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Biomedical subjects

K A Josephs

Publications and source records attributed to K A Josephs.

At least 19 recordsLinked to original sources
PubMed2006

Brain metal concentrations in chronic liver failure patients with pallidal T1 MRI hyperintensity.

BACKGROUND: Chronic liver failure may be associated with pallidal MRI T1 hyperintensity and heterogeneous neurologic syndromes, including parkinsonism, cognitive impairment, and others. Manganese accumulation may be responsible for the imaging and clinical findings. OBJECTIVE: To measure manganese plus other metal concentrations in pallidum and additional brain regions and to examine the corresponding neuropathology in cases of chronic liver failure. METHODS: Regional brain metal concentrations were measured in seven chronic liver failure cases, four with pallidal T1 hyperintensity and three with normal MRI, plus five controls. Neuropathologic examination employed alpha-synuclein and tau immunohistochemistry. RESULTS: In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI; manganese concentrations were also significantly elevated in all other brain regions. Copper was additionally increased in all brain regions, whereas other metal concentrations were similar to control values. Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative alpha-synuclein and tau immunostaining except for one case (intermediate Alzheimer disease pathology). CONCLUSION: In chronic liver failure, manganese accumulation is responsible for the pallidal MRI T1 hyperintensity. Pallidal copper was also elevated in affected cases, but copper does not have the paramagnetic properties to generate isolated T1 hyperintensity. Basal ganglia manganese or copper accumulation may be responsible for the parkinsonism sometimes seen in chronic liver failure. Pallidal MRI T1 hyperintensity is a biomarker of manganese overload.

Adult↗
PubMed2006

Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals.

The authors assessed the frequency of spinal cord alpha-synuclein pathology in neurologically asymptomatic individuals older than 60 years of age (N = 106). Using alpha-synuclein immunohistochemistry, nine cases (8%) had incidental Lewy neurites in the intermediolateral column and at least some alpha-synuclein pathology in the dorsal motor nucleus of the vagus, locus ceruleus, and central raphe nucleus. Sparse alpha-synuclein pathology was also detected in the substantia nigra, basal forebrain, amygdala, or cortex in all but two cases.

Aged↗
PubMed2006

Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP.

OBJECTIVE: To examine the relationship between early clinical features, pathologies, and biochemistry of the frontotemporal lobar degenerations (FTLDs), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). METHODS: The authors conducted pathologic reexamination with the most recent immunohistochemistry of all cases diagnosed with FTLD, PSP, and CBD between 1970 and 2004. The authors also reviewed the early clinical features for clinical diagnosis and application of published research criteria. RESULTS: Of 127 cases analyzed, 57 had a pathologic diagnosis of FTLD, 49 PSP, and 21 CBD. Of these, 38 were clinically reclassified as frontal variant frontotemporal dementia (FTD), 13 as progressive non-fluent aphasia (PNFA), 21 as CBD-like, 33 as PSP-like, and 13 with frontotemporal dementia with coexisting motor neuron disease (FTD-MND). The authors were unable to classify nine cases. All cases of FTD-MND were tau-negative and had pathologic evidence of motor neuron degeneration. All cases classified as PSP-like or CBD-like had tau-positive pathology. Of the 13 cases with PNFA, PSP and CBD accounted for almost 70% of the cases, while FTD was almost equally divided between tau-positive and tau-negative diseases. CONCLUSION: Frontotemporal lobar degeneration, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) have overlapping clinical features. The prediction of tau-positive pathology from a CBD or PSP-like presentation is good, while the frontotemporal dementia (FTD)-motor neuron disease syndrome almost certainly predicts motor neuron degeneration. Surprisingly, PSP and CBD accounted for most cases classified as progressive non-fluent aphasia. Frontal variant FTD is an unpredictable disease in terms of its biochemistry.

Aged↗
PubMed2006

Varied electrophysiologic patterns in spinocerebellar ataxia type 2.

