Biomedical subjects

Julie S Snowden

Publications and source records attributed to Julie S Snowden.

14 recordsLinked to original sources

PubMed2007

Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43.

We have investigated the extent and pattern of immunostaining for the TAR DNA-binding protein, TDP-43, in 37 patients with frontotemporal lobar degeneration with ubiquitin (UBQ) pathology (FTLD-U). We confirm that TDP-43 protein is a component of the UBQ immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII) and neurites of the cerebral cortex and hippocampus in FTLD-U. We further show that the same three histological patterns, previously identified by us according to the form, number and distribution of the UBQ-ir NCI, NII and neurites are equivalently present in TDP-43 immunohistochemistry. TDP-43 immunoreactive (TDP-43-ir) NCI with rounded, spicular or skein-type appearance were seen in motor neurones of the trigeminal or facial cranial nerve nuclei in one patient with frontotemporal dementia (FTD) and in the spinal cord in three patients with FTD + motor neurone disease (MND). In patients with MND alone, TDP-43-ir NCI are common in anterior horn cells of the spinal cord, and occasionally seen in neurones of the hypoglossus nucleus. We show that TDP-43-ir NCI are also present within neurones in the superior and inferior olives in FTLD-U, and in some patients with MND. Although TDP-43 is normally seen as a nuclear protein, nuclear TDP-ir was not observed in neurones of the cerebral cortex, brainstem and spinal cord in FTLD-U or MND when NCI were present. We conclude that the UBQ-ir lesions of FTLD and MND are defined by the presence of TDP-43, and that these disorders can be subsumed into a single disease entity under the umbrella of TDP-43 proteinopathy.

Adolescent↗

PubMed2006

Psychiatric disorders in preclinical Huntington's disease.

BACKGROUND: Psychiatric symptoms are a common feature of Huntington's disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period. OBJECTIVES: To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non-carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset. METHODS: Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non-carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow-up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset. RESULTS: Gene carriers and non-carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset. CONCLUSIONS: Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.

Adult↗

PubMed2006

Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease.

The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.

Age of Onset↗

PubMed2006

Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype.

We have investigated the extent and pattern of immunostaining for ubiquitin protein (UBQ) in 60 patients with frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U), 37 of whom were ascertained in Manchester UK and 23 in Newcastle-Upon-Tyne, UK. There were three distinct histological patterns according to the form and distribution of the UBQ pathology. Histological type 1 was present in 19 patients (32%) and characterised by the presence of a moderate number, or numerous, UBQ immunoreactive neurites and intraneuronal cytoplasmic inclusions within layer II of the frontal and temporal cerebral cortex, and cytoplasmic inclusions within granule cells of the dentate gyrus; neuronal intranuclear inclusions (NII) of a "cat's eye" or "lentiform" appearance were present in 17 of these patients. In histological type 2 (16 patients, 27%), UBQ neurites were predominantly, or exclusively, present with few intraneuronal cytoplasmic inclusions within layer II of the cerebral cortex, while in histological type 3 (25 patients, 42%), UBQ intraneuronal cytoplasmic inclusions either within the cortical layer II or in the granule cells of the dentate gyrus, with few or no UBQ neurites, were seen. In neither of these latter two groups were NII present. The influence of histological type on clinical phenotype was highly significant with type 1 histology being associated clinically with cases of frontotemporal dementia (FTD) or progressive non-fluent aphasia (PNFA), type 2 histology with semantic dementia (SD), and type 3 histology with FTD, or FTD and motor neurone disease (MND).

Adult↗

PubMed2006

Dementia lacking distinctive histology (DLDH) revisited.

Although immunohistochemistry has helped to classify the histology of frontotemporal lobar degeneration (FTLD), there have been many cases, described in the literature as showing "dementia lacking distinctive histology" (DLDH), in which this technique has failed to disclose signature pathological changes. Using an automated procedure we have repeated immunostaining for ubiquitin protein (UBQ) in 41 patients with FTLD, 25 of whom were previously considered, on the basis of UBQ immunostaining performed in Manchester, UK, to show FTLD-ubiquitin (FTLD-U) histology and 16 described as DLDH. Both the quality and amount of UBQ immunoreactive (UBQ-ir) pathology (neurites and intraneuronal cytoplasmic inclusions) was significantly increased using the newer staining method. Although the original histological diagnosis was confirmed in the 25 cases previously classified as FTLD-U, the median UBQ score for slides stained in Vancouver increased significantly compared to those stained in Manchester. More importantly, however, some degree of UBQ-ir changes was now disclosed in 13 of the 16 cases previously classified as DLDH and these were now classed as definite or probable FTLD-U. Of the remaining three DLDH cases, clinical diagnostic uncertainties could have explained the lack of specific pathology in two instances. Hence, we conclude that DLDH is a very rare disorder, and that lack of sensitivity for UBQ immunostaining is likely responsible for the failure to disclose this pathology and to provide a diagnosis of FTLD-U.

