[show abstract][hide abstract] ABSTRACT: Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aβ42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.
[show abstract][hide abstract] ABSTRACT: To address socioeconomic challenges associated with its increasing prevalence, data are needed on country-level resource use and costs associated with Alzheimer's disease (AD). GERAS is an 18-month observational study being conducted in France, Germany, and the UK (with an 18-month extension in France and Germany), aimed at determining resource use and total costs associated with AD, stratified by AD severity at baseline. Resource use information and time spent on informal care by non-professional caregivers was obtained using the Resource Utilization in Dementia instrument. Total baseline societal costs were based on four cost components: patient health care costs, patient social care costs, caregiver health care costs, and caregiver informal care costs. Overall, 1,497 community-dwelling patients with AD were analyzed at baseline. Estimated mean monthly total societal costs per patient at baseline differed significantly between groups with mild, moderate, and moderately severe/severe AD (p < 0.001 in each country): $\euro$1,418, $\euro$1,737, and $\euro$2,453 in France; $\euro$1,312, $\euro$2,412, and $\euro$3,722 in Germany; and $\euro$1,621, $\euro$1,836, and $\euro$2,784 in the UK, respectively. All cost components except caregiver health care costs increased with AD severity. Informal caregiver costs were the largest cost component accounting for about half to just over 60% of total societal costs, depending on country and AD severity group. In conclusion, GERAS study baseline results showed that country-specific costs increase with AD severity. Informal care costs formed the greatest proportion of total societal costs, increasing with AD severity independent of costing method. Longitudinal data will provide information on cost trends with disease progression.
Journal of Alzheimer's disease: JAD 04/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer's disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n = 544) were followed for 1 to 5 years. We used Cox's stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n = 222) and high (HR 3.67 95% CI 1.36-9.89, n = 139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n = 183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention.
Journal of Alzheimer's disease: JAD 02/2013; · 4.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: The core clinical feature of semantic dementia is a progressive yet selective degradation of conceptual knowledge. Understanding the cognitive and neuroanatomical basis for this deficit is a key challenge for both clinical and basic science. Some researchers attribute the deficit to damage to pan-modal conceptual representations that are independent of any particular sensory-motor modality and are represented in the ventrolateral anterior temporal lobes. Others claim that damage to modality-specific visual feature representations in the occipitotemporal 'ventral stream' is responsible. In the present study, we tested the hypothesis that concept degradation in semantic dementia involves a combination of these pan-modal and modality-specific elements. We investigated factors influencing knowledge of object concepts by analysing 43 sets of picture-naming data from patients with semantic dementia. We found a strong influence of two pan-modal factors: highly familiar and typical items were named more accurately than less familiar/atypical items at all stages of the disorder. Items associated with rich sensory-motor information were also named more successfully at all stages, and this effect was present for sound/motion knowledge and tactile/action knowledge when these modalities were studied separately. However, there was no advantage for items rich in visual colour/form characteristics; instead, this factor had an increasingly negative impact in the later stages of the disorder. We propose that these results are best explained by a combination of (i) degradation of modality-independent conceptual representations, which is present throughout the disorder and is a consequence of atrophy focused on the ventrolateral anterior temporal lobes; and (ii) a later additional deficit for concepts that depend heavily on visual colour/form information, caused by the spreading of atrophy to posterior ventral temporal regions specialized for representing this information. This explanation is consistent with a graded hub-and-spoke model of conceptual knowledge, in which there is a gradual convergence of information along the temporal lobes, with visual attributes represented in the posterior cortex giving way to pan-modal representations in the anterior areas.
