Gordon K. Wilcock

Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination

BACKGROUNDnThere are many reports of psychological morbidity in spousal carers of patients with dementia. The consequences of this increased stress on the immune system are unclear. We investigated whether antibody responses to influenza vaccination differed between carers and a control group, and the relation of the antibody response to the hypothalamic-pituitary-adrenal (HPA) axis.nnnMETHODSn50 spousal carers of dementia patients, median age 73 years (IQR 66-77), and 67 controls (68 years [66-71]) of similar socioeconomic status were enrolled. Anxiety and depression were measured by the Savage Aged Personality Screening Scale and stress by the Global Measure of Perceived Stress scale. Principal-component analysis was used to yield a summary score of emotional distress from these two scales. Salivary cortisol concentrations were measured over a single day at three times (0800-1000, 1100-1300, and 2000-2200). Participants received a trivalent influenza vaccine and IgG antibody titres to each strain were measured on days 0, 7, 14, and 28.nnnFINDINGSnMean scores of emotional distress were significantly higher in carers at each time point than in controls (all p<0.0003). Mean (SD) salivary cortisol concentrations, calculated as area under the curve (AUC), were higher in carers than controls at all three assessments (6 months 16.0 [8.0] vs 11.2 [4.4], p=0.0001; respectively). Eight (16%) of 50 carers and 26 (39%) of 67 controls had a four-fold increase in at least one of the IgG titres (p=0.007). There was an inverse relation between AUC cortisol and IgG antibody titre to the Nanchang strain that was significant on day 14 (r=-0.216, p=0.039).nnnINTERPRETATIONnElderly carers of spouses with dementia have increased activation of the hypothalamic-pituitary-adrenal axis and a poor antibody response to influenza vaccine. Carers may be more vulnerable to infectious disease than the population of a similar age.

A Long-Term Comparison of Galantamine and Donepezil in the Treatment of Alzheimer’s Disease

ObjectiveTo compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer’s disease.Patients and Study DesignThis was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer’s disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks.Main outcome measuresThe effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed.ResultsBrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients’ scores on the MMSE at week 52 did not differ significantly from baseline (−0.52 ± 0.39, p < 0.5 vs baseline), whereas donepezil patients’ scores deteriorated significantly from baseline (−1.58 ± 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12–18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 ± 0.80 versus baseline, compared with an increase of 4.08 ± 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p ≤ 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments.Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.ConclusionsSignificant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

Structural MRI changes detectable up to ten years before clinical Alzheimer's disease.

Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimers disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel-based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow-up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology.

Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy

Neprilysin (NEP) degrades amyloid-&bgr; (A&bgr;) and is thought to contribute to its clearance from the brain. In Alzheimer disease (AD), downregulation of NEP has been suggested to contribute to the development of cerebral amyloid angiopathy (CAA). We examined the relationship among NEP, CAA, and APOE status in AD and elderly control cases. NEP was most abundant in the tunica media of cerebrocortical blood vessels and in pyramidal neurons. In homogenates of the frontal cortex, NEP protein levels were reduced in AD but not significantly; NEP enzymatic activity was significantly reduced in AD. Immunohistochemistry revealed a reduction of both vascular and parenchymal NEP. The loss of vessel-associated NEP in AD was inversely related to the severity of CAA, and analysis of cases with severe CAA showed that levels of vascular NEP were reduced to the same extent in A&bgr;-free and A&bgr;-laden vessels, strongly suggesting that the reduction in NEP is not simply secondary to CAA. Possession of APOE &egr;4 was associated with significantly lower levels of both parenchymal and vascular NEP. Colinearity of &egr;4 with the presence of moderate to severe CAA precluded assessment of the independence of this association from NEP levels. However, logistic regression analysis showed low NEP levels to be a significant independent predictor of moderate to severe CAA.

Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function

Vitamin B12 assay is part of the routine investigation of dementia, although few studies have investigated the effects of treatment on cognition. We examined the effects of B12 treatment on neuropsychological function and disease progression in patients presenting with dementia or cognitive impairment.

ALPHA -2 MACROGLOBULIN POLYMORPHISM AND ALZHEIMER DISEASE RISK IN THE UK

There is a genetic component in the aetiology of Alzheimer disease1 (AD). Recently, Blacker et al. reported an odds ratio of 3.56 for being affected by AD in individuals carrying at least one copy of an -2 macroglobulin gene (A2M) allele (A2M*2) corresponding to a deletion near the 5´ splice site of exon 18 (2). Cases were aged 50 years and older and 22% had autopsy diagnoses2. This effect was independent of APOE. We tried to replicate these findings using three different samples. Our first sample was composed of 125 autopsy-confirmed AD cases from Brain Banks in England and 218 elderly non-demented controls. Where age of onset was documented, 3 cases were younger than 50 years and 30 cases were 50-65 years. In cases where the age at onset was not available, 35 individuals died before age 66, including 2 before 50 years. We used non-demented elderly English individuals as controls: 59 from Ely (a town 14 miles from Cambridge) aged 70 years and older meeting neither DSM-III-R nor AGECAT dementia criteria3; and 159 from Cambridge aged 84 years and older with Mini Mental State Examination (MMSE) scores of more than 23 (3). Our second sample was composed of 53 pairs of age-matched (within 5 years) demented cases and controls, aged 70 years and older, from the epidemiologically based Ely component of the Medical Research Council Cognitive Function and Ageing Study4. Cases met both DSM-III-R and AGECAT criteria3 and controls met neither of these dementia criteria. The controls used in our first sample included those from the matched case-control series with six unmatched controls from the same cohort.

