RESUMEN
INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Autofagosomas/metabolismo , Catepsina D/metabolismo , Degeneración Lobar Frontotemporal/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Lisosomas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. METHODS: Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). RESULTS: Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells. CONCLUSION: Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP-43 are more likely to be the cause of this.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/patología , Enfermedad de la Neurona Motora/patología , Degeneración Nerviosa/patología , Proteínas/genética , Anciano , Proteína C9orf72 , Expansión de las Repeticiones de ADN , Dipéptidos , Femenino , Degeneración Lobar Frontotemporal/genética , Humanos , Inmunohistoquímica , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/genética , Degeneración Nerviosa/genética , Neuronas/patologíaRESUMEN
AIMS: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). METHODS: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. RESULTS: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. CONCLUSIONS: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
Asunto(s)
Degeneración Lobar Frontotemporal/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Factores Asociados con la Proteína de Unión a TATA/metabolismo , beta Carioferinas/metabolismo , Adulto , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
There is accumulating evidence of preserved arithmetic knowledge in semantic dementia (SD), contrasting with patients' striking impairment in other domains of semantic memory. This important finding exemplifies domain specificity in the breakdown of semantic memory and supports notions of the functional independence of semantic number knowledge. Nevertheless, evidence for preserved arithmetic knowledge in SD comes largely from single case studies. It is not known whether such preservation is a universal finding, or whether it persists irrespective of disease severity. The present study examined performance of 14 SD patients, varying in the severity of their semantic impairment, on tasks assessing knowledge of arithmetic signs, and on single-digit and multi-digit calculation problems, permitting evaluation of fact retrieval and use of procedures. SD patients performed generally well compared to 10 healthy controls on tests of addition and subtraction. However, abnormalities were elicited, which were not explained by education or hemispheric side of atrophy, but increased as a function of semantic severity. Patients had difficulty identifying arithmetic signs. They used increasingly basic, inflexible strategies to retrieve multiplication table 'facts', and in multi-digit calculations they made procedural errors that pointed to a failure to understand the differential weighting of left and right hand columns. The pattern of responses and error types mirrors in reverse that found in children as they acquire arithmetic competence, and suggests a progressive degradation in conceptual understanding of arithmetic. Longitudinal study of two SD patients demonstrated an association between semantic decline and impaired arithmetic performance. The findings challenge the notion of arithmetic knowledge as a totally separate semantic domain and suggest that the temporal lobes play an important role in arithmetic understanding.
Asunto(s)
Demencia/fisiopatología , Conocimiento , Matemática , Semántica , Anciano , Anciano de 80 o más Años , Atrofia/etiología , Comprensión/fisiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Estadísticas no ParamétricasRESUMEN
A well-documented feature of Huntington's disease (HD) is disproportionate impairment in the ability to recognise the emotional expression of disgust. However, this finding has been challenged by studies that report no differential disgust impairment and attribute apparent differences across emotions to task difficulty. The present study sought to shed light on disparities in findings through a comparative study of emotion recognition in HD and frontotemporal dementia (FTD). Ten HD, 12 FTD patients and 12 healthy controls were administered 10 tasks assessing facial and vocal recognition of emotions and comprehension of emotion terms. The findings were not consistent with either the 'selective disgust impairment' or 'task difficulty' view. Both HD and FTD groups were impaired compared to controls, deficits in HD being less severe. Impairments in FTD were elicited for all emotions whereas in HD they were demonstrated predominantly for negative emotions of fear, disgust and anger. Consistency in performance, despite varying task demands, excluded an explanation in terms of item difficulty, and was in keeping with the notion of distinct neural substrates for processing of negative emotions. Contrary to the notion of disproportionate disgust impairment, the most severe deficits in HD were elicited for anger, a finding that may have relevance for the poor anger control that is the hallmark of HD. The data raise the possibility that linguistic influences and conceptual complexities of the emotion of disgust may contribute to the variable finding of selective disgust impairment in HD.
