Michael F. Shanks

Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease

Alzheimers 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 Alzheimers disease. Voxel-based morphometry was used to correlate GM derived from T(1)-weighted MRI images of 31 patients with mild Alzheimers 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 Alzheimers 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 Alzheimers disease using voxel-based morphometry and other imaging modalities may further the understanding of the neural structures that mediate the genesis of abnormal behaviours.

Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease.

Twenty seven patients with mild AD were enrolled in a prospective open label controlled study of rivastigmine. Assessments included a range of neuropsychiatric and behavioural measures and rCBF using HMPAO SPECT at baseline, three and six months. Significant enhancement of frontal, parietal and temporal brain blood flow with related psychometric improvement was observed in twelve of the treated patients. A pattern of reduced rCBF and cognitive performance was observed in four unresponsive and eleven untreated patients. The results suggest that alterations in the clinical and cognitive status of patients receiving a cholinesterase inhibitor are paralleled by changes in rCBF. Longitudinal assessment with repeated imaging offers a method of better understanding the effects of cholinesterase inhibition on the AD brain.

Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction.

Delusional thinking and related behaviours are common symptoms in Alzheimers disease (AD). The aim of the study was to determine if any consistent cerebral image pattern can be identified using Tc99m-hexamethylpropyleneamine (HMPAO) SPET in AD patients with and without delusions. 18 AD patients with delusion and 15 AD patients without delusion underwent neuropsychological testing and regional cerebral blood flow imaging using Tc99m-HMPAO SPET. The reconstructed data was compared using regions of interest drawn over each cerebral lobe and a statistical parametric mapping (SPM) approach. The neuropsychological testing showed that there was no difference in the profiles of the deluded and non deluded AD patients. The imaging results showed a significant degree of image asymmetry. This took the form of a right hemisphere hypoperfusion mainly in the right frontal and limbic regions. The results do not indicate a specific focal site of hypoperfusion in the patients with delusion. They do, however, indicate that delusions in AD may be associated with areas of hypoperfusion in the right anterior hemisphere.

Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy

Alzheimers disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimers disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimers disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from −1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).

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 Alzheimers 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.

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 Alzheimers 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 Alzheimers 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.

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 Alzheimers 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.

The evolution of dysgraphia in Alzheimer’s disease

Evidence from recent studies suggests that writing may be an aspect of cognition capable of identifying impairments specific to patients with Alzheimers Disease (AD). The precise nature and progression of the writing disorder, however, remains unclear. The current study assessed the central and peripheral aspects of writing among a sample of minimal, mild and moderate AD patients and a group of healthy elderly controls on a narrative description task. Comparisons of the two groups indicated that AD patients suffer from a primary impairment at the semantic level. Even those in the minimal stages of the disease could be differentiated from controls on measures of word finding and information conveyed. This semantic impairment was coupled with a secondary milder impairment in phonological processing. The prevalence of phonological errors increased, but no shift in error type (plausible/implausible) was identified as the disease progressed. In addition to the central impairments, patients evinced damage at the peripheral level. In the more severe stages, patients experienced more problems with letter formation and stroke placement and tended to rely upon the more simplistic writing form of print. The writing impairment in AD is multi-componential in nature and follows the pattern of cortical deterioration reported in the brains of AD patients.

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

Semantic abilities deteriorate early in patients with Alzheimers 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.

Cholinesterase inhibition: is there evidence for disease-modifying effects?

Abstract Background: Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimers disease (AD). Symptomatic effects are mediated by the inhibition of acetyl- and/or butyryl-cholinesterase (AChE and/or BuChE) – the enzymes that degrade acetylcholine (ACh) in the synapse. However, ACh is also found outside the synapse (‘extracellular ACh’) where, among other activities, it plays a role in controlling inflammation and might impact on pathological changes. Objective/scope: New data and clinical findings are reviewed and discussed to build a preliminary case for possible disease-modifying effects of cholinesterase inhibition. Findings: Trials seeking to demonstrate disease-modifying effects in subjects with mild cognitive impairment failed to reach their primary endpoints, but these failures might relate to aspects of trial methods and analyses. A re-analysis of one of these trials, using a more sensitive model controlling for factors that predict progression to AD, showed a significant delay in progression to AD with dual cholinesterase inhibition over 3 to 4 years. Taken with other evidence, it is plausible that cholinesterase inhibition might contribute to disease modification. The detection of putative disease-modifying effects may be most easily implemented in certain patient subpopulations, and genotyping studies suggest a particular role for BuChE. Conclusion: Long-term inhibition of BuChE might be especially important when exploring any disease-modifying effects of cholinesterase inhibitors. Elucidation of the mechanisms involved could provide insights leading to the development of new treatments that modify the development and progression of AD.