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease

We have examined genomic DNA from 40 cases of autopsy-confirmed early-onset Alzheimer disease (EOAD) (age at onset <=65 years) that were all unselected for family history. We have sequenced the 10 exons and flanking intronic sequences of the presenilin-1 (PS-1) gene for all 40 individuals. A single mutation, a deletion of a G from the intron 4 splice-donor consensus sequence, was detected in two individuals in this study. The mutation was associated with two shortened transcripts, both with shifted reading frames resulting in premature-termination codons. All the PS-1 mutations described elsewhere have been missense or in-frame splice mutations, and recent data suggest that these result in disease by gain-of-function or dominant-negative mechanisms. The mutation that we have identified is likely to result in haploinsufficiency and would be most consistent with other mutations acting in a dominant-negative manner. However, we cannot exclude the possibility that the small amounts of truncated transcripts exert a gain of function. Since no other mutations or polymorphisms were detected in our patients, mutations in the coding regions and splice consensus sequences of PS-1 are likely to be rare in EOAD cases unselected for family history.

Tumour necrosis factor-α gene polymorphisms and Alzheimer's disease

Recent findings suggest that production of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), is increased in the brains of people with Alzheimers disease (AD). We used direct sequencing methods on a section of the enhancer/promoter region and on a smaller fragment located 10.5 kb upstream of the TNF-alpha gene to respectively examine TNF-alpha polymorphisms and TNF-a and -b microsatellite alleles in a cohort of 235 post-mortem confirmed AD and 130 control cases. None of the TNF-alpha point mutations or microsatellite alleles investigated proved to be independent risk factors for AD. However, when -308/A, -238/G and TNF-a2 were examined as a 2-1-2 haplotype, we observed that the absence of that haplotype was significantly associated with AD (P = 0.014, Fishers exact test) suggesting that the 2-1-2 haplotype may be protective against AD.

Obesity, abdominal obesity and Alzheimer disease.

Background/Aims: Obesity has a strong association with vascular and metabolic diseases, which have been linked with Alzheimer disease (AD). While recent studies have reported an association between mid-life obesity and dementia, the role of later-life obesity is less clear. This study investigated the relation between AD, obesity and abdominal obesity at later-life in a case-control study. Methods: Participants were 50 consecutive patients with probable AD from memory disorders clinics in Launceston, Australia, and Bristol, England, and 75 cognitively normal controls. Height and weight [from which body mass index (BMI) was calculated] and hip and waist circumferences (from which waist-hip ratio was calculated) were measured. Participants were classified according to their BMI as: underweight (BMI <20.0 kg/m2); normal weight (BMI 20.0–24.9 kg/m2); overweight (BMI 25–29.9 kg/m2), or obese (BMI ≧30 kg/m2). They were classified as abdominally obese if their waist-hip ratio was >0.9 (men) or >0.8 (women). Results: AD was associated with obesity [OR 9.5, 95% CI 2.4–37.3, p = 0.001], underweight (OR 5.4, CI 0.9–33.7, p = 0.07) and abdominal obesity (OR 2.5, CI 1.1–5.7, p = 0.027) using logistic regression analyses adjusted for age, sex and location. The inclusion of metabolic risk factors in the model increased the ORs for obesity (OR 12.6, CI 2.8–56.5, p = 0.001) and underweight (OR 7.9, CI 1.0–66.3, p = 0.056). Conclusion: AD may be associated with obesity, underweight and abdominal obesity at later life. Larger prospective studies are required to investigate this further.

Premorbid effects of APOE on synaptic proteins in human temporal neocortex.

APOE affects the risk of Alzheimers disease (AD) and course of several other neurologic diseases. Experimental studies suggest that APOE influences synaptogenesis. We measured the concentration of two presynaptic proteins, synaptophysin and syntaxin 1, and also postsynaptic density-95 (PSD95), in superior temporal cortex from 42 AD and 160 normal brains, and determined the APOE genotypes. The concentration of both presynaptic proteins was approximately two-thirds lower in AD than normal brains and that of PSD95 one-third lower. No effect of APOE on synaptic proteins was found in advanced AD. However, in normal brain, epsilon4 was associated with lower concentrations of all three synaptic proteins and epsilon2 with significantly elevated PSD95 (p=0.03). A combined measure of synaptic proteins showed a significant linear decrease from epsilon2 through epsilon3 to varepsilon4 (p=0.01). APOE influences the concentration of synaptic proteins in normal superior temporal cortex and may thereby affect the response to injury, and the risk and outcome of a range of neurologic diseases.