describes a patient with a right temporal lobe variant (RTLV) of frontotemporal lobar degeneration (FTLD). Methods: The study was undertaken when the patient was completely independent in her environment and had not complained of any cognitive problems. Results: Under general neuropsychological assessment, the patient showed no notable deficit other than a difficulty in recognizing famous people by looking at photographs of their faces. Subsequent in‐depth evaluation indicated prosopagnosia: the patient presented with an impaired ability to recognize the faces of famous people and family members, whereas her visuospatial abilities were intact. Because the patient was able to recognize familiar people by their voices, the impairment was not a general loss of knowledge about people, but an inability to access this knowledge from visual stimuli (i.e. via the visual modality). The patient also exhibited a ‘within‐category’ learning deficit; however, her ability to learn from ‘across‐category’ visual stimuli remained intact. Conclusions: Overall, the results of the present study support the proposed model of RTLV of FTLD, where the first sign would be the disruption of face recognition components, leading to a selective form of associative prosopagnosia. Further, the co‐occurrence of face and ‘within‐category’ object learning deficits favor an interpretation in which a more generalized deficit occurs ‘earlier’ in the sequence of events associated with the object recognition process.     

Progressive spinal axonal degeneration and slowness in ALS2-deficient mice

OBJECTIVE: Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons. The goal of this study was to elucidate how the motor system is affected by the deletion of ALS2. METHODS: ALS2-deficient mice were generated by gene targeting. Motor function and upper and lower motor neuron pathology were examined in ALS2-deficient mice and in mutant superoxide dismutase 1 (SOD1) mice that develop ALS-like disease from expression of an ALS-linked mutation in SOD1. RESULTS: ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice. Despite the vulnerability of these spinal axons, lower motor neurons in ALS2-deficient mice were preserved. Behavioral studies demonstrated slowed movement without muscle weakness in ALS2(-/-) mice, consistent with upper motor neuron defects that lead to spasticity in humans. INTERPRETATION: The combined evidence from mice and humans shows that deficiency in ALS2 causes an upper motor neuron disease that in humans closely resembles a severe form of hereditary spastic paralysis, and that is quite distinct from amyotrophic lateral sclerosis.     

Progressive aphasia without dementia: two cases with focal spongiform degeneration

Two patients with the syndrome of progressive aphasia without evidence of generalized dementia underwent postmortem neuropathological examinations. In both patients, characteristic changes of Alzheimer's disease, Pick's disease, or Creutzfeldt-Jakob disease were absent. Both patients showed a focal spongiform change involving primarily layer 2 of the left inferior frontal gyrus (and temporal cortex in Patient 1) and a mild astrocytosis in layer 2 and deeper cortical layers. This focal, spongiform cortical degeneration in patients with progressive aphasia does not appear to duplicate any known central nervous system degenerative disease.     

Progressive degeneration of dopamine system functions after transient cerebral oligemia in rats

A reduction in cerebral blood flow to oligemic levels was achieved in pentobarbital-anesthetized adult rats by clamping both carotid arteries (BCCA) for 60 min. To assess the extent to which the animals' dopaminergic system was affected over an increasing time span, their spontaneous locomotor activity in an unfamiliar environment and in response to the subcutaneous administration of apomorphine was tested at various times after either BCCA or sham operation. Eight to 14 days after the operation, it was possible to observe a diminished locomotor activity in response to apomorphine injection in BCCA as compared with sham-operated animals, while oral stereotypical behavior such as licking was increased. At 3 months, there was only a subtle decrease in apomorphine-induced locomotor activity, and stereotypical behavior was similar in both groups. At 7 months, the BCCA rats covered shorter distances than sham-operated controls during the habituation phase; after apomorphine injection, more stereotypic movements, such as, e.g., sniffing, were observed, and less running. Twelve months after surgery, no further differences could be observed between the two groups during the habituation phase, but the injection of apomorphine led to increased stereotypic sniffing movements, rearing and locomotor activity in BCCA animals to a greater extent than in the controls. At 12 months, sensorimotor disturbances elicited by the rota rod test, which were only transiently observed at 11 weeks and 7 months, did not appear any different from the normal age-related motor decline of the sham-operated controls. The animals' motor co-ordination in the chimney test was not significantly disturbed during the time between 7 and 12 months after surgery. At 15 months, nocturnal locomotor activities in BCCA rats were significantly decreased. In situ hybridization (ISH) histochemistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons 19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal number remained the same. The present results show that just as is already known for the immature rat brain, the adult rat brain, too, reacts to a transient decrease in its blood supply by appearance of long-lasting alterations in function, and that even a single oligemic episode is capable of inducing progressive dopaminergic dysfunctions and ultimately the partial loss of striatal D1RmRNA.     

Progressive and selective degeneration of motoneurons in a mouse model of SMA

Spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by the degeneration of motoneurons of the spinal cord and brainstem, results from loss-of-function mutations in the survival motor neuron gene (smn). The goal of these experiments was to analyse axons and cell bodies of motoneurons in different regions of the CNS during disease progression in a mouse model of SMA carrying a deletion of the exon 7 directed to neurons. These experiments demonstrate a progressive loss of motor axons and of motoneurons in the CNS. This is the first study that describes a selective neurodegeneration in this line of mice and underlines the importance of exon 7 in some populations of motoneurons for survival in vivo.     

Progressive peripheral neuron degeneration in ataxia-telangiectasia: an electrophysiological study in children

Electrophysiological examinations were performed on 32 children aged three to 17 years who had typical clinical manifestations of ataxia-telangiectasia (AT). EMG findings demonstrated neurogenic lesions, more pronounced in the distal leg muscles of older children where they resembled the picture characteristic of motor neuron disease. Electrophysiological and nerve conduction results showed that generalised, progressive, sensory nervous system degeneration, with neurogenic amyotrophy affecting the distal part of the lower limbs, is an established feature of this disease and can be considered one of the diagnostic characteristics of AT. This allows the syndrome to be classified as an hereditary spinocerebellar degeneration.     

Progressive degeneration of the right temporal lobe studied with positron emission tomography.

A 79 year old man with a twelve year progressive history of prosopagnosia and recent naming difficulty, in whom other intellectual skills were preserved, is described. Positron emission tomography (PET) revealed an area of right temporal lobe hypometabolism, with an additional area of less severe hypometabolism at the left temporal pole. This may represent an example of progressive focal cortical degeneration similar to that associated with primary progressive dysphasia, but affecting the right temporal lobe.     

Progressive deficits in retrograde axon transport precede degeneration of motor axons in acrylamide neuropathy

Single injection of acrylamide (1.3 mmol/kg, i.p.) inhibited retrograde axon transport of [125I]tetanus toxin in hen sensory and motor axons. Retrograde axon transport deficits appeared within hours of dosing with acrylamide. The inhibitory effect of acrylamide on retrograde axon transport was transient since transport deficits were not detectable 35 h after dosing. Acrylamide impaired the retrograde movement but not the uptake of [125I]tetanus toxin in the axon. Multiple doses of acrylamide (0.42 mmol/kg, i.p.) induced progressive clinical signs of acrylamide neuropathy that correlated with increasing deficits in retrograde axon transport of [125I]tetanus toxin to ventral spinal cord. Deficits were also observed in sensory neurons but were not statistically significant. Accumulated decrements in retrograde axon transport may be the underlying cause of degeneration of motor axons in acrylamide neuropathy in fowl.