Alzheimer Disease: Nestor PJ

Nestor PJ, Scheltens P, Hodges JR. · University Neurology Unit, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. · Nat Med. · Pubmed #15298007 No free full text.

Abstract: The combination of an aging population and the promise, possibly in the near future, of disease-modifying therapies have made the characterization of the early stages of Alzheimer's disease (AD) a topic of major research interest. In this article we review recent progress in our understanding of the evolution of early AD with particular reference to the symptomatic pre-dementia stage designated 'mild cognitive impairment', emphasizing work on the early cognitive profile and associated neuroimaging studies.

Pereira JM, Williams GB, Acosta-Cabronero J, Pengas G, Spillantini MG, Xuereb JH, Hodges JR, Nestor PJ. · Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK. · Neurology. · Pubmed #19433738 No free full text.

Abstract: OBJECTIVE: Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy. METHODS: Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed. RESULTS: The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy. CONCLUSIONS: While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.

Kipps CM, Nestor PJ, Acosta-Cabronero J, Arnold R, Hodges JR. · Cognitive Disorders Group, Wessex Neurological Centre, Southampton University NHS Trust, Southampton, UK. · Brain. · Pubmed #19126572 No free full text.

Abstract: Social interaction is profoundly affected in the behavioural form of frontotemporal dementia (bvFTD) yet there are few means of objectively assessing this. Diagnosis of bvFTD is based on informant report, however a number of individuals with a clinical profile consistent with the disease have no imaging abnormality and seem to remain stable, with doubt about the presence of underlying neurodegenerative pathology. We aimed to quantify aspects of the behavioural disorder and link it to the underlying level of atrophy in socially relevant brain regions. We tested individuals with either bvFTD (N = 26) or Alzheimer's disease (N = 9) and 16 controls using The Awareness of Social Inference Test (TASIT) to assess their ability to identify emotion and sarcasm in video vignettes. A subset of bvFTD patients (N = 21) and controls (N = 12) were scanned using MRI within 6 months of assessment. There was marked impairment in the ability of bvFTD patients whose scans showed abnormalities to recognize sarcastic, but not sincere statements. Their capacity to interpret negative emotion was also impaired, and this appeared to be a major factor underlying the deficit in sarcasm recognition. Clinically diagnosed bvFTD patients whose scans were normal, Alzheimer's disease patients and controls had no difficulty in appreciating both types of statement. In a multivariate imaging analysis it was shown that the sarcasm (and emotion recognition) deficit was dependent on a circuit involving the lateral orbitofrontal cortex, insula, amygdala and temporal pole, particularly on the right. Performance on a more global test of cognitive function, the Addenbrooke's Cognitive Examination did not have a unique association with these regions. The TASIT is an objective test of social dysfunction in bvFTD which indexes the frontotemporal volume loss in bvFTD patients and provides an objective measure for separating behavioural patients who are likely to decline from those who may remain stable. These results provide additional evidence for the role of the orbitofrontal cortex and related structures in the processing of socially relevant signals, particularly those where negative emotion recognition is important.

Ahmed S, Mitchell J, Arnold R, Dawson K, Nestor PJ, Hodges JR. · Medical Research Council, Cognition and Brain Sciences Unit, Addenbrooke's Hospital, Cambridge, UK. · Alzheimer Dis Assoc Disord. · Pubmed #18580592 No free full text.

Abstract: Complaints related to memory are characteristic of normal ageing, affective disorders, and are a cardinal feature of amnestic mild cognitive impairment (aMCI), the proposed prodrome to Alzheimer disease proper. The aim of this study was to investigate the profile of subjective memory complaints in different cognitive syndromes. Subjective memory was assessed using the Cambridge Memory Complaints Questionnaire consisting of 20 questions about everyday aspects of memory. This was completed by 22 "worried well" (WW), 85 aMCI, and 40 semantic dementia (SD) patients at first presentation to a memory clinic. All patients were followed up for 2 years. A principal component factor analysis revealed 5 principal factors pertaining to working, episodic, topographical, and semantic memory. All factors, except topographical memory, reliably differentiated SD patients from other groups, with aMCI and WW patients complaining significantly more about working and episodic memory, and SD patients complaining significantly more about semantic memory. WW and aMCI patients, however, could not be differentiated, even those aMCI patients who progressed to dementia. Memory complaints are strikingly similar to the description of typical core deficits in SD patients. The sole reliance on memory complaints for insight into memory functioning and diagnosing aMCI is problematic.

Pereira JM, Nestor PJ, Williams GB. · Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Neuroimage. · Pubmed #18342543 No free full text.

