Authors: Hodges, John R.
Article Type: Review Article
Abstract: This review focuses on six key papers published in the mid 2000 s based on work conducted in Cambridge. The first two relate to clinico-pathological studies which established that Alzheimer's disease (AD) is a relatively common cause of focal cortical syndromes, notably progressive aphasia (largely nonfluent), progressive apraxia, and posterior cortical atrophy with complex visual symptoms. Building on these findings, criteria for the progressive aphasias have been developed which define the variant associated with AD (progressive logopenic aphasia). Memory in the dementias has been a major area of interest and one paper discussed here explored the neural basis for episodic …and semantic memory failure in AD and semantic dementia. Despite very different memory profiles, the two disorders both cause severe hippocampal hypometabolism and atrophy but differ in the degree of involvement of other memory related structures. This work drew attention to the role of pathology in non-hippocampal structures early in AD. The next two articles deal with the behavioral variant frontotemporal dementia (bvFTD) which we have shown is associated with breakdown in theory of mind, social reasoning, empathy, and emotion processing and contributed to work on the neural basis of social cognition. We also identified a subgroup of bvFTD who fail to progress over many years, termed phenocopy cases, who are differentiated by their lack of atrophy on MRI. The final paper described the application of the Addenbrooke's Cognitive Examination-Revised, which has proven a useful brief assessment tool for the early detection of a range of neurodegenerative disorders including AD and FTD. It also appears to be helpful in predicting those with mild cognitive impairment who will progress to frank dementia. Show more
Keywords: Addenbrooke's cognitive examination, Alzheimer's disease, episodic memory, frontotemporal dementia, Papez circuit, progressive aphasia, semantic dementia
DOI: 10.3233/JAD-2012-129038
Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S211-S217, 2013
Authors: Hodges, John R. | Piguet, Olivier
Article Type: Review Article
Abstract: The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, …and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking. Show more
Keywords: Behavioral variant frontotemporal dementia, diagnosis, genetics, interventions, pathology, prognosis, progressive nonfluent aphasia, semantic dementia
DOI: 10.3233/JAD-171087
Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1467-1480, 2018
Authors: Burrell, James R. | Hodges, John R.
Article Type: Review Article
Abstract: Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also …a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries. Show more
Keywords: Behavioral variant FTD, frontotemporal dementia, FTD-ALS, progressive non-fluent aphasia, semantic dementia, tau, TDP-43
DOI: 10.3233/JAD-2010-091513
Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 349-360, 2010
Authors: Gurd, Jennifer M. | Hodges, John R.
Article Type: Research Article
Abstract: In this paper, we describe the detailed neuropsychological investigation of two cases of progressive supranuclear palsy (PSP) and demonstrate word-finding difficulties associated with pervasive problems in word-retrieval. The pattern of deficits resembles that seen in Parkinson's Disease (PD) but is more severe, even in very mild PSP, and appears less amenable to cue facilitation. Performance on a variety of word-production tasks is compared, and experimental controls for motor effects on performance are included. The role of stimulus cues in speeded word-finding is addressed experimentally, as are central executive influences on task performance. This combines with functional brain-scan data from single …photon emission computed tomography (SPECT) which shows reduced frontal perfusion in one of the two cases. Show more
Keywords: Progressive supranuclear-palsy, Anomia, Neuropsychology, psychology, Dementia
DOI: 10.3233/BEN-1997-10106
Citation: Behavioural Neurology, vol. 10, no. 1, pp. 31-41, 1997