[show abstract][hide abstract] ABSTRACT: There are two contrasting views on the nature of comprehension impairment in semantic dementia: (a) that it stems from degradation of a pan-modal "hub" that represents core conceptual knowledge or (b) that it results from degradation of modality-specific visual feature knowledge. These theories make divergent predictions regarding comprehension of concrete versus abstract words in the disorder. The visual hypothesis predicts that concrete words should be particularly impaired because they depend heavily on visual information. In contrast, the pan-modal hub hypothesis holds that all types of knowledge are affected but predicts less severe impairment of concrete words because they have richer and more detailed semantic representations than abstract words. We investigated concreteness effects in the comprehension of six SD patients. Across nouns, verbs, synonymous and associative relationships, a clear and consistent pattern emerged: concrete words were always comprehended more successfully than abstract words. These findings extend those of previous studies and suggest that conceptual impairment in SD is not confined to concepts that rely on visual information. Instead, all types of knowledge are affected by the progressive deterioration of modality-invariant representations (required for coherent pan-modal concepts). Concrete words succumb less quickly by virtue of their richer and more detailed semantic representations.
[show abstract][hide abstract] ABSTRACT: Developing rehabilitation techniques to combat cognitive decline is a key goal of healthcare strategies aimed at promoting increased longevity and better quality of life for individuals with Alzheimer's disease (AD). In AD, problems with episodic memory and word-finding greatly affect everyday life and, as such, these symptoms provide a clear clinical target for therapeutic interventions. Errorless learning (EL) has been proposed as a particularly effective technique for relearning in individuals with memory dysfunction, including AD. However, EL learning has rarely been directly contrasted with other more traditional trial-and-error techniques (errorful learning or EF) in individuals with AD, especially in the context of alleviating word-finding problems. In the current study, we directly contrasted the therapeutic gains of an EL learning paradigm (consisting of reading/repetition of object names) with an EF learning technique (comprised of phonemic/orthographic cueing) in eight mild to moderate AD patients with pronounced anomia. Both techniques were administered concurrently in sessions run twice a week over a five-week period. Therapeutic gains were assessed at one week and five weeks post-intervention using confrontation naming. Our results suggest that, both at the group and individual patient level, EL and EF techniques were equally effective. Correlational analyses of overall therapy gains and background assessments of patient neuropsychology revealed that individuals with better scores on measures of semantic memory, pre-intervention naming, and recognition memory demonstrated larger therapy gains. No individual patient showed a significant advantage for EL over EF learning, however, for patients that showed a numerical advantage in this direction. These results suggest that either EL or EF therapy can be used to alleviate word-finding problems in AD.
[show abstract][hide abstract] ABSTRACT: Craniopharyngiomas are rare brain tumors within the area of the craniopharyngeal duct. They are often diagnosed in children and young people and can be associated with significant cognitive impairments such as memory and executive problems. This single-case report describes a brief investigation into the effectiveness of goal management training for dysexecutive problems following the removal and treatment of a craniopharyngioma in a young woman. In contrast to previous laboratory-based studies, we exploited naturally occurring distractions within the patient's work environment as periodic alerts to facilitate goal management. Following a 2-month intervention, the patient reported improvements in her ability to focus attention at work and performed significantly better on neuropsychological tests requiring organized behavior posttraining relative to pretraining. Thus, the exploitation of naturally occurring external distractions as periodic alerts to facilitate goal management can be an effective and easy-to-adopt cognitive rehabilitation strategy for dysexecutive problems associated with craniopharyngioma.
[show abstract][hide abstract] ABSTRACT: We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in patients with AD.
Based on pre-specified criteria, six studies were selected from among all donepezil clinical trials in AD. Individual items from nine ADL scales used in these trials were mapped to a standardized functional scale comprising 12 domains (six basic, six instrumental); scores were transformed to a 0-100 scale. External validation of this scale yielded a concordance rate of 90.8%. For each domain, mean change from baseline to 24 weeks in the placebo and donepezil groups was compared for the total population and for subgroups stratified by baseline disease severity. Study settings included outpatient, assisted living, and skilled nursing facilities. Participants comprised 2183 patients (donepezil, 1261; placebo; 922) with baseline Mini-mental State Examination (MMSE) scores 5-26.
