Martha G. MacAvoy

Apolipoprotein E ε4 Allele Is Unrelated to Cognitive or Functional Decline in Alzheimer’s Disease: Retrospective and Prospective Analysis

Objective: The apolipoprotein E (ApoE) Ε4 allele is a well-documented genetic risk factor for Alzheimer’s disease (AD). Its role, if any, in the progression of cognitive and functional impairment in AD has been the subject of discrepant reports in the literature. This study aimed to determine whether ApoE Ε4 dose is related to the progression of cognitive and functional decline in AD patients by combined retrospective and prospective analyses. Methods: A sample of 366 AD patients was genotyped for ApoE. Subjects received tests of cognition (Mini-Mental State Examination, MMSE; Alzheimer’s Disease Assessment Scale-Cognitive subscale, ADAS-Cog) and daily function (Instrumental Activities of Daily Living, IADL; Alzheimer’s Disease Cooperative Study-Activities of Daily Living, ADCS-ADL) at baseline and at multiple subsequent time points during their participation in a variety of research protocols. In retrospective analyses, scores on baseline cognitive and functional measures were compared cross-sectionally among genotype groups, controlling for duration of symptoms. In prospective analyses, longitudinal rates of change for each measure were computed by linear regression and compared across genotype groups. Results: No association was observed between ApoE Ε4 dose and any of the retrospective or prospective measures of cognitive or functional decline in this AD patient sample. Conclusions: Although ApoE Ε4 increases the risk for AD and decreases the age of disease onset in population studies, it did not significantly influence the rate of disease progression in cognitive or functional domains in our sample.

Comparison of the smooth eye tracking disorder of schizophrenics with that of nonhuman primates with specific brain lesions.

The smooth pursuit eye tracking deficit (ETD) often associated with schizophrenia has generated enormous interest over the last 20 years. The deficit is observed in about 80% of schizophrenics and in half of their first degree relatives. It is not affected by neuroleptic medication and is not due to inattention. A review of 52 studies (and actual records when available) on ETD in schizophrenia reveals that the deficit can consistently be described as low gain pursuit augmented with catch-up saccades and often peppered with intrusive saccades. A review of the brain areas that have been shown to be involved in pursuit provides the necessary background for the subsequent section which details the nature of the smooth tracking deficits following experimental lesions. This section reveals that the ETD following lesions of the frontal lobe is unique in that it closely resembles the ETD of schizophrenics. This finding lends further support for frontal lobe theories of schizophrenia.

Apolipoprotein E e4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

The apolipoprotein E (ApoE) ɛ4 allele is a well-documented genetic risk factor for sporadic Alzheimers disease (AD). Its association with psychopathology among AD patients has been the subject of discrepant reports. We aimed to determine whether ApoE ɛ4+ and ɛ4– AD patients exhibit a different risk profile for psychotic symptoms and other behavioral disturbances. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity of psychotic and other behavioral symptoms in a sample of n=266 AD patients who had been genotyped for ApoE. Multiple logistic regression models were used to calculate the association between the ApoE ɛ4 allele and the presence of psychotic symptoms (delusions or hallucinations). Exploratory analyses were also conducted to determine the impact of disease severity on ɛ4 effects and to examine the association between ɛ4 and other behavioral symptoms. ApoE ɛ4 was significantly associated with psychotic symptoms (odds ratio (OR)=1.87, 95% CI=1.07–3.29, P=0.029), adjusting for age, sex, education, and MMSE score. More stringent definitions of clinically significant psychosis yielded similar results. Exploratory analyses suggested that this effect accrued specifically from patients with severe-stage AD and primarily from an association between ɛ4 and delusions. The ɛ4 allele did not appear to influence the development of most other behavioral symptoms in our sample. In conclusion, AD patients who carry the ApoE ɛ4 allele are at greater risk than noncarriers for developing psychotic symptoms, particularly as the severity of their dementia progresses.

Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer's disease

Although the ApoE epsilon4 allele is well-established as the most important genetic risk factor for Alzheimers disease (AD), the effects of this allele on regional brain atrophy in AD patients remain controversial. We performed MRI-based volumetric measurements of the hippocampus and amygdala (normalized to intracranial volume) in 32 epsilon4+ AD patients, 23 epsilon4- AD patients, and 42 cognitively normal elderly control subjects. Analysis of covariance revealed that amygdaloid volume was significantly smaller (19.2%) in ApoE epsilon4+ than epsilon4- AD patients, controlling for disease severity (F = 10.62; d.f. = 1,52; p = 0.002; ANCOVA). Alternatively, when ApoE epsilon4 dose was considered, this effect appeared to accrue from a difference between the 0epsilon4 and each of the other two AD groups, with no significant difference between the 1epsilon4 and 2epsilon4 AD groups. Hippocampal volumes and asymmetry indices for hippocampus and amygdala did not differ between epsilon4 carriers and noncarriers. These results suggest accelerated atrophy of the amygdala in AD in association with ApoE epsilon4 and provide further evidence for regionally specific effects of this allele.