Authors: Pennington, Catherine | Hodges, John R. | Hornberger, Michael
Article Type: Research Article
Abstract: Impaired episodic memory is currently an exclusion criterion for behavioral variant frontotemporal dementia (bv-FTD), although prior studies have shown that neuropsychological memory performance varies from very impaired to intact in such patients. Our study investigated i) whether this variability might be due to the admixture of true bv-FTD and phenocopy syndrome patients and ii) the neural correlates of episodic memory deficits in bvFTD. Groups of patients with true bvFTD (n = 14), phenocopy syndrome (n = 6), Alzheimer's disease (AD) (n = 14), and healthy controls (n = 15) underwent memory testing and had MRI scanning with ratings of regional …brain atrophy. Phenocopy patients did not differ to controls on memory scores or atrophy ratings. By contrast, bvFTD and AD patients were impaired on both measures in comparison to controls and more importantly, bvFTD and AD did not differ on memory scores. Atrophy patterns differed, with AD showing typical medial temporal lobe atrophy, while bvFTD patients had predominantly prefrontal cortex atrophy. In bvFTD neuropsychological memory performance correlated with frontal atrophy ratings while in AD significant correlations were found between memory and both medial temporal lobe and frontal atrophy ratings. Taken together, out data shows that bvFTD patients can show a similar degree of episodic memory impairment on neuropsychological tests to AD patients, however, the neural correlates differ. The previously variable reported memory performance in bvFTD is likely due to the inclusion of phenocopy patients, who are mostly undistinguishable from controls. These findings have implications for the diagnosis of bvFTD. Show more
Keywords: AD, behavioral variant frontotemporal dementia (bvFTD), episodic memory, MRI, phenocopy syndrome
DOI: 10.3233/JAD-2011-101668
Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 261-268, 2011
Authors: Kumfor, Fiona | Hodges, John R. | Piguet, Olivier
Article Type: Research Article
Abstract: Background: Events which are imbued with emotion are typically remembered vividly and with more confidence than similar non-emotional events. The extent that emotional enhancement of memory is compromised in neurodegenerative disorders is unclear, despite differential effects of dementia on emotion processing ability. Objective: To examine emotional enhancement of memory using an ecologically valid task in progressive nonfluent aphasia (PNFA), an expressive language subtype of frontotemporal dementia, in comparison to Alzheimer’s disease (AD) and matched-controls. Methods: Twenty-five dementia patients (13 PNFA, 12 AD) and 10 controls viewed either an emotionally arousing or a closely matched non-emotional story. Multiple-choice recognition memory was …tested after a 1-hour delay. The alternate story was presented two weeks later. Results: PNFA showed a similar level of memory for the emotional and neutral story, whereas both controls and AD remembered significantly more details from the emotional than the neutral story. Correlation analyses indicated that in PNFA, emotional story memory correlated with reduced emotion recognition, whereas in AD, neutral story memory correlated with visual recall memory performance only. Furthermore, in PNFA, reduced emotional memory enhancement was associated with increased carer stress and depression. Conclusion: Emotional memory enhancement is absent in PNFA, whereas emotion facilitates memory for real-life events in AD. Disrupted emotional memory enhancement in PNFA is associated with reduced emotion recognition ability, suggesting that widespread emotion processing dysfunction is present in this disease. Crucially, loss of emotional enhancement influences carer wellbeing, which represents an important avenue for future studies to examine. Show more
Keywords: Carer, depression, emotion, episodic memory, frontotemporal dementia, hippocampus, insula, stress
DOI: 10.3233/JAD-140351
Citation: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 201-210, 2014
Authors: Savage, Sharon A. | Piguet, Olivier | Hodges, John R.
