Memory difficulties are not always a sign of incipient dementia: a review of the possible causes of loss of memory efficiency.

INTRODUCTION OR BACKGROUND: Memory problems are a very common reason for presenting to primary care. There is a need for better treatments for dementia. Increased government and media interest may result in greater number seeking help for memory problems, which may not reduce the dementia gap but rather increase numbers seen who do not have dementia. This review highlights the issues around the diagnostic criteria and terminology used for people with memory complaints. SOURCES OF DATA: A comprehensive literature search using PubMed using keywords for articles on subjective memory decline (SMD)/impairment/complaints, subjective cognitive decline (SCD), mild cognitive impairment (MCI) and functional memory disorder (FMD). AREAS OF AGREEMENT: There is a need for early accurate detection of dementia syndromes so that trials of new treatments can begin earlier on the disease process. AREAS OF CONTROVERSY: Diagnostic criteria and terminology used for disorders of memory including SCD, MCI and FMD. GROWING POINTS: This article reviews SCD and whether this can be used to predict Alzheimer's disease. The review also discusses the terminology used for non-progressive memory problems and the long-term outcomes for this patient group. AREAS TIMELY FOR DEVELOPING RESEARCH: The accurate distinction of premorbid dementia syndromes from benign non-progressive memory problems. Studies of treatment options for people with benign non-progressive memory problems and longer-term follow-up to determine which patients develop chronic problems.

Differentiating normal from pathological brain ageing using standard neuropsychological tests.

To diagnose Alzheimer's disease (AD) early, tests sensitive to neuropathology and insensitive to normal ageing are of greatest benefit. We used several neuropsychological tests to identify those best suited to distinguishing Mild Cognitive Impairment (MCI) and early AD from normal ageing. Impairments in long-term memory were found in older adults and these were even greater in MCI and AD. Older adults outperformed young controls on category fluency and produced later acquired and less familiar words. Older adults also outperformed both patient groups on this task producing more words which were significantly later acquired, less familiar and less typical. Decline in long-term memory appears nonspecific and in the early stage of AD cannot help the differentiation between normal and pathological brain ageing. Normal ageing has no negative effects on verbal fluency, and impairment on this task signals not only established AD, but also its prodromal MCI stage.

Cognitive stimulation: the evidence base for its application in neurodegenerative disease.

Multiple modalities of cognitive stimulation (CS) have been designed and tested in samples of patients with probable Alzheimer's disease (AD). Despite the substantial inter-study variability, an overall positive impact of CS is reported. This impact has been especially observed in general measures of cognition. The mechanisms by which cognitive exercises would be beneficial for high-order cortical functions are still largely undetermined, however. When CS has been applied to patients with mild cognitive impairment (who are at the prodromal stage of AD) more stringent methodological criteria and designs were used and studies have been of greater clinical and research relevance. At this disease stage, a positive impact of CS has been reported in a range of different cognitive domains, and even at a neuro-computational level by the measurement of test-retest modifications of brain function. The effects of CS in healthy adults have also been studied. This population allows researchers to explore and test specific neural mechanisms possibly underlying the effect of pen-and-paper or computerised exercises. The evidence from these studies and those contributing to a better understanding of the pathophysiology of AD has led to devising forms of CS as preventive and therapeutical measures for neurodegenerative diseases based on novel frameworks of brain structure, function and connectivity. An extensive review of the literature was carried out to clarify whether CS is effective in AD and mild cognitive impairment and, together with the evidence from studies in healthy participants, to identify the relevant mechanisms that might sustain this effectiveness.

Awareness and confabulation.

OBJECTIVE: A single case study with control and normative data of a 74-year-old retired businessman with amnestic mild cognitive impairment, who had spontaneous confabulations concerning fantastic exploits and magical powers as well as déjà vécu experiences. METHODS AND RESULTS: His neuropsychological profile showed episodic memory impairment including deficits of recent episodic autobiographical memories and of recognition, but performance was within normal limits on tests assessing source memory for words, the ability to suppress irrelevant items on a continuous recognition memory task, and the detection of stimulus frequency. There were discrete impairments in an ad hoc test measuring his ability to detect and discriminate the source of a range of material including information derived from personal and public events, invented material, and episodes culled from his personal reading. Although his source memory for autobiographical information was normal, he attributed 20% of the invented material and personal readings and 15% of the public events either to his own experience or to that of someone he knew personally or to someone else. CONCLUSIONS: This evidence suggests that none of the current theoretical accounts of spontaneous confabulations is sufficiently explanatory. Instead, an argument is developed that both fantastic confabulation and déjà vécu arose from a more fundamental disorder of awareness.