123I-5-IA-85380 SPECT Imaging of Nicotinic Receptors in Alzheimer Disease and Mild Cognitive Impairment

Postmortem binding studies have established that the concentration of α4β2-nicotinic acetylcholine receptors (α4β2-nAChR) is reduced in advanced Alzheimer disease (AD). However, the status of this receptor in mild or prodromal AD has remained the subject of controversy. Methods: We compared α4β2-nAChR availability in 8 brain regions of living human subjects who had AD and mild cognitive impairment (MCI) with that in age-matched healthy control subjects by using the ligand 123I-5-IA-85380 (123I-5-IA) and SPECT. All subjects (n = 32) were nonsmokers; they were administered 123I-5-IA as a bolus plus a constant infusion and imaged 6–8 h later under equilibrium conditions. The effect of diagnosis on regional α4β2-nAChR availability (regional brain activity/total parent concentration in plasma, proportional to the binding potential) was analyzed using multivariate analysis of covariance, controlling for the effects of age and sex. Results: Despite a significant overall effect of diagnostic group on mean α4β2-nAChR availability, univariate analyses revealed no group differences for any brain region analyzed. An exploratory analysis of the relationship between regional α4β2-nAChR availability and neuropsychologic variables yielded several plausible correlations. However, after Bonferroni adjustment, only the correlation between the anterior cingulate and the Trail Making Test, Part B, in the healthy control subjects remained significant. Conclusion: These results are consistent with several postmortem and in vivo studies suggesting the preservation of nAChRs during the prodromal and early stages of AD. They support the interpretation that nAChR and other cholinergic reductions in AD are late-stage phenomena.

Striatal dopamine transporters correlate with simple reaction time in elderly subjects

The decline in motor performance that accompanies advanced age has unclear neurobiological substrates but may relate, in part, to degeneration of the nigrostriatal dopamine system. This research tested the hypothesis that striatal dopamine transporter (DAT) availability in healthy elderly individuals was related to measures of motor performance. Thirty-six healthy volunteers (18 male, 18 female) who ranged in age from 68 to 88 (75.4+/-4.9 years) received a neuropsychological evaluation that included two primary motor measures (tested with dominant hand): (1) simple reaction time (SRT); and (2) finger tapping (FT). Subjects underwent SPECT scanning with [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT) for measurement of striatal DAT availability. A ratio of specific to nondisplaceable brain uptake (i.e., radical V3 =[striatal-occipital]/occipital), a measure proportional to the binding potential (B(max)/K(D)), was derived. SRT was significantly correlated with striatal DAT availability with or without controlling for the contribution of age. However, contrary to hypothesis, FT was not correlated with striatal DAT availability. Comparison measures, including episodic memory and general intelligence, were also unrelated to striatal DAT availability. These results demonstrate that a loss of nigrostriatal dopaminergic function likely contributes to slowing of reaction speed with advancing age.

Regional distribution and behavioral correlates of 5-HT2A receptors in Alzheimer's disease with [18F]deuteroaltanserin and PET

Postmortem studies show reductions in brain serotonin 2A (5-HT(2A)) receptors in Alzheimers disease (AD). Converging evidence also suggests that serotonergic dysregulation may contribute to behavioral symptoms that frequently occur in AD. This study aimed to define regional reductions in 5-HT(2A) binding in AD patients and to examine their behavioral correlates. Nine patients with probable AD and eight elderly controls were studied using a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with positron emission tomography (PET). Region of interest analyses were performed on PET images coregistered to MRI scans. The outcome measures BP(P) (ratio of specific brain uptake to total plasma parent concentration) and BP(ND) (ratio of specific to nondisplaceable uptake) were obtained for pertinent cortical and subcortical regions. AD patients showed a statistically significant decrease in the anterior cingulate in both BP(P) and BP(ND), but in no other region. Within the AD patient sample, no significant correlations were observed between regional 5-HT(2A) binding and behavioral measures, including depressive and psychotic symptoms. These results confirm a reduction in cortical 5-HT(2A) receptors in AD, specifically in the anterior cingulate. However, in a limited AD patient sample, they fail to demonstrate a relationship between regional 5-HT(2A) binding and major behavioral symptoms.

BDNF variants, premorbid educational attainment, and disease characteristics in Alzheimer's disease: an exploratory study.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal survival, growth, and differentiation. The role of BDNF in learning and memory suggests that it may also modulate the clinical course of Alzheimers disease (AD). This study aimed to determine whether BDNF genetic variants are related to premorbid educational attainment, progression of cognitive and functional decline, and associated neuropsychiatric symptoms in AD patients. A sample of AD subjects (N = 341) was genotyped for the BDNF polymorphisms: Val66Met, C270T, and G-712A. Subjects received tests of cognition and daily function at baseline and at multiple subsequent time points. They were also characterized for the frequency and severity of neuropsychiatric symptoms. There was a significant effect of Val66Met genotype on educational attainment (F = 7.49, df = 2,329, P = 0.00066), with Met/Met homozygotes having significantly lower education than both the Val/Met and Val/Val groups. No association was observed between any BDNF polymorphism and measures of cognitive or functional decline. The T-allele of the C270T polymorphism was associated with a higher prevalence of neuropsychiatric symptoms and specifically with the presence of hallucinations. The effect of the Val66Met polymorphism on premorbid educational attainment is intriguing and should be verified in a larger sample.