Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes.

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.

Arithmetic knowledge in semantic dementia: is it invariably preserved?

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.

Emotion recognition in Huntington's disease and frontotemporal dementia.

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.

Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.

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.

Inferring thought and action in motor neurone disease.

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.

Accuracy of single-photon emission computed tomography in differentiating frontotemporal dementia from Alzheimer's disease.

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.

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia.

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.

Primary angiitis of the central nervous system: emerging variants.

BACKGROUND: Primary angiitis of the central nervous system (PACNS), a serious disease, has not featured prominently in the spectrum of multi-organ disease seen in vasculitis clinics. AIM: To evaluate the presentation, natural history and features of PACNS variants and compare to those of systemic vasculitides. DESIGN: Retrospective analysis. METHODS: Patients (n=105) presented during 1988-2003 to a tertiary regional vasculitis clinic receiving unselected disease types. Data were collected from a clinical database, patient and laboratory records. RESULTS: The frequency of PACNS presentation rose over the study period, compared with most of the other vasculitides. When PACNS was divided into small- and middle-sized vessel disease (SVD/MVD), their clinical courses differed substantially. SVD PACNS was responsive to immunosuppressive drugs, but relapsed during prolonged periods in all patients on maintenance immunosuppressives, or after withdrawal of treatment, causing recurrent, severe and irreversible CNS injury. MVD PACNS had isolated episodes at presentation, with a paucity of relapses during prolonged follow-up. DISCUSSION: Similarities between SVD PACNS and microscopic polyarteritis suggest the former may represent a limited form of the latter. MVD PACNS has a distinctly more benign relapse pattern than its multisystem counterpart polyarteritis nodosa. Acute-phase serology was useful in designating inflammatory processes at presentation of patients presenting with encephalopathy caused by SVD only, but were unhelpful in defining relapses in this form of PACNS, the definition of which in all cases rested on clinical assessment and MR scanning. Direct cerebral angiography was not diagnostic in any case of SVD PACNS; positive brain biopsy is diagnostically unequivocal, but the total clinical syndrome with imaging may establish a diagnosis with highest probability. In MVD PACNS, angiography with MR scan proved diagnostic. We suggest an algorithm for a rational, minimally invasive approach to investigation. In PACNS, SVD and MVD are important variants, and decisions about therapy should incorporate these distinctions.

The use of [99mTc]-HM-PAO in the diagnosis of primary degenerative dementia.

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.

Somatostatin-like immunoreactivity in lumbar cerebrospinal fluid from neurohistologically examined demented patients.

The concentration of somatostatin-like immunoreactivity (SLI) in lumbar cerebrospinal fluid was measured in clinically suspected examples of either Alzheimer's disease (AD) or Pick's disease and controls. No significant correlation was found between the concentration of SLI and the age (22-73 years) of controls. Histological examination of brain material from the demented patients enabled the samples to be divided into AD and examples of clinically suspected AD or Pick's disease without specific histological change. The mean concentration of SLI was only slightly reduced in patients with AD in the presenium compared to control, and was unaltered from control in the examples of AD of senile age. The group of demented patients without specific histological change had a reduced concentration of SLI in lumbar CSF compared to control patients.

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.

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.

Social cognition in frontotemporal dementia and Huntington's disease.

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.

Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease.

There is little information about major constituents of the brain in Alzheimer's disease. In the case of amino acids most of the previous data are contradictory. These have been interpreted in an anatomic and neurotransmitter as well as a metabolic context. To help clarify this, the contents of 14 amino acids and ethanolamine were determined in samples of neocortex from diagnostic craniotomies of 15 demented patients (10 with Alzheimer's disease) and other neurosurgical procedures (57 patients, 18 with intractable depression). A comprehensive survey of the effects of possible complicating factors on the concentrations of amino acids showed that artefacts were few; this was in contrast to a post mortem series of brains (16 with Alzheimer's disease and 16 controls; six regions assayed). We have used the ante mortem data to provide the basis for an accurate comparison of amino acid values between Alzheimer and control samples. In Alzheimer's disease, the mean contents of many amino acids were slightly higher (sum of the increases of those significantly affected was 15 nmol/mg protein) whereas glutamate content alone was significantly reduced (by 16 nmol/mg protein). This was not a feature of depression or a group of patients with other dementias. Glutamate content of Alzheimer samples was related to pyramidal neuron density in cortical layer III. These alterations were detected relatively early during the course of Alzheimer's disease and are considered to be due to loss of corticocortical glutamatergic association pathways.

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.

Mitochondrial function in brain tissue in primary degenerative dementia.

Previous in vitro and in vivo studies of the brain in Alzheimer's disease indicated alterations in metabolism related to energy production although the relationships between these changes remains obscure. To help resolve this issue, in vitro oxygen uptake by homogenates of fresh samples of frontal neocortex from patients with dementia and neurosurgical controls has been examined as a measure of energy-related metabolism and mitochondrial function. Maximal respiratory rates (measured in the presence of an uncoupling agent) were similar for samples from 7 controls, 5 patients with Alzheimer's disease and two patients diagnosed clinically as Pick's disease, suggesting that there was little or no effect of these dementias on the maximal metabolic capacity of the tissue. However, under some conditions producing sub-maximal metabolic activity (which are of potentially greater physiological relevance) oxygen uptake rates were significantly elevated in the dementia group. The ratio of oxygen uptake rates in the presence and absence of ADP was significantly reduced (to 58% of control; P less than 0.02) for the dementia patients compared with controls, possibly indicative of partial mitochondrial uncoupling. These results indicate metabolic changes expressed in vitro which may be relevant to the pathogenesis of Alzheimer's disease and some related dementias.

Amino acid release from biopsy samples of temporal neocortex from patients with Alzheimer's disease.

Tissue prisms prepared from neurosurgical samples of temporal neocortex of Alzheimer and control patients, upon depolarization preferentially released aspartate, glutamate and gamma-aminobutyrate (GABA). The Alzheimer and control samples did not significantly differ in the pattern of amino acid release, although acetylcholine synthesis by the Alzheimer tissue prisms was greatly reduced. There was no correlation between the efflux of any amino and acetylcholine synthesis. These observations suggest that in Alzheimer's disease there are no major changes in the extracellular concentrations of these putative amino acid transmitters.

Catecholaminergic neurones assessed ante-mortem in Alzheimer's disease.

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.

The contribution of single photon emission tomography to the clinical differentiation of degenerative cortical brain disorders.

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.

A 99mTc-HMPAO single-photon emission computed tomography study of Lewy body disease.

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.