Profiling spontaneous speech decline in Alzheimer's disease: a longitudinal study.

OBJECTIVE: This study aims to document the nature and progression of spontaneous speech impairment suffered by patients with Alzheimer's disease (AD) over a 12-month period, using both cross-sectional and prospective longitudinal design. METHODS: Thirty one mild-moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex oral description task at baseline. The AD patients then underwent follow-up assessments at 6 and 12 months. RESULTS: Cross-sectional comparisons indicated that mild-moderate AD patients produced more word-finding delays (WFDs) and empty and indefinite phrases, while producing fewer pictorial themes, repairing fewer errors, responding to fewer WFDs, produce shorter and less complex phrases and produce speech with less intonational contour than controls. However, the two groups could not be distinguished on the basis of phonological paraphasias. Longitudinal follow-up, however, suggested that phonological processing deteriorates over time, where the prevalence of phonological errors increased over 12 months. Discussion Consistent with findings from neuropsychological, neuropathological and neuroimaging studies, the language deterioration shown by the AD patients shows a pattern of impairment dominated by semantic errors, which is later joined by a disruption in the phonological aspects of speech.

Translocation of the embodied self without visuospatial neglect.

This is the case report of RB, a 68-year-old retired woman who, following an extensive right sided ischaemic stroke, showed hemiplegia, anosognosia and allochiria, but no somato-sensory deficits and no visuospatial neglect. A high resolution 3D MRI structural scan of her brain was acquired to define the structural damage in detail. Morphometric analyses of grey and white matter data revealed a large lesion which involved most of her right parietal, temporal, and mesial frontal cortex, with partial sparing of the right dorsolateral prefrontal cortex and part of the posterior corpus callosum. Detailed examination showed that RB attributed sensory stimuli, both on the left and on the right, to the opposite side of her body. This mirror reversed representation of her body caused misattribution of items even in the absence of stimulation, as for instance when the patient spontaneously reported pain in her right knee while pointing to her left knee. RB's neuropsychological profile showed normal or borderline performance on most cognitive tasks. Language comprehension was intact and she could tell left from right without difficulty in all instances except for those referable to her soma. To our knowledge this is the first description of severe allochiria for body representation in the absence of neglect. The evidence from this case supports the developing concept that the body representation is not simply a systematic registration of proprioceptive inputs, but that the brain has a more sophisticated high level representation of one's body map which is updated on the basis of multimodal information.

Influence of APOE status on lexical-semantic skills in mild cognitive impairment.

This study characterized the relationship between apolipoprotein E (APOE) status and residual semantic abilities in amnestic mild cognitive impairment (MCI). APOE status (ε4 carrier/non ε4 carrier) was determined in 30 amnestic MCIs and in 22 healthy matched non ε4 carrier controls. The lexical characteristics (age of acquisition, typicality, familiarity) of words produced in a category fluency task were determined. MCIs produced fewer words than controls and these were also earlier acquired and more familiar. The words produced by MCI ε4 carriers were earlier acquired than those of non ε4 carriers. Analyses limited to the first 10 words produced by patients and controls showed similar findings and also revealed that MCI subgroups retrieved first more typical words than controls. Follow up showed higher conversion to Alzheimer's disease (AD) in MCI ε4 carriers than in non ε4 carriers. These findings show that a significant proportion of phenotype variability in performance on category fluency in people at increased AD risk is influenced by genetic factors. These findings explain why category fluency deficits, together with episodic memory deficits, are the only consistent early deficits in MCI patients who convert to AD.

The neuroanatomical substrate of lexical-semantic decline in MCI APOE ε4 carriers and noncarriers.

Lexical-semantic competency in mild cognitive impairment (MCI) ε4 carriers was used as an endophenotype, and gray matter volume in MCI ε4 carriers/noncarriers and in noncarrier controls was compared. Residual gray matter volumes were correlated with age of acquisition values for words from a category fluency task, an index of semantic competency. MCI patients had significantly impoverished lexical-semantic output compared with controls, more marked in MCI ε4 carriers. Smaller volumes in the left hippocampus, bilateral regions of the uncus, and posterior cingulate cortex were associated with a tendency to retrieve earlier acquired words in the category fluency task in MCI ε4 carriers, whereas poor semantic performance in MCI noncarriers was associated with smaller volumes in the left uncus, bilateral regions of the parahippocampal gyrus, and hippocampus, and also in a large number of neocortical regions. There was a significant semantic competency by genotype interaction in the left perirhinal cortex, in a number of left frontal and temporal areas and in the right inferior parietal lobule and precuneus. MCI ε4 carriers, when compared with noncarriers, had lower gray matter volume values confined to the right precuneus and the cerebellum bilaterally, but the converse comparison showed that MCI noncarriers had lower values in extensive frontal, temporal, and parietal regions of the neocortex. Similar brain volumetric variations linked to genotype were found in minimal-to-mild AD. The results suggest a relatively specific impact of apolipoprotein E (APOE) ε4 burden and underline the value of linguistic assessment in preclinical diagnosis.