Abstract: This paper considers the effects of using magnetic resonance scans with different voxel dimensions in voxel-based morphometry studies. This is of potential relevance to many longitudinal studies or any ad-hoc study that relies on pre-existing databases of subjects. In order to study this effect, a group of controls were contrasted with a group of semantic dementia as well as with a group of Alzheimer's disease patients using a mixture of different voxel dimensions scans on each side of the statistical test. Scans were interpolated using a sinc function in order to obtain a different voxel depth. The effects were measured by comparing the output of each analysis to the benchmark in which all scans had the original depth (and highest resolution), both visually and through the computation of the root-mean-square error difference between the resulting t-maps. It was shown that the impact is highly dependent on the scan itself, with some images showing more robustness to the interpolation process, and hence yielding fewer differences. A measure of robustness is proposed, which may be used in order to understand the impact of mixing different dimensions or adjusting them for each scan. Indiscriminate use of voxel dimensions on both groups was found to produce more errors (false positives/false negatives) than does an approach involving the use of balanced groups and a voxel dimension nuisance covariate.

Ahmed S, Mitchell J, Arnold R, Nestor PJ, Hodges JR. · Medical Research Council, Cognition and Brain Sciences Unit, Cambridge, UK. · Dement Geriatr Cogn Disord. · Pubmed #18212499 No free full text.

Abstract: BACKGROUND/AIMS: We investigated whether an initial neuropsychological assessment could predict rapid progression over 12 months, from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). METHODS: A longitudinal study compared the neuropsychological profiles of 27 normal controls and 18 aMCI patients at baseline and 12 months. Results: At 12 months, 24 control subjects followed up remained cognitively normal. 7 aMCI patients (6 multiple-domain aMCI and 1 single-domain aMCI) progressed to AD, and 11 were non-progressors. Prognosis was best captured by a combination of associative learning, the paired associate learning task (PAL), and global cognition, the Addenbrooke's Cognitive Examination (ACE). CONCLUSION: The PAL and ACE can sensitively detect meaningful differences in scores at baseline and may be used as prognostic indicators. Multiple-domain aMCI patients progressed rapidly to AD and may be more usefully labelled as early stage AD.

Acosta-Cabronero J, Williams GB, Pereira JM, Pengas G, Nestor PJ. · Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK. · Neuroimage. · Pubmed #18065243 No free full text.

Abstract: This study evaluates the application of (i) skull-stripping methods (hybrid watershed algorithm (HWA), brain surface extractor (BSE) and brain-extraction tool (BET2)) and (ii) bias correction algorithms (nonparametric nonuniform intensity normalisation (N3), bias field corrector (BFC) and FMRIB's automated segmentation tool (FAST)) as pre-processing pipelines for the technique of voxel-based morphometry (VBM) using statistical parametric mapping v.5 (SPM5). The pipelines were evaluated using a BrainWeb phantom, and those that performed consistently were further assessed using artificial-lesion masks applied to 10 healthy controls compared to the original unlesioned scans, and finally, 20 Alzheimer's disease (AD) patients versus 23 controls. In each case, pipelines were compared to each other and to those from default SPM5 methodology. The BET2+N3 pipeline was found to produce the least miswarping to template induced by real abnormalities, and performed consistently better than the other methods for the above experiments. Occasionally, the clusters of significant differences located close to the boundary were dragged out of the glass-brain projections -- this could be corrected by adding background noise to low-probability voxels in the grey matter segments. This method was confirmed in a one-dimensional simulation and was preferable to threshold and explicit (simple) masking which excluded true abnormalities.

Mori T, Ikeda M, Fukuhara R, Sugawara Y, Nakata S, Matsumoto N, Nestor PJ, Tanabe H. · Department of Neuropsychiatry, Ehime University School of Medicine, Toon city, Ehime 791-0295, Japan. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #16311897 No free full text.

Abstract: We examined alteration of regional cerebral blood flow (rCBF) in a case of Alzheimer's disease (AD) patient with musical hallucination. To detect regions related to musical hallucination, single-photon emission computed tomography (SPECT) imaging of the patient and nine sex, age, and cognitive function-matched AD patients without delusions and hallucinations were compared using statistical parametric mapping 99 (SPM99). In comparison with controls, the patient had increased rCBF in left temporal regions and left angular gyrus. This profile could be relevant to the neuroanatomical basis of musical hallucinations.

Nestor PJ, Fryer TD, Hodges JR. · University of Cambridge, Neurology Unit, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. · Neuroimage. · Pubmed #16300967 No free full text.