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Demencia/fisiopatología , Emociones/fisiología , Enfermedad de Huntington/fisiopatología , Reconocimiento en Psicología/fisiología , Adulto , Anciano , Conducta de Elección/fisiología , Expresión Facial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología , Estadísticas no ParamétricasRESUMEN
Foreign accent syndrome (FAS) is a rare speech disorder characterised by the emergence of a new accent, perceived by listeners as foreign. FAS has usually been described following focal brain insults, such as stroke. We describe the unusual case of a woman presenting with FAS as the earliest symptom of progressive degenerative brain disease. At presentation, she showed no language or other cognitive impairment, and functional and structural brain imaging were normal. Follow-up 1 year later revealed the emergence of mild expressive language problems. Repeat functional neuroimaging showed mild hypoperfusion of the perisylvian speech area of the left hemisphere, and structural imaging showed mild left perisylvian atrophy. We interpret the case as an unusual presentation of primary progressive non-fluent aphasia. The case provides further evidence of the variable and circumscribed nature of the clinical presentation of focal cerebral degeneration.
Asunto(s)
Afasia Progresiva Primaria/patología , Encéfalo/patología , Fonética , Medición de la Producción del Habla , Conducta Verbal , Anciano , Afasia Progresiva Primaria/diagnóstico , Atrofia/diagnóstico por imagen , Atrofia/patología , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Degeneración Nerviosa/patología , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
RATIONALE: Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). OBJECTIVES: To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. MATERIALS AND METHODS: Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. RESULTS: In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. CONCLUSIONS: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.
Asunto(s)
Demencia/metabolismo , Lóbulo Frontal/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Serotonina/metabolismo , Lóbulo Temporal/metabolismo , Anciano , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Colina O-Acetiltransferasa/metabolismo , Demencia/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Parietal/metabolismo , Lóbulo Parietal/patología , Cambios Post Mortem , Receptor Muscarínico M1/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Ácido Kaínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estudios Retrospectivos , Lóbulo Temporal/patología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
The traditional assumption that classical motor neurone disease (MND) invariably spares cognitive function is now recognised to be incorrect. Deficits have most commonly been demonstrated on executive tasks suggesting impaired function of frontal systems. Yet, crucial aspects of frontal lobe function have not hitherto been explored. The study used tests of theory of mind (ToM) (interpretation of cartoons and stories) to examine the ability of 16 patients with MND to interpret social situations and ascribe mental states to others. Only minor differences were elicited in the MND group as a whole compared to controls, and performance was not differentially affected for cartoons and stories requiring inference of another's mental state (mental) compared to control (physical) cartoons and stories. However, abnormalities were elicited on both mental and physical tasks in a subgroup of patients with bulbar signs. Moreover, examination of individual patient scores revealed a spectrum of performance ranging from normal to severely impaired. Errors were qualitatively similar to those seen in frontotemporal dementia (FTD). Performance on the ToM tasks was significantly correlated with conventional, untimed measures of executive function, suggesting that ToM deficits in MND are likely to be linked to a more general executive failure. The findings contribute to the understanding of ToM performance in neurodegenerative disease and provide further evidence of the association between MND and FTD.
