Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI.

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.

Alterations in working memory networks in amnestic mild cognitive impairment.

Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.

Differences in cognitive profile between TIA, stroke and elderly memory research subjects: a comparison of the MMSE and MoCA.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 ('normal' cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. METHODS: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. RESULTS: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. CONCLUSIONS: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic.

Differential effects of the APOE genotype on brain function across the lifespan.

Increasing age and carrying an APOE ε4 allele are well established risk factors for Alzheimer's disease (AD). The earlier age of onset of AD observed in ε4-carriers may reflect an accelerated aging process. We recently reported that APOE genotype modulates brain function decades before the appearance of any cognitive or clinical symptoms. Here we test the hypothesis that APOE influences brain aging by comparing healthy ε4-carriers and non-carriers, using the same imaging protocol in distinct groups of younger and older healthy volunteers. A cross-sectional factorial design was used to examine the effects of age and APOE genotype, and their interaction, on fMRI activation during an encoding memory task. The younger (N=36; age range 20-35; 18 ε4-carriers) and older (35 middle-age/elderly; age range 50-78 years; 15 ε4-carriers) healthy volunteers taking part in the study were cognitively normal. We found a significant interaction between age and ε4-status in the hippocampi, frontal pole, subcortical nuclei, middle temporal gyri and cerebellum, such that aging was associated with decreased activity in e4-carriers and increased activity in non-carriers. Reduced cerebral blood flow was found in the older ε4-carriers relative to older non-carriers despite preserved grey matter volume. Overactivity of brain function in young ε4-carriers is disproportionately reduced with advancing age even before the onset of measurable memory impairment. The APOE genotype determines age-related changes in brain function that may reflect the increased vulnerability of ε4-carriers to late-life pathology or cognitive decline.

Safety and efficacy of galantamine in subjects with mild cognitive impairment.

OBJECTIVE: To assess the safety of galantamine in subjects with mild cognitive impairment (MCI), the ability of galantamine to benefit cognition and global functioning in subjects with MCI, and the ability of galantamine to delay conversion to dementia. METHODS: In two studies, 2,048 subjects, 990 in Study 1 and 1,058 in Study 2, with a Clinical Dementia Rating (CDR) = 0.5, CDR memory score > or =0.5, without dementia were randomized to double-blind galantamine (16-24 mg/day) or placebo for 24 months. Primary efficacy endpoint at month 24 was number (%) of subjects who converted from MCI to dementia (CDR > or = 1.0). RESULTS: There were no differences between galantamine and placebo in 24-month conversion rates (Study 1: 22.9% [galantamine] vs 22.6% [placebo], p = 0.146; Study 2: 25.4% [galantamine] vs 31.2% [placebo], p = 0.619). Mean CDR-sum of boxes declined less with galantamine than placebo at 12 and 24 months in Study 1 (p = 0.024 [12 months] and p = 0.028 [24 months]), but not in Study 2 (p = 0.662 [12 months] and p = 0.056 [24 months]). Digit Symbol Substitution Test scores improved with galantamine in Study 1 at 12 months and in Study 2 at 24 months (Study 1: p = 0.009 [month 12] and p = 0.079 [Month 24]; Study 2: p = 0.154 [month 12] and p = 0.020 [month 24]). The most frequently reported adverse event was nausea (galantamine, 29%; placebo, 10%). Serious AEs occurred in 19% of each group. Mortality of the cohort after retrospectively determining the status of subjects (98.3%) at 24 months was 1.4% (galantamine) and 0.3% (placebo); RR (95% CI), 1.70 (1.00, 2.90). CONCLUSIONS: Galantamine failed to significantly influence conversion to dementia. Galantamine was generally well tolerated. Whereas recorded mortality was greater in the galantamine group than in the placebo group in the original per-protocol assessment, a post hoc analysis of the cohort was consistent with no increased risk.

Caveolin-1 and -2 and their relationship to cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) affects over 90% of patients with Alzheimer's disease (AD) and increases the risk of cerebral haemorrhage and infarction. Caveolae--cholesterol-enriched plasmalemmal microinvaginations--are implicated in the production of amyloid beta peptide (Abeta). Caveolin-1 (CAV-1) is essential for the formation of caveolae. Caveolin-2 (CAV-2) is expressed at the plasma membrane only when in a stable hetero-oligomeric complex with CAV-1. CAV-1 and CAV-2 are highly co-expressed by endothelium and smooth muscle. Recent studies suggest that down-regulation of CAV-1 causes a reduction in alpha-secretase activity and consequent accumulation of Abeta. We have used quantitative immunohistochemical techniques to assess the relationship between CAV-1 and CAV-2 with respect to Abeta accumulation in the cerebral vasculature in a series of post mortem brains. CAV-1 and CAV-2 were co-expressed within the tunica media and endothelium of cerebral blood vessels. There were regional differences in CAV-1 immunolabelling, which was significantly greater in the frontal cortex and white matter than in the parietal lobe (in both control and AD cases) or the temporal lobe (in AD alone). However, CAV-1 labelling in AD did not differ from that in controls in any of the three lobes examined. Assessment of CAV-1 labelling in relation to the severity of CAA showed CAV-1 to be significantly increased in the frontal white matter in a subgroup of AD cases with absent/mild CAA compared with controls with absent/mild CAA and to AD cases with moderate/severe CAA, but the latter groups did not show significant differences from one another. CAV-1 labelling did not vary with age, gender, APOE genotype, post mortem delay or brain weight. Only segments of blood vessels with particularly abundant Abeta and extensive loss of smooth muscle actin showed loss of CAV-1 and CAV-2 from the tunica media. Within these vessels endothelial CAV-1 was preserved and discontinuous CAV-2 labelling was noted along the outer aspect of the vessel wall. Our findings suggest that alterations in the expression of vascular CAV-1 and CAV-2 are unlikely to play a role in the development of CAA in AD.