Adult↗

PubMed2005

Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation.

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration (FTLD). Clinical misdiagnosis rate was low with only 3 patients (4%) failing to show pathological changes consistent with this diagnosis; 1 patient had Alzheimer's disease and 2 had cerebrovascular disease (CVD). In the remaining 67 patients, the most common underlying histological cause was ubiquitin pathology with 24 (36%) cases so affected. In these, ubiquitin-positive inclusions were present in the cerebral cortex as small, rounded or crescent-shaped structures within the cytoplasm of neurones of layer II, together with coiled or curvilinear bodies within neurites, and in the hippocampus as small, solid and more spherical-shaped inclusion bodies within the cytoplasm of dentate gyrus granule cells. In one patient, "cat's eye" or "lentiform" intranuclear ubiquitin inclusions were also present. The second most common histological type was dementia lacking distinctive histology (DLDH), in which neither tau nor ubiquitin inclusions were present, with 16 cases (24%) being affected. Pick-type histology was seen in 14 cases (21%) and tau histological changes associated with frontotemporal dementia (FTD) linked to chromosome 17 (FTDP-17) were present in 11 cases (16%). One case (1%) showed an unusual tau pathology that could not be allocated to any of the other tau groups. Only 1 case (1%) had neuronal intermediate filament inclusion dementia. No cases with ubiquitinated, valosin-containing protein-immunoreactive intranuclear inclusion bodies of the type seen in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia were seen. Clinicopathological correlation showed that any of these histological subtypes can be associated with FTD. However, for FTD with motor neurone disease (FTD+MND), semantic dementia or primary progressive aphasia (PA), the histological profile was either ubiquitin type or DLDH type; Pick-type histology was seen in only 1 case of PA. None of these latter three clinical subtypes was associated with a mutation in tau gene and FTDP-17 type of tau pathology. All cases of progressive apraxia were associated with Pick-type histology. Present data therefore indicate that, although ubiquitin pathology is the most common histological form associated with FTLD, this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.

Adenosine Triphosphatases↗

PubMed2005

Brief report: errorless versus errorful learning as a memory rehabilitation approach in Alzheimer's Disease.

Previous studies concerned with the use of errorless learning (EL) in memory rehabilitation of patients with Alzheimer's disease (AD) combined EL with other techniques, such as expanded rehearsal, to facilitate learning. These studies focused on the re-learning of previously familiar information and did not investigate the learning of novel information. The aim of the present study was to investigate if EL provides a better training technique for AD patients than errorful learning (EF). For this purpose, learning of familiar material and learning of novel associations in four patients with probable AD was compared under EL and EF conditions. Combined data analysis demonstrated a significant advantage of EL over EF both for old and novel learning. However, patients also learned significantly in the EF condition and the EL effect was not large enough to reach significance on an individual level. It is suggested that EL may be most beneficial for patients with profound amnesia, and in situations that make effortful processing difficult, but that residual explicit memory capacities may override EL benefits.

Aged↗

PubMed2003

Progressive anomia with preserved oral spelling and automatic speech.

We report a patient, Newton, with a progressive classical anomia resulting from focal degeneration of the left hemisphere. In naming tasks Newton spelt aloud picture names that he could not retrieve, indicating a dissociation between orthography and phonology. Unusually, his writing and letter-pointing performance were impaired and spelling was achieved only through alphabet recitation. A study of automatic speech tasks demonstrated strikingly preserved naming performance on automatic compared to nominative tasks. We argue that automatic tasks provide phonological cues that facilitate phonological activation. With progression of disease Newton has shown increasing difficulty reading and repeating words, which we interpret in terms of a progressive elevation in the threshold for activation of phonology. Phonological cueing of picture names has yielded superior naming than word reading and even repetition, a finding consistent with the notion that task characteristics influence likelihood of phonological activation and naming success, but contrary to the notion that there exist separate task-specific output systems. We conclude that Newton exhibits a unique pattern of deficits, which have theoretical relevance for the debate on the relationship between phonology and orthography, the role of automatic speech and the relationship between naming, reading and repetition.

Aged↗

PubMed2003

Surface dysgraphia in a regular orthography: apostrophe use by an Italian writer.

The dual-route model of writing assumes two basic procedures involved in writing: lexical and non-lexical. The lexical route is fundamental in opaque orthographies such as English; from its impairment surface dysgraphia arises. Evidence for the role of a lexical route in transparent languages such as Italian, which have a regular orthography, has been more limited. We report a case study of ES, an Italian patient suffering from degenerative brain disease, who presented with a selective disorder of writing. He showed the unusual phenomenon of inserting an apostrophe inappropriately in the spellings of words. Neuropsychological evaluation provided evidence of loss of orthographic meaning of the apostrophe and a pattern of writing performance consistent with surface dysgraphia. There was also evidence of an accompanying surface dyslexia. We conclude that examination of apostrophe use provides a valuable means of detecting surface dysgraphia in the Italian language. The findings point to the need for cognitive models of writing to account for "dumb symbols" of language such as the apostrophe. This unique case provides a further example of the variety of clinical presentations of focal cerebral degeneration.