Abstract: Semantic dementia (SD) and Alzheimer's disease (AD) are both disorders in which early pathology affects the temporal lobe yet they produce distinct syndromes of declarative memory impairment-loss of established semantic knowledge with relatively preserved episodic memory in the former and the converse in the latter. Groups with mild SD and mild AD who showed a double dissociation in these two aspects of declarative memory were studied-the SD group's episodic memory and the AD group's semantic knowledge each being comparable to controls. Positron emission tomography and volumetric magnetic resonance imaging were used to map deficits in regional cerebral metabolic rate and mesial temporal lobe (MTL) atrophy, respectively. Episodic memory impairment in AD was associated with dysfunction of an integrated network (mesial temporal lobe, mamillary bodies, dorso-mesial thalamus and posterior cingulate). Semantic memory impairment in SD was associated with bilateral rostral temporal lobe hypometabolism. The SD group had comparable MTL atrophy and hypometabolism to that found in AD but the remainder of their limbic-diencephalic network was preserved suggesting that the latter explains their ability to acquire new episodic memories. The results challenge the view that amnesia in early AD can be explained by the degree of MTL damage alone while showing that semantic impairment can occur with damage restricted to the rostral temporal lobes.

Nestor PJ, Fryer TD, Ikeda M, Hodges JR. · University of Cambridge, Neurology Unit, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. · Eur J Neurosci. · Pubmed #14622168 No free full text.

Abstract: Previous group studies using positron emission tomography to assess resting cerebral glucose metabolism in very early Alzheimer's disease and mild cognitive impairment have identified the posterior cingulate and adjacent cingulo-parietal cortex as the first isocortical area to develop hypometabolism. We studied the profile of resting cerebral glucose metabolism in individuals with mild cognitive impairment to assess whether more specific and stereotyped regional hypometabolism would be evident across subjects. The study found that the most consistently hypometabolic region between individual subjects was a subregion of the posterior cingulate, the retrosplenial cortex (BA 29/30). This result is discussed in the context of regional connectivity, focal lesion evidence and functional activation studies of episodic memory paradigms in both normal and Alzheimer's disease groups. We propose that the retrosplenial cortex may represent a key junction between prefrontal areas involved in implementing retrieval strategies for episodic memory and hippocampal-based mnemonic processing; we therefore interpret the retrosplenial hypometabolism as a probable contributor to the memory impairment seen in mild cognitive impairment by disconnecting these two anatomical networks.

Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. · University of Cambridge, Neurology Unit, Addenbrooke's Hospital, Cambridge, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #14617709 links to  free full text

Abstract: BACKGROUND: The term "posterior cortical atrophy" (PCA) refers to a clinical syndrome in which higher order visual processing is disrupted owing to a neurodegenerative disorder, the most commonly associated pathology being Alzheimer's disease. OBJECTIVE: To map the topography of hypometabolic brain regions in a group of subjects with PCA who had undergone detailed neuropsychological characterisation. METHODS: Resting cerebral metabolism was measured with ((18)F)fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with PCA (n = 6), typical Alzheimer's disease (n = 10), and healthy controls (n = 10). The data were analysed using statistical parametric mapping (SPM99) and region of interest techniques. RESULTS: Clinically, the PCA subjects showed predominant visuospatial deficits (including features of Balint's syndrome) consistent with damage to the dorsal stream of visual processing. Compared with the controls, the PCA group showed marked glucose hypometabolism primarily affecting the posterior cerebral hemispheres (right worse than left). In addition, the PCA group showed two symmetrical areas of hypometabolism in the region of the frontal eye fields. Compared with typical Alzheimer's disease, the PCA group had selective hypometabolism in the occipito-parietal region (right much worse than left). CONCLUSIONS: The neuropsychological and PET findings are consistent with damage predominantly to the dorsal stream of visual processing. Frontal eye field hypometabolism secondary to loss of input from the occipito-parietal region may be the mechanism for the ocular apraxia seen in Balint's syndrome.

Nestor PJ, Fryer TD, Smielewski P, Hodges JR. · University of Cambridge, Neurology Unit, Cambridge, United Kingdom. · Ann Neurol. · Pubmed #12953266 No free full text.

Abstract: The neural basis of the amnesia characterizing early Alzheimer's disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.