How are quality of life ratings made? Toward a model of quality of life in people with dementia.

Quality of life (QOL) has become a focus of research in dementia. In measuring QOL, the views of people with dementia often have not been considered as researchers have proposed that they may not be able to articulate their opinions. This paper counters this belief, presenting a study using a grounded theory methodology to explore the issues that people with dementia felt were important for their QOL. Further, we propose a model of QOL including hypothesised links between important issues (including family and health), QOL and other variables. Twenty-five participants took part in one of nine focus groups. The groups included participants with mild to severe dementia with ages ranging from 49 to 93 years. Results indicate that most of the participants were willing and able to talk about their QOL. Of the 25 participants, only two said that their cognitive problems affected their QOL. Twenty-two issues were discovered through analysis to contribute to QOL, including continuingto live in your own home, independence, spouse and other family, feeling happy and feeling useful. People with dementia used social comparisons in talking about their QOL, as well as direct evaluation of their own happiness. A model of QOL based on theories of coping and response shift is suggested. The fact that so few of the participants talked about disease-orientated issues challenges the large cognitive components included in many QOL measures for use with people with dementia.

Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease.

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.

APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein.

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.

Age-related changes in the preattentional detection of visual change.

The ability to detect changes in the environment which occur outside the focus of current awareness is essential if the individual is to be able to divert attention to biologically salient stimuli. The preattentional mechanism underlying the automatic detection of stimulus change in the auditory modality has been extensively studied by recording an event-related potential known as the mismatch negativity. Recently a homologous response from the visual cortex has also been described. Ageing has been shown to affect the efficiency of preattentional processing in the auditory modality, a factor which may contribute to cognitive changes in the elderly. It is unclear whether a similar effect occurs in the visual system. To investigate this issue the visual mismatch negativity was recorded from 12 older adults and 24 younger adults. Whereas the younger adults displayed a robust visual MMN, that evoked in the older adults was significantly reduced in amplitude. The results are indicative of age-related deficits in automatic visual processing.

The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials.

OBJECTIVE: To evaluate the effect of selegiline in the treatment of patients with Alzheimer's disease, in terms of cognitive performance, functional ability, emotional state (including behaviour and mood) and global response. Data Sources The Cochrane database of trials, Embase, Medline and Psychlit. Study Selection Unconfounded, double-blind, randomised trials of selegiline compared with placebo reported before 31 December 1998. Data Extraction The reviewers selected trials for inclusion. Individual patient data were sought, but when these could not be retrieved summary data were extracted from published papers. RESULTS: Of 27 identified trials, 14 met the inclusion criteria. Individual patient data were retrieved from eight trials on 821 patients. Summary data were extracted from five trials on 240 patients. No data were available from one trial on 12 patients, which was therefore excluded from the meta-analysis. Fixed and random effects meta-analyses were performed on standardised mean differences. For cognition there was a statistically significant difference between selegiline and placebo at 4-6 weeks and 8-17 weeks after randomisation (at 8-17 weeks: smd=0.45 [95% confidence interval 0.03 to 0.88]), but this disappeared at later assessments. The size of the treatment difference was considered unlikely to be of clinical importance. Although there was a statistically significant difference at 4-6 weeks for activities of daily living, this disappeared at later assessments (at 8-17 weeks: smd=0.33 [-0.33, 0.69]). There were no statistically significant differences or clinically relevant differences between selegiline and placebo in terms of emotional state or global response. CONCLUSION: Although there was some evidence of improvement with selegiline in the short term in cognition and activities of daily living, the magnitude of the effect did not reach clinical importance. There was no evidence of long term effects.

Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease.

