Biomedical subjects

John R Hodges

Publications and source records attributed to John R Hodges.

At least 19 recordsLinked to original sources

PubMed2006

The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia.

Structural brain imaging and neuropsychological data implicate the orbital aspects of prefrontal cortex in the developing neuropathology of fvFTD. Damage to this region is associated with deficient performance on laboratory tasks assessing theory of mind (ToM) and affective decision-making (DM), but the relationship between these two capacities in patients with prefrontal cortex dysfunction is unclear. We studied a group of patients with early/mild fvFTD (n=20) and a group of matched normal controls (n=10) on the Iowa gambling task (IGT) of affective decision-making, and the "reading the mind in the eyes" (MIE) and "faux pas" (FP) tests of ToM. The fvFTD group was impaired in both ToM tasks and the IGT. While performance measures from the two ToM tasks were significantly correlated, they were not associated with IGT performance. This suggests that whilst similar prefrontal circuitry is implicated in ToM and DM tasks, these cognitive domains may be independent. In clinical settings, the IGT may be useful as a complementary tool to the frontal test battery for patients with early/mild fvFTD. Deficits in decision-making and ToM observed in this study have distinct but additive effects upon the development of social behaviour in patients with prefrontal dysfunction.

Aged↗

PubMed2006

Differentiating the roles of the hippocampus and perirhinal cortex in processes beyond long-term declarative memory: a double dissociation in dementia.

There is increasing evidence to suggest that the hippocampus and perirhinal cortex may mediate processes beyond long-term declarative memory. We assessed patients with Alzheimer's disease (AD) or semantic dementia (SD) on a visual oddity judgment task that did not place an explicit demand on long-term memory and is known to be sensitive to hippocampal and perirhinal cortex lesions. Importantly, within the medial temporal lobe, AD is associated with predominant hippocampal atrophy, whereas SD patients have greater perirhinal cortex damage. The AD group was selectively impaired in oddity judgment for scenes, whereas the SD patients demonstrated a deficit in face oddity judgment only. This compelling double dissociation supports the idea that the hippocampus and perirhinal cortex may be critical for the processing of scenes and objects, respectively, in the domain of perception or very short-term working memory.

Aged↗

PubMed2006

Evolution of cognitive deficits and conversion to dementia in patients with mild cognitive impairment: a very-long-term follow-up study.

Ten patients with mild cognitive impairment (MCI) underwent extensive neuropsychological evaluation at 12-monthly intervals for a minimum of 6 years. All 10 patients declined and 5 have now died. The onset of dementia, as defined by a fall in global cognitive function (MMSE <24) or activities of daily living (Clinical Dementia Rating Scale; CDR) ranged from 1 to 8 years with generally good concordance between these measures. The rate of decline on the MMSE was highly variable ranging from 0.86 to 2.83 points per year. Other than a consistent impairment on tests of episodic memory and category fluency (8 out of 10), other early cognitive deficits were difficult to define and tended to be unstable in the early stages. Impairment of semantic memory, visuo-spatial and attentional abilities eventually developed but the sequence of deficit acquisition was heterogeneous. These findings are discussed in the light of current views of MCI. Amnestic MCI may not be an accurate concept unless semantic memory impairment is also considered as an integral core deficit. Full-blown dementia may take many years to develop in patients with MCI but was a universal feature in this study.

Activities of Daily Living↗

PubMed2006

Mild cognitive impairment: applicability of research criteria in a memory clinic and characterization of cognitive profile.