Anosognosia for memory impairment in Alzheimer's disease.

UNLABELLED: Stewart G, McGeown WJ, Shanks MF, Venneri A. Anosognosia for memory impairment in Alzheimer's disease. Objective To investigate whether patients with Alzheimer's disease (AD) were able to alter their awareness of memory deficits after exposure to a memory task. METHODS: Thirty normal older adults and 23 mild AD patients participated in the study. Anosognosia was assessed using discrepancies between self- and informant-evaluations of cognitive and functional performance. Participants estimated their performance on the Verbal Paired Associates task at different points in time (before, immediately after the task and after a 1-h delay). RESULTS: AD patients were generally less able to judge their memory abilities than healthy older adults, and tended to overestimate their task performance beforehand. Their prediction accuracy increased immediately after the task, but after a 1-h delay, they again misjudged their abilities at pretesting accuracy levels. Self-carer discrepancy scores of awareness of deficits in memory and other areas correlated significantly with memory tests but not with other neuropsychological tasks in the assessment, and larger discrepancy scores were associated with poorer performance. CONCLUSION: AD patients can monitor their task performance online, but are unable to maintain awareness of their deficits over time. Loss of awareness of memory deficits (or of any other deficits) in early stage AD may indicate damage to a system which updates a personal knowledge base with recent information. Failure to retain this information impedes abstraction from episodic to semantic memory.

Responders to ChEI treatment of Alzheimer's disease show restitution of normal regional cortical activation.

Clinical trials of cholinesterase inhibitor (ChEI) drugs, although generally reporting only minimal improvements in patients with Alzheimer's disease (AD), indicate that a subgroup of patients may respond substantially to treatment. This study aimed to assess the clinically variable ChEI treatment effects in a group of patients with mild AD using a semantic association and an N-back light working memory activation paradigm. Twenty-six patients with probable mild AD treated with a ChEI for 20 weeks were retrospectively divided into responders and non-responders. Patients were classified as responders if their Clinician's Interview Based Impression of Change (CIBIC - Plus) score was four or less and if they had an increase of at least two points on the MMSE. These criteria resulted in two subgroups comprising nine responders and seventeen non responders. Nine healthy elderly age-matched controls were also recruited as a comparison group. ChEI treatment was accompanied by significant modulation of task induced activation increases in both fMRI tasks in AD responders. The effect of ChEI response was in effect a restoration of regional brain function in the same areas used by elderly controls when performing these tasks. In non-responders decrements in task related activation were observed and over time activation patterns appeared less like the elderly controls. Screening semantic fluency scores correlated negatively with activation increases at retest. In the paper, a tentative explanation is offered of why subgroups of patients with a similar clinical diagnosis and level of clinical severity show a different physiological response to ChE inhibition.

Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's disease research has largely concentrated on the study of cognitive decline, but the associated behavioural and neuropsychiatric symptoms are of equal importance in the clinical profile of the disease. There is emerging evidence that regional differences in brain atrophy may align with variant disease presentations. The objective of this study was to identify the regions of decreased grey matter (GM) volume which were associated with specific neuropsychiatric behaviours in patients with mild Alzheimer's disease. Voxel-based morphometry was used to correlate GM derived from T(1)-weighted MRI images of 31 patients with mild Alzheimer's disease and specific neuropsychiatric symptoms and behaviours measured by the Neuropsychiatric Inventory. Delusions were associated with decreased GM density in the left frontal lobe, in the right frontoparietal cortex and in the left claustrum. Apathy was associated with GM density loss in the anterior cingulate and frontal cortex bilaterally, the head of the left caudate nucleus and in bilateral putamen. Agitation was associated with decreased GM values in the left insula, and in anterior cingulate cortex bilaterally. Neuropsychiatric symptoms of Alzheimer's disease seem to associate with neurodegeneration of specific neural networks supporting personal memory, reality monitoring, processing of reward, interoceptive sensations and subjective emotional experience. The study of neurodegenerative disorders such as Alzheimer's disease using voxel-based morphometry and other imaging modalities may further the understanding of the neural structures that mediate the genesis of abnormal behaviours.

Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level.

The anatomical bases of semantic retrieval deficits in early Alzheimer's disease.

