Biomedical subjects

D Neary

Publications and source records attributed to D Neary.

At least 19 recordsLinked to original sources

PubMed2002

Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease, frontotemporal dementia and vascular dementia.

OBJECTIVES: Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) are the three most common causes of young onset dementias. Most neuroimaging studies of these disorders have involved comparisons with normal controls. The aims of this study were to examine the clinical diagnostic value of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) (in combination and in isolation) in the differentiation of one form of dementia from another from amongst a group of AD, FTD and VaD. METHODS: T1 weighted MRI images and 99mTc-HMPAO SPECT images were obtained from consecutive patients with FTD (n=21), AD (n=23) and VaD (n=20) and rated visually by experienced neuroradiologists and nuclear medicine physicians. RESULTS: Asymmetrical atrophy was seen only in FTD. Frontotemporal dementia patients were the most atrophic whereas severe atrophy was rarely observed in VaD. Severe frontal atrophy (unilaterally or bilaterally) and/or asymmetrical atrophy on MRI is highly diagnostic (sensitivity 0.71, specificity 0.93, LR 10.24) of FTD from within a group of FTD and non-FTD (AD, VaD) patients. Mild or severe parietal atrophy with severe reduction in parietal regional cerebral blood flow on SPECT is diagnostic (sensitivity 0.71, specificity 0.76, LR 3.02) of AD from within a group of AD and non-AD (VaD, FTD) patients. CONCLUSION: Anatomical (MRI) and functional (SPECT) imaging provide different information and a combination of these modalities improves diagnostic specificity.

Aged↗

PubMed2002

Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene.

Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Age of Onset↗

PubMed2001

Longitudinal evaluation of cognitive disorder in Huntington's disease.

The study investigated longitudinal change in cognitive function in 87 patients with Huntington's disease (HD), using a range of neuropsychological tests, which tap mental manipulative abilities, memory, and frontal executive skills. Over a 1-year period the largest changes were noted in letter fluency, object recall, and Stroop Test performance, whereas no changes were noted over more than 3 years on the modified Wisconsin Card Sorting Test. Contrary to expectation, greater change was evident over 1 year for tasks with low compared to high cognitive demands. The differential sensitivity of tasks was attributed in part to inherent characteristics of the tests themselves: their capacity to detect minor gradations of change and their vulnerability to practice effects. However, the greater change for relatively automatic, speed-based tasks with low cognitive demands was interpreted as reflecting the evolution of HD, with a greater magnitude of change occurring in basal ganglia than cortical function. One purpose of the study was to identify tasks sensitive to the progression of HD and hence most suitable for the evaluation of therapies. Despite reaching statistical significance by virtue of the large group size, numerical differences in test scores over 1 year were very small, suggesting that the use of such tests to evaluate change in individuals or small groups of subjects would be problematic. The data highlight the slow progression of HD, the limitations of standard cognitive tests in detecting change over short periods, and the need for therapeutic studies that encompass a relatively prolonged time frame.

Adult↗

PubMed2001

Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia.

OBJECTIVES: The study aimed to increase understanding of behavioural changes in frontotemporal dementia (FTD) and identify features that best differentiate FTD from Alzheimer's disease (AD) and cerebrovascular dementia (CvD). METHODS: A semi-structured questionnaire was administered to carers of 30 FTD, 75 AD and 34 CvD patients. RESULTS: Behavioural changes that strongly discriminated FTD from AD and to a lesser extent CvD were loss of emotions and insight, selfishness, disinhibition, personal neglect, gluttony and sweet food preference, wandering, motor and verbal stereotypies, loss of pain, echolalia and mutism. Irritability, hyposexuality and hypersomnia did not discriminate. Emotional, eating and stereotyped behaviours correctly classified 95% of patients using regression analysis. CONCLUSIONS: Behavioural characteristics accurately differentiate FTD from AD and CvD. The findings highlight the particular importance of affective change in FTD, and underline the role of the frontotemporal lobes in emotion.

Adult↗

PubMed2001

Distinct behavioural profiles in frontotemporal dementia and semantic dementia.

OBJECTIVE: To test predictions that frontotemporal dementia and semantic dementia give rise to distinct patterns of behavioural change. METHODS: An informant based semistructured behavioural interview, covering the domains of basic and social emotions, social and personal behaviour, sensory behaviour, eating and oral behaviour, repetitive behaviours, rituals, and compulsions, was administered to carers of 41 patients with semantic dementia and with apathetic (FTD-A) and disinhibited (FTD-D) forms of frontotemporal dementia. RESULTS: Consistent with prediction, emotional changes differentiated FTD from semantic dementia. Whereas lack of emotional response was pervasive in FTD, it was more selective in semantic dementia, affecting particularly the capacity to show fear. Social avoidance occurred more often in FTD and social seeking in semantic dementia. Patients with FTD showed reduced response to pain, whereas patients with semantic dementia more often showed exaggerated reactions to sensory stimuli. Gluttony and indiscriminate eating were characteristic of FTD, whereas patients with semantic dementia were more likely to exhibit food fads. Hyperorality, involving inedible objects, was unrelated to gluttony, indicating different underlying mechanisms. Repetitive behaviours were common in both FTD and semantic dementia, but had a more compulsive quality in semantic dementia. Behavioural differences were greater between semantic dementia and FTD-A than FTD-D. A logistic regression analysis indicated that emotional and repetitive, compulsive behaviours discriminated FTD from semantic dementia with 97% accuracy. CONCLUSION: The findings confirm predictions regarding behavioural differences in frontotemporal and semantic dementia and point to differential roles of the frontal and temporal lobes in affect, social functioning, eating, and compulsive behaviour.