BACKGROUND: We explored the applicability of recently proposed research criteria for mild cognitive impairment (MCI) in a memory clinic and changes in case definition related to which memory tests are used and the status of general cognitive function in MCI. METHOD: A total of 166 consecutive GP referrals to the Cambridge Memory Clinic underwent comprehensive neuropsychological and psychiatric evaluation. RESULTS: Of 166 cases, 42 were excluded (significant depression 8, established dementia 29 and other disorders 5). Of 124 non-demented, non-depressed patients, 72 fulfilled Petersen's criteria for amnestic MCI based upon verbal memory performance [the Rey Auditory Verbal Learning Test (RAVLT)] and 90 met criteria if performance on verbal and/or non-verbal memory tests [the Rey figure recall or the Paired Associates Learning test (PAL)] was considered. Of the 90 broadly defined MCI cases, only 25 had pure amnesia: other subtle semantic and/or attention deficits were typically present. A further 12 were classed as non-amnestic MCI and 22 as 'worried well'. CONCLUSIONS: Definition of MCI varies considerably dependent upon the tests used for case definition. The majority have other cognitive deficits despite normal performance on the Mini-mental State Examination (MMSE) and intact activities of daily living (ADL) and fit within multi-domain MCI. Pure amnesic MCI is rare.

Aged↗

PubMed2006

Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging.

OBJECTIVE: To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI). DESIGN: Patients were enrolled into this prospective cohort study over a period of 15 years; cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. SETTING: Regional early-onset dementia clinic. PARTICIPANTS: Thirty-one participants diagnosed clinically with behavioral-variant FTD. Intervention Rating of MRIs. MAIN OUTCOME MEASURES: Death or institutionalization after a minimum of 3 years' follow-up indicated poor prognosis, while the ability to live independently was regarded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis. RESULTS: Patients with normal or borderline MRI findings (n = 15) showed significantly longer survival to institutionalization or death than those (n = 16) with definite frontotemporal atrophy (mean +/- SE, 9.3 +/- 1.7 years vs 3.0 +/- 0.7 years; P<.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not. CONCLUSIONS: Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.

Aged↗

PubMed2006

Clinical and pathological characterization of progressive aphasia.

OBJECTIVE: The clinical and neuropathological categorization of patients presenting with progressive aphasia is an area of controversy. This study aimed to characterize a large group of progressive aphasic patients from a single center (n = 38), first clinically by case note review, and then pathologically. METHODS: Hierarchical cluster analysis of the cases according to their clinical language deficits was used to establish an unbiased, data-driven classification. RESULTS: This analysis revealed two groups of cases corresponding to the syndromes of progressive nonfluent aphasia (n = 23) and semantic dementia (n = 15). Postmortem analysis showed a majority in both groups of pathologies from the spectrum of frontotemporal lobar degeneration: the most frequent were non-Alzheimer's disease (AD) tauopathy in the nonfluent cases (10 of 23) and frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions in the fluent cases (8 of 15). Despite rigorous exclusion of cases with clinically significant memory deficits or other cognitive impairments, the pathology of AD was present in approximately one third of each group (overall 12 of 38), although often with an atypical neuroanatomical distribution. INTERPRETATION: Progressive aphasia is best seen as a composite of two conditions, on both clinical and pathological levels: progressive nonfluent aphasia and semantic dementia.

Alzheimer Disease↗

PubMed2006

The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening.

UNLABELLED: There is a clear need for brief, but sensitive and specific, cognitive screening instruments as evidenced by the popularity of the Addenbrooke's Cognitive Examination (ACE). OBJECTIVES: We aimed to validate an improved revision (the ACE-R) which incorporates five sub-domain scores (orientation/attention, memory, verbal fluency, language and visuo-spatial). METHODS: Standard tests for evaluating dementia screening tests were applied. A total of 241 subjects participated in this study (Alzheimer's disease=67, frontotemporal dementia=55, dementia of Lewy Bodies=20; mild cognitive impairment-MCI=36; controls=63). RESULTS: Reliability of the ACE-R was very good (alpha coefficient=0.8). Correlation with the Clinical Dementia Scale was significant (r=-0.321, p<0.001). Two cut-offs were defined (88: sensitivity=0.94, specificity=0.89; 82: sensitivity=0.84, specificity=1.0). Likelihood ratios of dementia were generated for scores between 88 and 82: at a cut-off of 82 the likelihood of dementia is 100:1. A comparison of individual age and education matched groups of MCI, AD and controls placed the MCI group performance between controls and AD and revealed MCI patients to be impaired in areas other than memory (attention/orientation, verbal fluency and language). CONCLUSIONS: The ACE-R accomplishes standards of a valid dementia screening test, sensitive to early cognitive dysfunction.