Asunto(s)
Enfermedad de la Neurona Motora/psicología , Anciano , Cognición/fisiología , Estudios de Cohortes , Demencia/psicología , Femenino , Humanos , Enfermedad de Huntington/psicología , Lenguaje , Masculino , Memoria/fisiología , Procesos Mentales/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Percepción Social , Percepción Espacial/fisiología , Ingenio y Humor como Asunto/psicologíaRESUMEN
BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the commonest causes of presenile dementia. In the absence of a biological marker, diagnosis is reliant on clinical evaluation. Confirmation is often sought from neuroimaging, including single-photon emission computed tomography (SPECT). Most previous SPECT studies lack pathological validation. AIM: To examine the accuracy of SPECT in differentiating FTD from AD in patients with subsequent pathological confirmation. METHODS: Technetium-99-labelled hexamethyl propylene amine oxime SPECT images obtained at initial evaluation in 25 pathologically confirmed cases of FTD were examined. These images were visually rated by an experienced blinded nuclear medicine consultant and compared with those of 31 patients with AD, also with pathological validation. RESULTS: A reduction in frontal cerebral blood flow (CBF) was more common in FTD and was of diagnostic value (sensitivity 0.8, specificity 0.65 and likelihood ratio (LR) 2.25; 95% CI 1.35 to 3.77). A pattern of bilateral frontal CBF reduction without the presence of associated bilateral parietal CBF change is diagnostically more accurate (sensitivity 0.80, specificity 0.81 and +LR 4.13, 95% CI 1.96 to 8.71). Diagnostic categorisation (FTD or AD) on the basis of SPECT alone was less accurate than clinical diagnosis (based on neurology and detailed neuropsychological evaluation). One patient with FTD was initially clinically misdiagnosed as AD, owing to the lack of availability of full neuropsychological assessment. However, SPECT correctly diagnosed this patient, providing a diagnostic gain of 4%. CONCLUSION: Technetium-99-labelled hexamethyl propylene amine oxime SPECT CBF patterns provide valuable information in the diagnosis of FTD and AD. These data can be better used as an adjunct to clinical diagnosis if pathology is to be correctly predicted in life.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Demencia/diagnóstico por imagen , Anciano , Encéfalo/irrigación sanguínea , Diagnóstico Diferencial , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos , Flujo Sanguíneo Regional , Estudios Retrospectivos , Sensibilidad y Especificidad , Exametazima de Tecnecio Tc 99m , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.
Asunto(s)
Afasia de Broca/genética , Demencia/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Anciano , Afasia de Broca/metabolismo , Afasia de Broca/patología , Afasia de Broca/psicología , Mapeo Encefálico/métodos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Demencia/metabolismo , Demencia/patología , Demencia/psicología , Progresión de la Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Linaje , Progranulinas , Lóbulo Temporal/metabolismo , Tomografía Computarizada de Emisión de Fotón Único , Ubiquitina/metabolismoRESUMEN
The clinical value of single photon emission computed tomography (SPECT) in the differential diagnosis of dementia due to cerebral atrophy was evaluated by comparing the pattern of distribution [99mTc]-HM-PAO in three dementing conditions. Imaging was carried out in 26 patients with suspected Alzheimer's disease, 14 with dementia of the frontal-lobe type, and 13 with progressive supranuclear palsy. Images were evaluated and reported without knowledge of clinical diagnosis with respect to regions of reduced uptake of tracer. Reduced uptake in the posterior cerebral hemispheres was characteristic of Alzheimer's disease, while selective anterior hemisphere abnormalities characterized both dementia of the frontal-lobe type and progressive supranuclear palsy. The latter conditions could be distinguished on the basis of the appearance of integrity of the rim of the frontal cortex. The technique has an important role in the differentiation of degenerative dementias.
Asunto(s)
Demencia/diagnóstico por imagen , Compuestos Organometálicos , Oximas , Tecnecio , Anciano , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Exametazima de Tecnecio Tc 99m , Tomografía Computarizada de EmisiónRESUMEN
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.
Asunto(s)
Adaptación Psicológica , Corea/fisiopatología , Enfermedad de Huntington/psicología , Adolescente , Adulto , Anciano , Cognición , Negación en Psicología , Femenino , Humanos , Enfermedad de Huntington/fisiopatología , Masculino , Persona de Mediana Edad , Percepción , AutoimagenRESUMEN
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.