The autosomal dominant ataxias are a heterogenous group of disorders. Almost 30 different genetic loci have been identified. Spinocerebellar ataxia type 2 (SCA2) is one of many autosomal dominant cerebellar ataxias. Electrophysiologic studies in SCA2 have shown mainly a sensory neuropathy or neuronopathy. To determine if electrophysiologic testing reveals concomitant or isolated involvement of motor nerves in SCA2 we reviewed historic and electrophysiologic data on all cases of genetically confirmed SCA2 who underwent nerve conduction studies and needle electromyographic during initial evaluation at our institution. We performed electrophysiologic studies in six genetically confirmed, unrelated, cases of SCA2 and discovered that in three patients, there were findings consistent with motor neuronopathy or neuropathy without sensory involvement. One patient had normal results and only one had a pure sensory neuropathy or neuronopathy. The sixth patients had mixed sensorimotor neuropathy. This is the first study that demonstrates isolated involvement of motor neurons and/or axons occur in SCA2. Therefore, electrophysiologic findings in SCA2 are not limited to mainly a sensory neuropathy but are varied and can even mimic slowly progressive motor neuron disease.

Adolescent↗
PubMed2006

The corticobasal syndrome triggered by central pontine myelinolysis.

Single case reports have described movement disorders including parkinsonism, dystonia and chorea, but not corticobasal syndrome as a consequence of central pontine and extrapontine myelinolysis. We report a case of a 61-year-old woman who developed progressive asymmetric parkinsonism with ideomotor apraxia and cortical sensory deficits following central pontine myelinolysis.

Basal Ganglia Diseases↗
PubMed2006

Neuropsychological profiles of manganese neurotoxicity.

The etiology of manganese neurotoxicity is heterogenous and includes exposure to welding fumes, chronic liver failure, and chronic total parental nutrition (TPN). We recently reported that cognitive impairment occurs in welders and patients with chronic liver failure who had evidence of manganese neurotoxicity including abnormal magnetic resonance imaging (MRI) basal ganglia T1 hyperintensity. In this study, we compared the neuropsychological profiles of patients with manganese neurotoxicity and basal ganglia T1 hyperintensities from three different etiologies: welding, chronic liver failure, and chronic TPN. Across all three groups, the neuropsychological profiles suggest frontal and subcortical cognitive impairment, with more widespread abnormalities occurring in the non-welding groups.

Adult↗
PubMed2006

The alpha-synuclein gene in multiple system atrophy.

BACKGROUND: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested. METHOD: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated. RESULTS AND CONCLUSION: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Gene Expression↗
PubMed2005

Survival in two variants of tau-negative frontotemporal lobar degeneration: FTLD-U vs FTLD-MND.

Pathologic diagnoses in frontotemporal lobar degeneration (FTLD) include tau-positive FTLD and tau-negative FTLD. Two variants of tau-negative FTLD are FTLD with motor neuron disease (FTLD-MND) and FTLD with motor neuron disease type inclusions but without motor neuron disease (FTLD-U). An analysis of patient outcomes in these cases reveals that FTLD-MND has significantly shorter survival than FTLD-U, suggesting that FTLD-MND is a more aggressive disease process.

Age of Onset↗
PubMed2005

Neurologic manifestations in welders with pallidal MRI T1 hyperintensity.

BACKGROUND: Neurologic symptoms have been attributed to manganese fumes generated during welding. Increased T1 MRI signal in the basal ganglia is a biologic marker of manganese accumulation. Recent studies have associated welding and parkinsonism, but generally without MRI corroboration. OBJECTIVE: To characterize the clinical and neuropsychological features of patients with MRI basal ganglia T1 hyperintensity, who were ultimately diagnosed with neurotoxicity from welding fumes. METHODS: The medical records of welders referred to the Department of Neurology with neurologic problems and basal ganglia T1 hyperintensity were reviewed. RESULTS: All eight patients were male career welders with increased T1 basal ganglia signal on MRI of the brain. Several different clinical syndromes were recognized: a parkinsonian syndrome (three patients), a syndrome of multifocal myoclonus and limited cognitive impairment (two patients), a mixed syndrome with vestibular-auditory dysfunction (two patients), and minor subjective cognitive impairment, anxiety, and sleep apnea (one patient). Neuropsychometric testing suggested subcortical or frontal involvement. Inadequate ventilation or lack of personal respiratory protection during welding was a common theme. CONCLUSIONS: Welding without proper protection was associated with syndromes of parkinsonism, multifocal myoclonus, mild cognitive impairment, and vestibular-auditory dysfunction. The MRI T1 hyperintensity in the basal ganglia suggests that these may have been caused by manganese neurotoxicity.