There is considerable interest in the status of calbindin immunoreactive neurones in Alzheimer's disease (AD) but previous studies have produced widely differing results. Here we describe calbindin neurones in temporal neocortex from 18 severely demented patients with neuropathologically confirmed AD and 13 age and post-mortem delay matched, neurologically normal controls. Calbindin immunoreactive neurones were small and round in layers II-IV, and pyramidal in layers IIIc and V. There were significantly more calbindin positive neurones in controls than in AD (mean+/- SD, for each comparison P < 0.01): superior temporal lobe, AD = 3.32 +/- 2.24, Control (C) = 24.83 +/- 10.8; middle temporal lobe, AD = 3.6 +/- 4.94, C = 26.09 +/- 15.7; inferior temporal lobe, AD 3.69 +/- 3.6, C = 25.25 +/- 16.9. Furthermore, there was an age-related increase in immunopositive neurones in the superior (r2 = 0.37, P = 0.046) and inferior (r2 = 0.75, P = 0.01) temporal gyri in controls. In AD the number of calbindin positive neurones did not change with age. This is the first report of such an age-related increase in controls, and it suggests that this, rather than a decrease in AD, accounts for the overall difference between AD and controls. It is possible that an increase in intraneuronal calbindin protects these cells from degeneration and that failure of such a neuroprotective mechanism is a significant contributory factor in the pathogenesis of AD.

Attentional control in Alzheimer's disease.

Attentional control of executive function declines during the early stages of Alzheimer's disease. Controversy exists as to whether this decline results from a single global deficit or whether attentional control can be fractionated, with some aspects being more vulnerable than others. We investigated three proposed domains of attention, namely (i) focal attention, based on simple and choice reaction times; (ii) the capacity to resist distraction in a visual search task; and (iii) the capacity to divide attention between two simultaneous tasks. For each domain, two levels of difficulty were used to study Alzheimer's disease patients, who were compared with elderly and young control subjects. The unitary attentional hypothesis predicted that the impacts of level of difficulty, age and disease would be qualitatively similar across the three attentional domains. In fact we observed different patterns for each domain. We obtained no differential impairment for patients in the focal attentional task, whereas patients were somewhat more susceptible than control subjects to the similarity of the distractor items in visual search. Finally, we observed marked impairment in the capacity of Alzheimer's disease patients to combine performance on two simultaneous tasks, in contrast to preserved dual-task performance in the normal elderly group. These results suggest a need to fractionate executive processes, and reinforce earlier evidence for a specific dual-task processing deficit in Alzheimer's disease.

Recombinant human nerve growth factor for clinical trials: protein expression, purification, stability and characterisation of binding to infusion pumps.

Nerve growth factor (NGF) has been suggested to be of therapeutic benefit to patients with Alzheimer's disease. One of the early changes in this disease is a loss of cholinergic function within the brain, and NGF is able to rescue cholinergic neurons both in vitro and in vivo. We describe the production of recombinant human beta-NGF (rhNGF), using baculovirus infection of insect cells; its purification, formulation and subsequent stability for use in clinical trials. Tests were also carried out to monitor release of protein from infusion pumps and catheters for intracerebroventricular administration (icv). Initial problems with non-specific binding were overcome using a blocking formula.

Identification and structure of the nerve growth factor binding site on TrkA.

Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system and has been implicated as a possible therapeutic target molecule in a number of neurodegenerative diseases, especially Alzheimer's disease. NGF binds with high affinity to the extracellular region of a tyrosine kinase receptor, TrkA, which comprises three leucine-rich motifs (LRMs), flanked by two cysteine-rich clusters, followed by two immunoglobulin-like (Ig-like) domains. We have expressed the second Ig-like domain as a recombinant protein in E. coli and demonstrate that NGF binds to this domain with similar affinity to the native receptor. This domain (TrkAIg(2)) has the ability to sequester NGF in vitro, preventing NGF-induced neurite outgrowth, and in vivo, inhibiting NGF-induced plasma extravasation. We also present the three-dimensional structure of the TrkAIg(2) domain in a new crystal form, refined to 2.0 A resolution.

The pupillary light reflex in aging and Alzheimer's disease.

The pupillary light reflex is reported to be reduced in amplitude in Alzheimer's disease (AD). The purpose of this study was to determine whether this effect is measurable under conditions typical of clinical rather than laboratory settings. A head-mounted infra-red videopupillometer was used to measure the amplitude of pupillary constriction in 12 patients with probable AD, 12 healthy age-matched older adults and 12 young adults. The constriction to the onset of bright light relative to the resting amplitude was significantly reduced in AD compared with both control groups. This result is consistent with an acetylcholine-related deficit in AD and supports the findings of Prettyman et al. and Fotiou et al. The impairment is likely to be caused by degeneration in relays in the midbrain but cholinergic deficits in the peripheral parasympathetic pathway cannot be excluded. The variation in pupillary response between individuals may preclude its use for diagnostic purposes. However, if the changes in pupillary response in AD are related to change in neurotransmitter status, then the value of such a technique may be in its use in providing an objective, non-invasive monitor of physiological abnormality with which to follow disease progression and treatment efficacy.

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.

OBJECTIVE: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimer's disease. DESIGN: Randomised, double blind, parallel group, placebo controlled trial. SETTING: 86 outpatient clinics in Europe and Canada. PARTICIPANTS: 653 patients with mild to moderate Alzheimer's disease. INTERVENTION: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. MAIN OUTCOME MEASURES: Scores on the 11 item cognitive subscale of the Alzheimer's disease assessment scale, the clinician's interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. RESULTS: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer's disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician's interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study. CONCLUSION: Galantamine is effective and well tolerated in Alzheimer's disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.