Nestor PJ, Graham NL, Fryer TD, Williams GB, Patterson K, Hodges JR. · University of Cambridge, Neurology Unit, Addenbrooke's Hospital, UK. · Brain. · Pubmed #12902311 links to  free full text

Abstract: Progressive non-fluent aphasia (PNFA) is a syndrome in which patients lose the ability to communicate fluently in the context of relative preservation of single word comprehension and non-linguistic cognitive abilities. Neuroimaging in case studies with PNFA has failed to identify a consistent neural substrate for the language disorder. In this study of a group of patients (n=10) whose presenting complaint was progressive dysfluency, resting cerebral metabolism was measured using [18F]fluorodeoxyglucose-PET and analysed with the technique of statistical parametric mapping (SPM). Regional atrophy was assessed with voxel-based morphometry (VBM). Seven patients had a 'pure' PNFA syndrome, while the remaining three had additional features of a more pervasive dementia. Compared with controls, the patients showed hypometabolism in several regions that, most notably, included the left anterior insula/frontal opercular region. The VBM analysis revealed only one small area of atrophy in the left peri-Sylvian region. Analysis of the pure PNFA cases (n=7) relative to controls yielded qualitatively similar results to those of the whole group, suggesting that these cases were also at risk of a more generalized dementia, a finding borne out in subsequent follow-up of two cases to date. The PNFA group was then compared with a group with Alzheimer's disease (n=10) whose clinical profile did not include non-fluent aphasic features. In this analysis, the only persisting hypometabolic region was that centred over the left anterior insula. VBM did not identify any regional differences in atrophy between PNFA and Alzheimer's disease. In the light of current theories of fluent language production, the findings offer anatomical evidence that the breakdown in fluency is due to a motor articulatory planning deficit (speech apraxia) combined with a variable degree of agrammatism.

Nestor PJ, Graham KS, Bozeat S, Simons JS, Hodges JR. · Addenbrooke's Hospital, University of Cambridge Neurology Unit, Box 165, Cambridge CB2 2QQ, UK. · Neuropsychologia. · Pubmed #11792404 No free full text.

Abstract: Studies of autobiographical memory in semantic dementia have found relative preservation of memories for recent rather than remote events. As semantic dementia is associated with progressive atrophy to temporal neocortex, with early asymmetric sparing of the hippocampus, this neuropsychological pattern suggests that the hippocampal complex plays a role in the acquisition and retrieval of recent memories, but is not necessary for the recall of older episodic events. In an alternative view of memory consolidation, however, the hippocampus plays a role in the retrieval of all autobiographical memories, regardless of the age of the memory [Curr. Opin. Neurobiol. 7(1997)217]. This 'multiple trace theory' predicts that patients with semantic dementia should show no effects of time in their autobiographical recall. In this article, we ask whether it is possible to reconcile the data from semantic dementia with the multiple trace theory by investigating whether the time-dependent pattern of autobiographical retrieval seen in the disease is due to (i) patients showing this effect being exceptional in their presentation; and/or (ii) patients with semantic dementia exhibiting impaired strategic retrieval from concomitant frontal damage. A series of experiments in patients with semantic dementia, the frontal variant of frontotemporal dementia and Alzheimer's disease clearly demonstrates that neither of these two factors can explain the documented effect of time seen in semantic dementia. Nonetheless, we discuss how damage to semantic knowledge could result in an autobiographical memory deficit and suggest that data from semantic dementia may be consistent with both views of hippocampal involvement in long-term memory.

Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, Hodges JR. · University of Cambridge Neurology Unit, Addenbrooke's Hospital, UK. · Neurology. · Pubmed #11113213 No free full text.

Abstract: OBJECTIVES: To validate a simple bedside test battery designed to detect mild dementia and differentiate AD from frontotemporal dementia (FTD). METHODS: Addenbrooke's Cognitive Examination (ACE) is a 100-point test battery that assesses six cognitive domains. Of 210 new patients attending a memory clinic, 139 fulfilled inclusion criteria and comprised dementia (n = 115) and nondementia (n = 24) groups. The composite and the component scores on the ACE for the two groups were compared with those of 127 age- and education-matched controls. Norms and the probability of diagnosing dementia at different prevalence rates were calculated. To evaluate the ACE's ability to differentiate early AD from FTD, scores of the cases diagnosed with dementia with a Clinical Dementia Rating < or = 1 (AD = 56, FTD = 24, others = 20) were compared. RESULTS: Two cut-off values for the ACE composite score (88 and 83) were of optimal utility depending on the target population. The ACE had high reliability, construct validity, and sensitivity (93%, using 88 as cut-off). Using the lower cut-off of 83, the ACE had a higher sensitivity (82%) and predictive value than the Mini-Mental State Examination for a wide range of dementia prevalence. The ACE differentiated AD from FTD, and the VLOM ratio (derived using component scores: [verbal fluency + language]/[orientation + memory]) of <2.2 for FTD and >3.2 for AD was highly discriminating. CONCLUSION: The ACE is a brief and reliable bedside instrument for early detection of dementia, and offers a simple objective index to differentiate AD and FTD in mildly demented patients.