Adult↗
PubMed2005

Late-onset frontotemporal dementia associated with progressive supranuclear palsy/argyrophilic grain disease/Alzheimer's disease pathology.

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer's disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Age of Onset↗
PubMed2005

Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia.

Progressive supranuclear palsy (PSP) is a clinicopathological entity typically presenting as an akinetic rigid syndrome with early falls, axial rigidity, vertical supranuclear gaze palsy and levodopa resistance. Pathological features consist of tau deposition in neuronal and glial cells located mainly in subcortical and brainstem structures. Rare cases with the pathological diagnosis of atypical PSP have been described in which neocortical tau deposition is more widespread than what is usually seen in typical PSP. Progressive nonfluent aphasia (PNFA) is a syndrome characterized by spontaneous nonfluent speech and early preserved comprehension of language. Apraxia of speech (AOS) is a motor speech disorder that may be a feature of PNFA. We report the clinical and pathological findings of four cases that presented with features most consistent with PNFA predominated by AOS. Pathological features in these four cases included the typical features of PSP subcortically and in brainstem structures, but combined with tau-positive neuronal and glial pathology in the neocortex. Comprehensive semiquantitative analyses of tau burden including neurofibrillary tangles and pretangles, coiled bodies, tufted astrocytes and threads were undertaken in the four cases of atypical PSP and compared to 10 cases of typical PSP. Semiquantitative analysis demonstrated that in atypical PSP, the pathology shifts from subcortical grey and brainstem regions, commonly affected in typical PSP, towards neocortical regions. This shift in pathology accounts for the presentation of PNFA and AOS observed in our patients, as well as the lack of classic features of PSP. These cases demonstrate that atypical PSP can present as AOS and PNFA without the classic features of PSP.

Adult↗
PubMed2005

Mapping the onset and progression of atrophy in familial frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) may be inherited as an autosomal dominant disease. Studying patients "at risk" for developing FTLD can provide insights into the earliest onset and evolution of the disease. METHOD: We carried out approximately annual clinical, MRI, and neuropsychological assessments on an asymptomatic 51 year old "at risk" family member from a family with FTLD associated with ubiquitin-positive and tau-negative inclusion bodies. We used non-linear (fluid) registration of serial MRI to determine areas undergoing significant regional atrophy at different stages of the disease. RESULTS: Over the first 26 months of the study, the patient remained asymptomatic, but subsequently developed progressive speech production difficulties, and latterly severe orofacial dyspraxia, dyscalculia, frontal executive impairment, and limb dyspraxia. Regional atrophy was present prior to the onset of symptoms, and was initially centred on the left dorsolateral prefrontal cortex and the left middle frontal gyrus. Latterly, there was increasing asymmetric left frontal and parietal atrophy. Imaging revealed excess and increasing global atrophy throughout the study. Neuropsychological evaluation revealed mild intellectual impairment prior to the onset of these clinical symptoms; frontal executive and left parietal impairment subsequently emerged, culminating in widespread cognitive impairment. Fluid registered MRI allowed the emerging atrophy patterns to be delineated. CONCLUSION: We have demonstrated the onset and progressive pattern of in vivo atrophy in familial FTLD using fluid registered MRI and correlated this with the clinical features. Fluid registered MRI may be a useful technique in assessing patterns of focal atrophy in vivo and demonstrating the progression of degenerative diseases.

Atrophy↗
PubMed2004

Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes: broadening the clinical picture to include progressive supranuclear palsy.

The frontotemporal lobar degenerations (FTLDs) are a group of disorders in which the clinical picture is not necessarily predictive of the underlying neuropathology. The FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U) subtype is pathologically characterized by ubiquitin-positive, tau and alpha-synuclein-negative neuronal cytoplasmic inclusions in the frontotemporal cortex and hippocampal dentate fascia. When similar pathological changes are accompanied by histological features of motor neuron disease (MND), the term FTLD-MND is used. The latter pathological changes may be found in patients with or without clinical evidence of MND. We retrospectively reviewed the clinical details of three patients with a rapidly progressive, levodopa-unresponsive bradykinetic-rigid syndrome and frontal cognitive impairment. A diagnosis of progressive supranuclear palsy (PSP) had been considered in all three cases at initial presentation. Two of the cases fulfilled clinical diagnostic criteria for PSP, which was the final clinical diagnosis during life. Pathological analysis showed typical histological appearances of FTLD-MND in two cases and of FTLD-U in one case. Semi-quantitative analysis of pathological load seemed to correlate with the clinical phenotype. FTLD-U or FTLD-MND should be considered in the differential diagnosis of progressive frontal dementia with an akinetic rigid syndrome and supranuclear gaze palsy or Steele-Richardson-Olszewski disease.