Significant treatment differences favoring donepezil were observed for five items (two instrumental and three basic). Patients with moderate AD at baseline (MMSE 10-17) demonstrated the greatest treatment effect.
Functional data were successfully pooled using standardizing methodology. A beneficial effect of donepezil treatment on function was demonstrated using this standardized functional scale. Similar analyses from studies with other anti-dementia drugs may help to determine the generalizability of these findings and potentially encourage use of functional assessment as a clinical tool.
International Psychogeriatrics 09/2010; 22(6):973-83. · 2.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: In his Philosophical Investigations, Wittgenstein famously noted that the formation of semantic representations requires more than a simple combination of verbal and nonverbal features to generate conceptually based similarities and differences. Classical and contemporary neuroscience has tended to focus upon how different neocortical regions contribute to conceptualization through the summation of modality-specific information. The additional yet critical step of computing coherent concepts has received little attention. Some computational models of semantic memory are able to generate such concepts by the addition of modality-invariant information coded in a multidimensional semantic space. By studying patients with semantic dementia, we demonstrate that this aspect of semantic memory becomes compromised following atrophy of the anterior temporal lobes and, as a result, the patients become increasingly influenced by superficial rather than conceptual similarities.
Proceedings of the National Academy of Sciences 02/2010; 107(6):2717-22. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) and Posterior Cortical Atrophy (PCA), the visual variant of Alzheimer's disease, are neurodegenerative diseases that present with progressive deterioration in visual perception. However, little is known about the precise nature underlying the complex visual deficits associated with both conditions. The present study compared DLB, PCA, and healthy control participants, in four visual tasks designed to measure the efficiency of the visual system at different levels of processing. In ascending order of complexity there were tasks of visual acuity, line orientation, contour integration, and rotated object comparison. DLB patients did not differ from controls in low level visual functions of visual acuity and line orientation, suggesting that early visual processing areas including V1 were relatively preserved, consistent with pathology evidence (Yamamoto et al., 2006). However, higher level visual functions of contour integration, mediated by extrastriatal areas, and the most complex task of object rotation, relying on processing within inferior temporal (IT), parietal, and frontal cortices, were impaired in DLB. In contrast, PCA patients were impaired in all tasks, consistent with evidence of widespread pathology within occipital and parietal areas in PCA. The latter suggests that both lower and higher level visual impairments contribute to the complex visual symptoms associated with PCA.
[show abstract][hide abstract] ABSTRACT: Dimebon (latrepirdine) has received widespread publicity as a potential therapy for Alzheimer's disease following a very positive phase 2 study carried out in Russia and published in the Lancet in 2008. In this study there were improvements over 6 months in all endpoints (cognitive, global, daily function and behaviour), with continuing improvement at 12 months in cognition and daily function. A more recent multinational phase 3 study, however, showed no improvements whatsoever and no difference between the two drug-treated groups and the placebo group. Of note, there was little deterioration in any of the groups after 6 months in contrast to the placebo group in the phase 2 study. The potential reasons for these disappointing results are discussed, as well as the implication for dimebon and drug treatment in Alzheimer's disease.
Alzheimer's Research and Therapy 01/2010; 2(5):25. · 4.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Errorless learning (EL) principles have been shown to enable people with memory impairments to acquire various types of information (Grandmaison & Simard, 2003; Wilson, 2005). However, the effects of EL, based on simple repetition only, tend to be limited with regards to their size and longevity. The present study investigated whether EL could be improved by actively engaging people with Alzheimer's disease in the learning process. Patients learned the names of famous faces over 10 training sessions, treated either with a non-learning control, a simple repetition EL procedure, or an EL condition in which responses had to be self-generated. Cued recall rates after the final training session were significantly greater for the names treated with the self-generated EL technique compared to the control and the repetition EL conditions. In addition, there was evidence that patients with less severe general cognitive impairment benefit more from active generation than more severely impaired patients. The implications of this research for individualised memory rehabilitation programmes are discussed.