Behavior↗

PubMed2000

Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS).

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Molecular classification of the dementias.

Most patients with frontotemporal dementia do not have taupathology as shown by immunohistochemistry. The use of the term tauopathy to classify frontotemporal dementia is inappropriate.

Brain↗

PubMed2000

Apolipoprotein E epsilon4 allele has no effect on age at onset or duration of disease in cases of frontotemporal dementia with pick- or microvacuolar-type histology.

Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. Here we have investigated the frequency of the epsilon4 allele of the Apolipoprotein (APOE) gene in FTD and in other non-Alzheimer forms of dementia related to FTD such as Motor Neurone disease dementia, semantic dementia, progressive aphasia, progressive supranuclear palsy, and corticobasal degeneration. In none of these diagnostic groups did we find a significant increase in the APOE epsilon4 allelic frequency, compared to population values. Neither did we observe any affects of the epsilon4 allele upon age at onset or duration of disease. We conclude therefore that polymorphic variations in the APOE gene do not modulate either the occurrence or progression of these non-Alzheimer forms of dementia.

Adult↗

PubMed2000

Classification and description of frontotemporal dementias.

A number of distinct clinical syndromes have been described that are associated with focal degeneration of the frontal and temporal lobes and have a non-Alzheimer pathology. The nosological status of frontotemporal lobar degeneration (FTLD) has been a matter of controversy, in view of the diversity of clinical manifestations and distribution and nature of histopathological change. This paper describes the major clinical syndromes of frontotemporal dementia, progressive aphasia, and semantic dementia; it discusses their underlying pathologies and considers their molecular status. Common histopathological changes are demonstrated across the three clinical syndromes, highlighting the link between these clinical disorders. It has been suggested that these disorders should be regarded as tauopathies on the basis of the tau pathology seen in a number of cases and the mutations in the tau gene in some familial cases. However, in a series of 47 consecutive autopsy series of FTLD, only 36% had tau pathology and 10% mutations in the tau gene, suggesting that FTLD does not constitute a unitary etiological disorder and that its characterization as a tauopathy may be potentially misleading.

Aged↗

PubMed2000

The electroencephalogram in dementia with Lewy bodies.

OBJECTIVES: Dementia with Lewy bodies (DLB) is the second commonest neurodegenerative cause of dementia. While there is consensus on the clinical diagnostic criteria for DLB, the use of EEG to increase the diagnostic sensitivity has not been substantiated. MATERIAL AND METHODS: We studied the resting EEG findings in 18 consecutive patients with DLB and compared them with a control group of 20 patients with "probable" Alzheimer's disease (AD). We aimed to evaluate the use of EEG in a representative sample of patients with DLB. RESULTS: All patients with DLB fulfilled accepted clinical criteria for DLB. The DLB group had a more severe dementia than the AD group, as measured by the Mini-Mental State Examination (MMSE) test (DLB mean MMSE 9.4 and AD mean MMSE 17.2) despite a similar duration of overall severity of illness. The EEG was slow in both groups, predominantly in the 4-7 Hz range. Although there was no statistically significant difference in the EEG findings between the DLB and AD groups, there was a correlation between the EEG score and MMSE score (Spearman Rank correlation rs = -0.61, P < 0.001). CONCLUSION: These findings suggest that although patients with DLB have a more aggressive course than AD, EEG abnormalities do not differ in the 2 groups. However, we believe the EEG provides important supporting diagnostic information in DLB.

Aged↗

PubMed1999

Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia.

Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.

Adult↗

PubMed1999

Neuropsychiatric aspects of frontotemporal dementias.

Frontotemporal dementia (FTD) is a clinically distinct disorder that is under-recognized. A primary focus of recent research has been to delineate neuropsychiatric features that best discriminate FTD from other dementias, and to identify test instruments that elicit differentiating characteristics most effectively. Additional studies have taken advantage of the clinical and anatomic selectivity that is the hallmark of FTD to explore the functions of different regions of the frontal and temporal lobes. Symptomatic treatments for FTD have shown some promise, raising the potential for improved management in the future.

Dementia↗

PubMed1999

Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer's disease and frontotemporal dementia.