Semantic abilities deteriorate early in patients with Alzheimer's disease (AD) and their residual language is characterised by strong lexical effects such as the age of acquisition of words and their typicality. The anatomical bases of this early semantic degradation have not been fully explored. To clarify which neural structures, when atrophic, alter lexical-semantic function in patients with very mild AD, this study correlated the lexical attributes of words produced in a semantic fluency task with grey matter density values from 3D MRI scans of mild AD patients. The voxel-based analyses showed a significant correlation between the lexical attributes characterising residual linguistic production in early AD patients and the integrity of regions of the medial temporal lobes, especially in areas of the perirhinal and parahippocampal cortex. This correlation was present in both hemispheres. There were no correlations within these structures with scores on neuropsychological tests not involving semantic or episodic memory. The results have implications for the role of medial temporal structures in episodic and semantic retrieval and argue against a unitary function of these structures in respect of episodic and semantic memory processes. This evidence suggests that specialised regions within the hippocampal complex engage in processes of encoding and retrieval for both semantic and episodic memories.

Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease.

This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment. Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients.

Provoked confabulations in Alzheimer's disease.

Confabulation in Alzheimer's disease (AD) has been the subject of limited investigation. When studied, the phenomenon has been found to share characteristics with memory distortions produced by neurologically intact individuals. Previous studies that have investigated confabulation in AD have failed to take into account the characteristics of the disease and the presence of confabulations in the retrieval of recent autobiographical memory (ABM). The aim of this study was to develop a test that could investigate the tendency to confabulate in recent autobiographical memory that was specifically created for eliciting confabulatory behaviours in patients with AD. Four experiments have been carried out. In Experiment 1, AD patients who have yet to show confabulatory behaviour were compared to elderly adults. The results revealed that AD patients produced significantly more confabulations on the new test compared to elderly adults. Experiment 2 investigated if the results of the initial experiment were due to AD patients having limited working memory capacity that would lead to difficulties in performing the test compared with elderly adults as AD patients would be in a condition of memory overload. The results showed that even when compared with the performance of elderly individuals under memory overload condition, AD patients still produced more confabulations than elderly adults. Using a correlational approach Experiments 3 and 4 revealed that a high production of provoked confabulatory answers were associated with poor scores on personal episodic memory measures but not with other measures of cognitive functioning such as working memory and/or executive function.

Patterns of impairment in autobiographical memory in the degenerative dementias constrain models of memory.

Detailed study of the autobiographical memory (ABM) impairments seen in different forms of degenerative dementia, in particular Alzheimer's disease (AD) and semantic dementia (SD) can inform neuropsychological models of memory. A modified ABM questionnaire which allowed more detailed analysis of episodic and semantic ABM was used to study the pattern of deficits in patients with minimal to mild Alzheimer's disease (AD) and in two patients with mild and moderate semantic dementia (SD). The questionnaire tested both cued and free recall. A group of healthy elderly was also tested. AD patients differed from controls in all measures. There was no clear temporal gradient for episodic ABM, but a modest gradient was observed for semantic ABM. The mild SD patient performed at control level for episodic ABM but showed a deficit within the range of the AD patients for semantic ABM except for the most recent life period. In contrast the moderate SD patient was impaired within the range of the AD patients for both episodic and semantic ABM. The evidence for differential impairment of episodic and semantic ABM retrieval in AD and SD is interpreted as supporting the multiple trace model of memory.

The age of acquisition of words produced in a semantic fluency task can reliably differentiate normal from pathological age related cognitive decline.

This study examined differences in the characteristics of words produced by healthy elderly controls and by patients with Alzheimer's disease (AD) in a semantic fluency task (generating words from the categories of animals and fruit). Ninety-six AD patients (MMSE 13-29) and 40 controls matched for age and socio-cultural background completed a semantic fluency task. Length, frequency, typicality and age of acquisition (AoA) values were obtained for each word generated. In comparison with controls, AD patients generated fewer items, and their items were higher in frequency, shorter in length, more typical and earlier in AoA. Discriminant function analysis showed that AoA was the best predictor of group membership (patient/control). The mean AoA of words generated correctly classified 95% of controls and 88% of patients.

Empirical evidence of neuroprotection by dual cholinesterase inhibition in Alzheimer's disease.

Brain grey matter density changes were quantified using voxel based morphometry in 26 patients with minimal to mild Alzheimer's disease (AD) treated with three cholinesterase inhibitors over 20 weeks. Patients whose drug treatment also inhibited butyrylcholinesterase did not show the widespread cortical atrophic changes in parietotemporal regions invariably reported in untreated AD patients, and which were detectable in the subgroups treated with selective acetylcholinesterase inhibition. This finding is the first empirical evidence that dual cholinesterase inhibition may have neuroprotective potential in AD.