Aged↗

PubMed2006

Semantic knowledge in mild cognitive impairment and mild Alzheimer's disease.

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy control participants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memory measures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency and all three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-naming test. The mild AD group showed additional impairments on traditional measures of semantic memory, including naming high frequency items, comprehension and semantic association. Together these findings suggest that semantic memory impairments occur early in the course of AD, more specifically in patients with "amnesic" MCI, and provide further evidence that impaired category fluency reflects semantic breakdown.

Adult↗

PubMed2006

Semantic memory in Alzheimer's disease and the frontotemporal dementias: a longitudinal study of 236 patients.

Using semantic dementia (SD) as a reference point, the authors assessed semantic memory in four other neurodegenerative disorders: progressive nonfluent aphasia (PNFA), frontal variant frontotemporal dementia (fvFTD), Alzheimer's disease (AD), and posterior cortical atrophy (PCA). Individuals with SD were more impaired than other groups on semantic measures and showed a characteristic pattern across tasks: category fluency (CF) worse than letter fluency (LF), naming worse than comprehension, and visual and verbal comprehension equally affected, suggesting disruption to an amodal semantic system. Individuals with AD demonstrated a similar pattern to a milder degree. Although PNFA, fvFTD, and PCA groups had abnormal scores (relative to controls) on most semantic measures, their differing patterns across measures indicate that the apparent semantic impairment in these conditions is largely secondary to other factors.

Aged↗

PubMed2006

A case of voltage-gated potassium channel antibody-related limbic encephalitis.

BACKGROUND: A 56-year-old man presented to hospital with a 6-month history of recurrent episodes of altered behavior and 'odd' episodes. He had become apathetic and uninterested in his family. He had no relevant past medical or family history. General and physical neurological examinations were unremarkable, as was bedside cognitive testing. INVESTIGATIONS: Brain MRI scan, 24-h electroencephalogram, serum and cerebrospinal fluid testing for voltage-gated potassium channel antibodies, blood screening for tumors, CT scans of the chest, abdomen and pelvis, whole-body PET scan, neuropsychological examination, brain 18F-fluorodeoxyglucose-PET scan. DIAGNOSIS: Voltage-gated potassium channel antibody-related limbic encephalitis. MANAGEMENT: Antiepileptic drugs, immunomodulatory therapy, oral steroids, plasma exchange.

Anticonvulsants↗

PubMed2006

Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia.

The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in 'normalizing' the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the 'somatic marker' hypothesis of impaired decision-making following orbitofrontal dysfunction.

Aged↗

PubMed2006

Alzheimer's centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects.

This review commemorates 100 years of research into Alzheimer's disease and, by happy coincidence, the publication of 100 papers in Brain on the topic. The first part of the review traces the evolution of concepts and landmarks in the modern history of Alzheimer's disease. It highlights the continuing role of careful clinico-pathological studies which have set the stage for each major leap forwards, such as the emergence of the cholinergic hypothesis, and the realistation that subjects pass through an amnestic prodrome which is thought to reflect dysfunction of the hippocampal formation before the onset of full blown dementia. The contribution of structural and functional imaging is briefly described. The important contribution of publications in Brain is illustrated throughout the first section. The second part attempts to review the current status of our knowledge concerning behavioural, neuropsychological and neuropsychiatric aspects of the disease, emphasizing areas of continuing controversy.

Alzheimer Disease↗

PubMed2006

Frontotemporal dementia.