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Demencia/diagnóstico , Demencia/patología , Lóbulo Frontal/patología , Lóbulo Temporal/patología , HumanosRESUMEN
Frontotemporal dementia (FTD) and Huntington's disease (HD) are degenerative disorders, with predominant involvement, respectively of frontal neocortex and striatum. Both conditions give rise to altered social conduct and breakdown in interpersonal relationships, although the factors underlying these changes remain poorly defined. The study used tests of theory of mind (interpretation of cartoons and stories and judgement of preference based on eye gaze) to explore the ability of patients with FTD and HD to interpret social situations and ascribe mental states to others. Performance in the FTD group was severely impaired on all tasks, regardless of whether the test condition required attribution of a mental state. The HD group showed a milder impairment in cartoon and story interpretation, and normal preference judgements. Qualitative differences in performance were demonstrated between groups. FTD patients made more concrete, literal interpretations, whereas HD patients were more likely to misconstrue situations. The findings are interpreted as demonstrating impaired theory of mind in FTD, as one component of widespread executive deficits. In HD the evidence does not suggest a fundamental loss of theory of mind, but rather a tendency to draw faulty inferences from social situations. It is concluded that social breakdown in FTD and HD may have a different underlying basis and that the frontal neocortex and striatum have distinct contributions to social behaviour.
Asunto(s)
Cognición , Demencia/psicología , Enfermedad de Huntington/psicología , Percepción Social , Demencia/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Conducta Social , Lóbulo Temporal/patologíaRESUMEN
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.
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Demencia/clasificación , Lóbulo Frontal/patología , Lóbulo Temporal/patología , Anciano , Afasia , Demencia/diagnóstico , Demencia/psicología , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/clasificación , Enfermedad de la Neurona Motora/diagnóstico , MutaciónRESUMEN
Indices of dopaminergic and noradrenergic varicosities were assayed in neocortical tissue obtained at diagnostic craniotomy from patients with Alzheimer's disease in the presenium. Dopaminergic markers (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not significantly different from controls in either frontal or temporal cortex. In the frontal cortex, the release of endogenous dopamine and noradrenaline (in the presence of both resting and stimulating concentrations of potassium) was also unaffected whereas release of endogenous serotonin was significantly reduced. In the temporal cortex, noradrenergic markers (concentration of noradrenaline and uptake of radiolabelled noradrenaline) were significantly reduced, to at least 47% of mean control values. These deficits are interpreted as reflecting denervation and were present in patients examined only some two years after developing symptoms of dementia. The ratio of 3-methoxy-4-hydroxyphenylglycol to noradrenaline (a putative index of noradrenaline turnover) was elevated in the temporal cortex, suggesting increased activity of the remaining noradrenergic varicosities. Noradrenergic markers did not correlate with either clinical or histological indices of the severity of the disease which contrasts with presynaptic cholinergic and serotonergic markers.
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Enfermedad de Alzheimer/metabolismo , Catecolaminas/metabolismo , Corteza Cerebral/metabolismo , Adulto , Anciano , Corteza Cerebral/patología , Colina O-Acetiltransferasa/análisis , Trastornos del Conocimiento/metabolismo , Dopamina/metabolismo , Femenino , Ácido Homovanílico/análisis , Humanos , Técnicas In Vitro , Masculino , Metoxihidroxifenilglicol/análisis , Persona de Mediana Edad , Norepinefrina/metabolismo , Serotonina/metabolismoRESUMEN
The accurate clinical diagnosis of degenerative cortical brain disorders is a necessary prerequisite for patient management and the critical evaluation of new treatments. This study has evaluated the ability of single photon emission tomography (SPET) to differentiate between Alzheimer's disease (AD) and different forms of non-Alzheimer lobar atrophy (LA), using a multi-purpose system in widespread routine clinical use. 99mTc-HMPAO SPET was carried out in patients with AD and three clinical syndromes associated with LA: frontotemporal dementia (FTD), progressive non-fluent aphasia (PA) and semantic dementia (SD). Principal component (PC) analysis was performed on regional cerebral blood flow (rCBF) data and inter-group comparisons were performed for PC scores using multiple t-tests. Three PCs explained 86.5% of the variation in rCBF values between individual patients and normal controls. The first PC reflected the average rCBF value and separated patient groups from normal controls but failed to distinguish between patient groups. The second PC reflected anterior-posterior asymmetry and separated AD from all three forms of LA. This PC also separated FTD and SD from controls but failed to distinguish between FTD, PA and SD. The third PC reflected left-right asymmetry and separated PA from all other groups. 