OBJECTIVES: The diagnosis of Alzheimer's disease (AD) is now reliant on the use of NINCDS-ADRDA criteria. Other diseases causing dementia are being increasingly recognised--for example, frontotemporal dementia (FTD). Historically, these disorders have not been clearly demarcated from AD. This study assesses the capability of the NINCDS-ADRDA criteria to accurately distinguish AD from FTD in a series of pathologically proved cases. METHODS: The case records of 56 patients (30 with AD, 26 with FTD) who had undergone neuropsychological evaluation, brain imaging, and ultimately postmortem, were assessed in terms of whether at initial diagnosis the NINCDS-ADRDA criteria were successful in diagnosing those patients who had AD and excluding those who did not. RESULTS: (1) The overall sensitivity of the NINCDS-ADRDA criteria in diagnosing "probable" AD from 56 patients with cortical dementia (AD and FTD) was 0.93. However, the specificity was only 0.23; most patients with FTD also fulfilled NINCDS-ADRDA criteria for AD. (2) Cognitive deficits in the realms of orientation and praxis significantly increased the odds of a patient having AD compared with FTD, whereas deficits in problem solving significantly decreased the odds. Neuropsychological impairments in the domains of attention, language, perception, and memory as defined in the NINCDS-ADRDA statement did not contribute to the clinical differentiation of AD and FTD. CONCLUSION: NINCDS-ADRDA criteria fail accurately to differentiate AD from FTD. Suggestions to improve the diagnostic specificity of the current criteria are made.

Aged↗

PubMed1999

Overview of frontotemporal dementias and the consensus applied.

Frontotemporal dementia, progressive nonfluent aphasia and semantic dementia are distinct clinical syndromes arising from degeneration of the frontotemporal lobes, each syndrome being determined by the distribution of degenerative change within the brain. The Lund-Manchester consensus statement provided diagnostic guidelines for frontotemporal dementia, which were devised to improve its clinical and pathological recognition. The Lund-Manchester groups together with researchers from the United States, Canada and Europe have sought to build on those original criteria to produce a revised set of consensus criteria for each of the major clinical syndromes of frontotemporal lobe degeneration. It is hoped that these new criteria will serve to highlight an important and neglected form of dementia and provide the impetus for clinical and basic scientific research.

Dementia↗

PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗

PubMed1998

Awareness of involuntary movements in Huntington disease.

OBJECTIVE: To determine why patients with Huntington disease are apparently unaware of their involuntary movements. DESIGN: Correlative study using a subjective report questionnaire of physical symptoms and objective measures of neurologic and cognitive dysfunction. PATIENTS: Forty patients with Huntington disease attending a regional Huntington disease clinic. RESULTS: Patients were poor at reporting experiential symptoms of involuntary movements. There was no relationship between self-report of these symptoms and objective indices of motor dysfunction or severity of cognitive impairment. Patients could, however, report secondary consequences of their movement disorder, which correlated highly with nonchoreic indices of motor dysfunction. CONCLUSIONS: Patients with Huntington disease have impaired subjective experience of chorea. Denial of symptoms is likely to have a physiological basis and is not a secondary consequence of patients' cognitive impairment or a psychological defense against a debilitating disease.

Adaptation, Psychological↗

PubMed1998

A clinical role for 99mTc-HMPAO SPECT in the investigation of dementia?

OBJECTIVES: To provide the clinician with a guide to the clinical utility of 99mTc-HMPAO single photon emission computed tomography (SPECT) and to the interpretation of specific test results in the differential diagnosis of dementia. METHODS: Three hundred and sixty three patients with dementia were studied prospectively for a median three (range 1-6) years and classified into disease groups on the basis of established clinical criteria. The degree to which different patterns of cerebral blood flow (CBF) abnormality found on 99mTc-HMPAO SPECT imaging at the time of initial patient presentation modified clinical diagnoses was determined by calculating the likelihood ratios for pairwise disease group comparisons. The optimal clinical usage of 99mTc-HMPAO SPECT was determined by calculating the percentage of significant test results for each pairwise disease group comparison. RESULTS: Bilateral posterior CBF abnormality was found to significantly increase the odds of a patient having Alzheimer's disease as opposed to vascular dementia or frontotemporal dementia. Bilateral anterior CBF abnormality significantly increased the odds of a patient having frontotemporal dementia as opposed to Alzheimer's disease, vascular dementia, or Lewy body disease. "Patchy" CBF changes significantly increased the odds of a patient having vascular dementia as opposed to Alzheimer's disease. Unilateral anterior, unilateral anterior plus unilateral posterior, and generalised CBF abnormality failed to contribute to the differentiation of any of these forms of dementia. CONCLUSIONS: 99mTc-HMPAO SPECT was found to be most useful in distinguishing Alzheimer's disease from vascular dementia and fronto temporal dementia, and least useful in differentiating between Alzheimer's disease and Lewy body disease, and between vascular dementia, frontotemporal dementia, and progressive aphasia. It is suggested that CBF SPECT should be used selectively and as an adjunct to clinical evaluation and CT.

Aged↗

PubMed1998

Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.

OBJECTIVE: To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration. METHODS: Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members. RESULTS: The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text. CONCLUSIONS: The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.

Dementia↗