PURPOSE OF REVIEW: The syndromes of frontotemporal lobar degeneration are increasingly recognized as an important cause of early-onset dementia. Diagnostic consensus criteria have now been established for almost a decade, and form the framework for its clinical classification. While these criteria remain useful, a growing body of evidence suggests that revisions may be necessary to improve their validity and applicability. RECENT FINDINGS: In each individual syndrome, the core features are not uniformly present, and criteria that are currently used to exclude a condition, such as impaired episodic memory, are often present. Imaging, however, may warrant increased diagnostic prominence, particularly for diagnosis in semantic dementia and prognosis in behavioural syndromes. There is clinical and pathological overlap between the syndromes, but the clinical distinction between progressive nonfluent aphasia and semantic dementia is strengthening. Several series have refined our understanding of the correspondence between clinical syndromes and histopathological subtype: strong for tau-negative, ubiquitin-positive forms and more variable for tau-positive forms, yet prospective studies are still rare. The influence of genetic factors varies substantially across the syndromes. SUMMARY: Further research should aim to integrate detailed clinical, radiological, pathological and genetic information.

Aphasia, Primary Progressive↗

PubMed2006

Posterior cingulate neurometabolite profiles and clinical phenotype in frontotemporal dementia.

Proton magnetic resonance spectroscopy was used to compare metabolite levels from a posterior cingulate voxel in a group of patients with 2 syndromic subtypes of frontotemporal dementia (n=10) and an age and education-matched group with Alzheimer disease (n=10). Overall, frontotemporal dementia was indistinguishable from Alzheimer disease, though differences in N-acetylaspartate emerged between patients with the SD and progressive nonfluent aphasia subtypes, attributable to 2 atypical results among the latter. Such values may index cases with atrophy in posterior cortical regions presenting with progressive nonfluent aphasia.

Aged↗

PubMed2006

"Presemantic" cognition in semantic dementia: six deficits in search of an explanation.

On the basis of a theory about the role of semantic knowledge in the recognition and production of familiar words and objects, we predicted that patients with semantic dementia would reveal a specific pattern of impairment on six different tasks typically considered "pre-" or "non-" semantic: reading aloud, writing to dictation, inflecting verbs, lexical decision, object decision, and delayed copy drawing. The prediction was that all tasks would reveal a frequency-by-typicality interaction, with patients performing especially poorly on lower-frequency items with atypical structure (e.g., words with an atypical spelling-to-sound relationship; objects with an atypical feature for their class, such as the hump on a camel, etc). Of 84 critical observations (14 patients performing 6 tasks), this prediction was correct in 84/84 cases; and a single component in a factor analysis accounted for 87% of the variance across seven measures: each patient's degree of impairment on atypical items in the six experimental tasks and a separate composite score reflecting his or her degree of semantic impairment. Errors also consistently conformed to the predicted pattern for both expressive and receptive tasks, with responses reflecting residual knowledge about the typical surface structure of each domain. We argue that these results cannot be explained as associated but unrelated deficits but instead are a principled consequence of a primary semantic impairment.

Aged↗

PubMed2006

Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5' end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.

Adult↗

PubMed2005

Clinical, imaging and pathological correlates of a hereditary deficit in verb and action processing.

Selective verb and noun deficits have been observed in a number of neurological conditions and their occurrence has been interpreted as evidence for different neural networks underlying the processing of specific word categories. We describe the first case of a familial occurrence of a selective deficit of verb processing. Father (Individual I) and son (Individual II) developed a movement disorder resembling progressive supranuclear palsy (PSP) and associated with dementia. A second child of Individual II remained symptom-free on consecutive examinations. The dissociation between the processing of nouns and verbs in Individuals I and II was confirmed with different methods, including a longitudinal assessment of naming, comprehension, picture and word association, as well as a lexical decision task. The difference remained stable on follow-up testing despite overall deterioration. It was associated with left-sided frontal hypometabolism on FDG-PET imaging (Individual II) and with ubiquitin-positive inclusions on post-mortem examination (Individual I). The association of a selective verb deficit with a familial movement disorder raises the question whether related genetic factors might influence both movements and their abstract conceptual representations in the form of action verbs. By demonstrating a link between pathology, genetics, imaging and abstract cognitive impairments this study advances our understanding of degenerative brain disease with implications for both neuroscience and clinical practice.

Adult↗

PubMed2005

Declarative memory impairments in Alzheimer's disease and semantic dementia.

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.

Alzheimer Disease↗