Agraphia↗

PubMed2002

Relearning of verbal labels in semantic dementia.

Semantic dementia is a degenerative disorder of temporal neocortex characterised by loss of word and object concepts. There is limited evidence that temporary relearning of lost vocabulary may be possible, attributed to sparing of hippocampal structures. However, learning is variable across patients and factors underlying learning success are poorly understood. The study investigated relearning of object names in two severely anomic semantic dementia patients. Following memory models that assume that hippocampal memories require some neocortical representation to underpin them it was predicted that relearning would be influenced by patients' residual semantic information about stimuli. Experiment 1 confirmed that residual knowledge influenced learning success. On the assumption that neocortical knowledge encompasses concepts of space and time, as well as words and objects, it was predicted that learning would be affected by the availability of contextual (temporo-spatial) information. Experiment 2 demonstrated effective learning of object names, attributed to the patient's use of temporal order and spatial position knowledge. Retention of object names over months was linked to the patient's capacity for autobiographical experiential (temporo-spatial contextual) association. The findings indicate that relearning of lost vocabulary is possible in semantic dementia, indicating a role of the medial temporal lobes in the acquisition of semantic information. Effective learning does not imply reinstatement of lost concepts, but, it is argued, does involve some reacquisition of meaning. The findings challenge the traditional semantic-episodic memory dichotomy and are consistent with a "levels of meaning" account of semantic memory.

Anomia↗

PubMed2002

Dementing disorders: volumetric measurement of cerebrospinal fluid to distinguish normal from pathologic findings -- feasibility study.

The authors describe a magnetic resonance (MR) imaging technique to quantify the severity and distribution of cerebral atrophy by using automated volumetric analysis of the distribution of cerebrospinal fluid. The MR imaging technique demonstrated high diagnostic sensitivity and specificity in a group of healthy subjects and patients with dementing diseases. The authors conclude that this approach provides valuable clinical information that is complementary to information acquired with standard diagnostic practices.

Age Factors↗

PubMed2002

Behavior in Huntington's disease: dissociating cognition-based and mood-based changes.

The authors examined the relationship of three dimensions of behavioral change (Apathy, Depression, and Irritability) measured by the Problem Behaviors Assessment for Huntington's Disease (PBA-HD) to cognitive and motor indices of disease severity. The Apathy subscale was highly correlated with both cognitive and motor impairment; the Irritability and Depression subscales were not. The findings suggest that certain behavioral alterations are intrinsic to the evolution and progression of HD, whereas others are more variable and are independent of other indices of disease progression.

Activities of Daily Living↗

PubMed2002

Frontotemporal dementia.

BACKGROUND: Frontotemporal dementia accounts for up to 20% of cases of dementia in the presenium, yet remains poorly recognised. Diagnostic criteria have been devised to aid clinical diagnosis. AIMS: To provide an overview of clinical and pathological characteristics of frontotemporal dementia and its nosological status. METHODS: The review summarises consensus diagnostic criteria for frontotemporal dementia and draws on the authors' clinical experience of 300 frontotemporal dementia cases, and pathological experience of 50 autopsied cases. RESULTS: Frontotemporal dementia is characterised by pronounced changes in affect and personal and social conduct. Some patients also develop motor neuron disease. Mutations in the tau gene account for some but not all familial cases of frontotemporal dementia. CONCLUSIONS: Frontotemporal dementia is a focal form of dementia, which is clinically and pathologically distinct from other dementias. It represents an important model for understanding the functions of the frontotemporal lobes.

Aged↗

PubMedDate not supplied

New learning and remote memory in atypical Alzheimer's disease.

This paper presents the case of BB, an individual with an atypical posterior cortical presentation of Alzheimer's disease (AD). The severity of BB's visuo-spatial impairment far outweighed impairment of other cognitive functions. BB's case is also unusual in that despite a long history of progressive impairment, his cognitive symptoms remain relatively circumscribed. More specifically, BB's pattern of memory impairment was striking, since his impairment on formal psychometric tests of memory contrasted with his performance at clinical interview, where he talked lucidly about events in his past, and displayed remarkably well-preserved general semantic knowledge. On the basis of BB's clinical profile, it was hypothesised that his pattern of cognitive performance reflected an impairment of anterograde memory in the context of relative preservation of remote memory. Further investigations revealed that while BB's anterograde memory function was comparable to that of other AD patients, his remote memory was well preserved relative to other AD 'controls'. These findings are discussed in terms of typical and atypical presentations of Alzheimer's disease, and in terms of the possible fractionation of different aspects of long-term memory. The implications of these findings for our understanding of the neural bases of different types of retrograde memory (i.e. 'old' versus 'recent') are considered, with particular reference to the contrasting theoretical frameworks that have recently been advanced by Squire and Moscovitch.

Aged↗