Article Type: Research Article
Abstract: Background: Anomia is a common and debilitating symptom for many dementia sufferers, but is particularly marked in patients with the semantic variant of primary progressive aphasia, semantic dementia (SD). Recent studies have demonstrated that through cognitive training these patients can re-learn the names of objects, but it remains unclear whether this translates to improved use of these relearned words in contexts other than picture naming. Methods: Five SD patients completed a 2-month, online word training program and were assessed pre- and post-intervention on picture naming and spoken word-picture-matching plus two novel ecological tasks: video description and responses to verbal requests. …Results: All participants showed clear gains in naming the trained pictures (p < 0.001). Importantly, improvements were also observed for four out of the five patients on the video description task. Milder patients also demonstrated improved comprehension of verbal instructions. Severe SD patients showed improvements on matching trained words to pictures. As expected, improvements were not found for untrained items. Conclusion: There was clear evidence of generalization especially in patients with milder semantic impairments. Future studies should investigate the utility of this training in other forms of dementia. Show more
Keywords: computer-assisted intervention, cognitive rehabilitation, generalization, naming therapy, primary progressive aphasia, semantic dementia
DOI: 10.3233/JAD-131826
Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 309-317, 2014
Authors: Kamminga, Jody | O'Callaghan, Claire | Hodges, John R. | Irish, Muireann
Article Type: Research Article
Abstract: Background: Prospective memory (PM) is the ability to remember to execute an intended action either at a future time (Time-based PM) or when a specific event occurs (Event-based PM). Previous studies demonstrate impaired PM in Alzheimer’s disease (AD); however, the status of PM in frontotemporal dementia (FTD) remains unknown. Objective: To examine PM performance and its associated cognitive mechanisms, in two subtypes of FTD: semantic dementia (SD) and the behavioral variant of FTD (bvFTD), in comparison with matched AD and control participants. Methods: Twenty-four dementia patients (SD = 8; bvFTD = 8; AD = 8) and 12 age- and education-matched …controls underwent a shortened version of the Cambridge Behavioural Prospective Memory Test, as well as a standard neuropsychological test battery. Results: Compared to controls, SD patients exhibited preserved Time-based PM in the context of impaired Event-based PM, with the latter strongly associated with deficits in semantic processing. In contrast, bvFTD and AD patients demonstrated global PM impairments irrespective of subscale, which strongly correlated with deficits in delayed episodic retrieval for both groups. Caregiver reports of stereotypical behaviors were associated with compromised Event-based PM in SD and Time-based PM in bvFTD, with no such relationship evident in AD. Conclusion: This is the first study to investigate prospective memory in FTD syndromes. A relative sparing of Time-based PM was observed in SD, in contrast with global PM deficits in bvFTD. Disrupted PM processing was found to correlate with stereotypical behaviors in FTD syndromes, a finding that we suggest is worthy of further investigation. Show more
Keywords: Aging, alzheimer's disease, behavioral variant frontotemporal dementia, episodic memory, neuropsychological tests, prospective memory, semantic dementia
DOI: 10.3233/JAD-131118
Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 669-679, 2014
Authors: Schubert, Samantha | Leyton, Cristian E. | Hodges, John R. | Piguet, Olivier
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation. Objective: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD. Methods: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts. …Results: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group. Conclusions: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes. Show more
Keywords: Alzheimer’s disease, assessment of cognitive disorders/dementia, cohort study, executive function, frontotemporal dementia, memory
DOI: 10.3233/JAD-150802
Citation: Journal of Alzheimer's Disease, vol. 51, no. 3, pp. 775-782, 2016
Authors: Savage, Sharon A. | Piguet, Olivier | Hodges, John R.
Article Type: Research Article
Abstract: Background: Reduced insight commonly occurs in dementia and can be specific to one area of functioning. Despite recent models identifying a role for semantic memory, little investigation of insight has been conducted in semantic dementia (SD), with patients often described as being aware of their language problems. Objective: This study aims to investigate language insight in SD. Method: Twenty-two SD (n = 11 severe, n = 11 mild-moderate) and 9 nonfluent primary progressive aphasic patients completed three experimental language tasks to assess knowledge and awareness of certain words. Skills in evaluating language were tested by comparing performance ratings on the Cookie Theft …task with objective scoring. Awareness regarding the existence and previous use of certain words was tested using two additional tasks. Results: While SD patients were as accurate as nonfluent patients in rating their own performance on the Cookie Theft immediately following the task, they were significantly poorer at evaluating the same content re-recorded, or other examples of poor language. Compared to nonfluent patients, severe SD patients also made more errors identifying previously known low frequency words. Lastly, when tested on labels for specific aspects of an object, only SD patients made errors regarding the existence, or their past knowledge, of certain words. Conclusion: SD patients show a general awareness of their language impairments, but have difficulty evaluating language content. These difficulties adversely affect the ability to reflect upon current and past language skills producing an under-awareness of language deficits. This mild, secondary form of anosognosia appears to increase with greater levels of semantic impairment. Show more
Keywords: Anosognosia, cognitive awareness, frontotemporal dementia, primary progressive aphasia, self-appraisal
DOI: 10.3233/JAD-142703
Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 187-198, 2015