[show abstract][hide abstract] ABSTRACT: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD).
Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10-27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures).
At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients.
In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.
[show abstract][hide abstract] ABSTRACT: The vast majority of brain-injured patients with semantic impairment have better comprehension of concrete than abstract words. In contrast, several patients with semantic dementia (SD), who show circumscribed atrophy of the anterior temporal lobes bilaterally, have been reported to show reverse imageability effects, that is, relative preservation of abstract knowledge. Although these reports largely concern individual patients, some researchers have recently proposed that superior comprehension of abstract concepts is a characteristic feature of SD. This would imply that the anterior temporal lobes are particularly crucial for processing sensory aspects of semantic knowledge, which are associated with concrete not abstract concepts. However, functional neuroimaging studies of healthy participants do not unequivocally predict reverse imageability effects in SD because the temporal poles sometimes show greater activation for more abstract concepts. The authors examined a case-series of 11 SD patients on a synonym judgment test that orthogonally varied the frequency and imageability of the items. All patients had higher success rates for more imageable as well as more frequent words, suggesting that (1) the anterior temporal lobes underpin semantic knowledge for both concrete and abstract concepts, (2) more imageable items--perhaps because of their richer multimodal representations--are typically more robust in the face of global semantic degradation and (3) reverse imageability effects are not a characteristic feature of SD.
[show abstract][hide abstract] ABSTRACT: Treatment success in Alzheimer disease (AD) trials is generally based on benefits over placebo-treated controls. Consequently, variation in rates of decline among placebo-treated patients could impact outcomes from AD trials. In the present analyses, individual patient data [baseline Mini-Mental State Examination (MMSE): 10 to 26] were pooled from randomized, placebo-controlled studies of donepezil for AD conducted during the 1990s, and grouped by initiation year-group 1: 1990 to 1994; group 2: 1996 to 1999. Changes in MMSE and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were compared between groups 1 and 2 for placebo, and then between donepezil and placebo. Data were available from 3403 patients in 13 trials. Group 2 (post-1995) included patients with lower baseline MMSE scores, older patients, fewer males, more comorbidity, and more concomitant medications. MMSE decline by week 24 was significantly greater among group 1 (pre-1995) placebo patients versus group 2; a similar trend was observed with the ADAS-cog. Nevertheless, donepezil-mediated treatment effects were consistent over the decade of enrollment. These analyses suggest that patients are showing slower rates of cognitive decline in more recent trials compared with older trials, although having more comorbidities. This finding may have important potential implications for future clinical trial design.
[show abstract][hide abstract] ABSTRACT: Patients with semantic dementia (SD) make numerous phoneme migration errors when recalling lists of words they no longer fully understand, suggesting that word meaning makes a critical contribution to phoneme binding in verbal short-term memory. Healthy individuals make errors that appear similar when recalling lists of nonwords, which also lack semantic support. Although previous studies have assumed that the errors in these two groups stem from the same underlying cause, they have never been directly compared. We tackled this issue by examining immediate serial recall for SD patients and controls on "pure" word lists and "mixed" lists that contained a mixture of words and nonwords. SD patients were equally poor at pure and mixed lists and made numerous phoneme migration errors in both conditions. In contrast, controls recalled pure lists better than mixed lists and only produced phoneme migrations for mixed lists. We also examined the claim that semantic activation is critical for words in the primacy portion of the list. In fact, the effect of mixed lists was greatest for later serial positions in the control group and in the SD group recall was poorest towards the ends of lists. These results suggest that mixing nonwords with words in healthy participants closely mimics the impact of semantic degradation in SD on word list recall. The study provides converging evidence for the idea that lexical/semantic knowledge is an important source of constraint on phonological coherence, ensuring that phonemes in familiar words are bound to each other and emerge together in recall.