Aged↗
PubMed2004

Frontotemporal lobar degeneration and ubiquitin immunohistochemistry.

We set out to determine the frequency of the different pathologies underlying frontotemporal degeneration (FTD) in our brain bank series, by reviewing all cases of pathologically diagnosed FTD over the last 12 years. We identified and reviewed 29 cases of FTD and classified them using the most recent consensus criteria with further histological analysis of 6 initially unclassifiable cases. Detailed histological analysis of these 6 cases revealed variable numbers of ubiquitin-positive (tau and alpha-synuclein-negative) inclusions in 5 cases, consistent with the diagnosis of frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). As a consequence of the current re-evaluation, 18 (62%) of the 29 cases with FTD have underlying pathology consistent with FTLD-U. Therefore in our brain bank series of frontotemporal degeneration, most cases were non-tauopathies with FTLD-U accounting for 62% of all the diagnoses.

Aged↗
PubMed2004

Creutzfeldt-Jakob disease presenting as progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by an akinetic rigid syndrome with vertical supranuclear ophthalmoplegia, early falls, and levodopa resistance. The pathological substrate of PSP consists of filamentous tau degenerative lesions affecting neurons and glia. Other disorders can present with a similar clinical picture, most commonly corticobasal degeneration and multiple system atrophy. Non-neurodegenerative disorders are rare causes of the PSP syndrome. In this report we describe clinical and pathological features of two cases of Creutzfeldt-Jakob disease (CJD) presenting with the PSP syndrome and discuss which features may help prevent misdiagnosis. To our knowledge, this is the first report of cases of CJD with autopsy confirmation that presented with a PSP syndrome.

Aged↗
PubMed2003

Pathologically confirmed corticobasal degeneration presenting with visuospatial dysfunction.

Corticobasal degeneration (CBD) typically manifests as progressive asymmetric rigidity and apraxia, although other non-motor presentations have been reported. We report two patients with pathologically diagnosed CBD who presented with prominent visuospatial dysfunction. The pathological changes were maximal in the visual association cortices, but absent in 31 cases of pathologically proven CBD with more typical antemortem features. Underlying CBD should be considered in the differential diagnosis of patients with findings reflecting posterior cerebral dysfunction.

Aged↗
PubMed2003

Atrophy of superior cerebellar peduncle in progressive supranuclear palsy.

BACKGROUND: Pathologic changes in the superior cerebellar peduncles (SCP) are common in progressive supranuclear palsy (PSP), but atrophy of the SCP has never been systematically studied. OBJECTIVE: To investigate the SCP width in PSP cases and controls with morphometric methods. METHODS: The mean width of the SCP in transverse sections of the pons at the level of trigeminal nerve was determined in 48 PSP cases (29 men, 19 women; mean age 72.5 +/- 8.2 years) and 29 age-matched control subjects, many with neurodegenerative disorders that can be clinically mistaken for PSP. As the origin of the SCP is the cerebellar dentate nucleus, correlations were sought between SCP atrophy and severity of grumose degeneration in the dentate nucleus. RESULTS: The average width of the SCP was less in PSP (range 0.09 to 0.24 cm) than in controls (range 0.21 to 0.43 cm; Mann-Whitney U test, p < 0.001), including control cases that had been clinically misdiagnosed as PSP (range 0.26 to 0.41 cm). Severity of SCP atrophy normalized by brain weight correlated with disease duration (Spearman rank order correlation, r = 0.367, p = 0.028), suggesting that SCP atrophy is a relatively early feature of PSP. No correlation was found between grumose degeneration and SCP width. CONCLUSIONS: SCP atrophy is common in PSP and correlates with disease duration. Given that measurements of the SCP are within the resolution of MRI, it remains to be determined if SCP atrophy can be used as a diagnostic marker of PSP.

Adult↗