99mTc-HMPAO SPET is able to differentiate between degenerative cortical brain disorders in a simple and physiological meaningful way, thereby showing considerable potential as a routine tool in the clinical evaluation and differentiation of AD and LA.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Demencia/diagnóstico por imagen , Lóbulo Frontal/patología , Degeneración Nerviosa/fisiología , Lóbulo Temporal/patología , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Atrofia , Estudios de Casos y Controles , Circulación Cerebrovascular/fisiología , Diagnóstico Diferencial , Femenino , Lóbulo Frontal/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Temporal/diagnóstico por imagenRESUMEN
The purpose of this study was to investigate patterns of 99mTc-HMPAO single-photon emission computed tomography (SPECT) abnormality in Lewy body disease (LBD) and to compare findings with those encountered in Alzheimer's disease (AD). The study group comprised 20 consecutive patient referrals fulfilling clinical criteria for LBD. All patients had fluctuating cognitive impairment and 'subcortical' dysfunction with or without perceptuospatial and/or linguistic impairment. Six patients had asymmetrical signs of parkinsonism (three left-sided and three right-sided), and 14 patients had symmetrical features of extrapyramidal involvement. 99mTc-HMPAO SPECT imaging was performed on LBD patients and findings compared with those of 57 patients with 'probable' AD and 11 normal age-matched controls. Within the LBD and AD groups, patterns of cortical and subcortical blood-flow abnormality were compared with patterns of cognitive and neurological breakdown. LBD was associated with bilateral posterior cortical blood flow abnormality, a pattern strikingly similar to that found in AD. Within the LBD group, cortical blood-flow abnormality was found to reflect patterns of neurological dysfunction (parkinsonism) indicative of subcortical involvement. In contrast, cortical blood-flow changes did not reflect patterns of neuropsychological impairment suggestive of cortical dysfunction. Within the AD group, cortical blood-flow changes were mirrored by the pattern of neuropsychological impairment. Findings support the notion that cortical blood-flow abnormality in LBD might reflect a combination of direct cortical pathology and cortical deafferentation secondary to subcortical Lewy body pathology. It would appear that 99mTc-HMPAO SPECT imaging is of limited value in the clinical differentiation of LBD and AD.
Asunto(s)
Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Enfermedad de Alzheimer , Análisis de Varianza , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Organotecnecio , Oximas , Exametazima de Tecnecio Tc 99mRESUMEN
The brain of a 61-year-old patient with familial Alzheimer's disease, showing a missense (valine----glycine) mutation at codon 717 of the amyloid precursor gene, has been examined at postmortem. Sections of brain showed pathological features entirely typical of Alzheimer's disease with no unusual characteristics. It seems therefore that this particular mutation is indeed pathogenic and that the altered amyloid precursor protein resulting from expression of this mutation is processed in a way that triggers or promotes the pathological cascade of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patología , Adulto , Enfermedad de Alzheimer/genética , Codón , Femenino , Humanos , Mutación , Vías Nerviosas/citología , Vías Nerviosas/fisiologíaRESUMEN
Apolipoprotein E (ApoE) genotype was determined by polymerase chain reaction amplification and restriction digestion of DNA extracted from brain tissues of 26 patients with clinically diagnosed and pathologically verified lobar atrophy (LA) and from blood of a further 22 patients with clinical LA. Brain tissue from 50 patients with pathologically confirmed Alzheimer's disease (AD) was also examined. As has been previously reported, the ApoE E4 allele frequency was significantly increased in AD. However, no change in the frequency of ApoE alleles was found in two of the clinical and pathological forms of LA (dementia of frontal type and dementia of frontal type with motor neurone disease) although the ApoE E4 allele frequency was elevated in cases of non-fluent progressive aphasia in accordance with the presence of coincidental Alzheimer-type pathological changes.