Personality and the genetic risk for alcohol dependence.

The extent to which the genetic risk for alcohol dependence (AD) and conduct disorder (CD) and their common genetic risk overlap with genetic factors contributing to variation in dimensions of personality was examined in a study of 6,453 individuals from 3,383 adult male and female same-sex and unlike-sex twin pairs from the Australian Twin Registry. The associations between the personality dimensions of positive emotionality, negative emotionality, and AD and CD risk were modest, whereas the associations between behavioral undercontrol and AD and CD risk were substantially higher. Genetic influences contributing to variation in behavioral undercontrol accounted for about 40% of the genetic variation in AD and CD risk and about 90% of the common genetic risk for AD and CD. These results suggest that genetic factors contributing to variation in dimensions of personality, particularly behavioral undercontrol, account for a substantial proportion of the genetic diathesis for AD and most of the common genetic diathesis for AD and CD among both men and women. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease

BACKGROUND: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. OBJECTIVE: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. DESIGN: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. SETTING: Referral population to a hospital clinic between July 1988 and April 1996. MAIN OUTCOME MEASURES: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. RESULTS: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. CONCLUSIONS: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.     

Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia

OBJECTIVE: To compare the evolution of Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia by cognitive domain. SETTING: The University of Western Ontario Dementia Study, which is a registry of cases of dementia seen for secondary and tertiary assessment in a university memory disorders clinica with extensive follow-up data and histopathological confirmation of clinical diagnoses. PATIENTS: One hundred twenty-nine patients with definite or probable AD, 12 patients with definite or probable VaD, and 36 patients with definite or probable mixed dementia. METHODS: Patients were grouped as having an early, moderate, or advanced stage of disease according to the extended scale for dementia (ESD). The ESD was subdivided into cognitive domains, and the domain scores were compared for each stage of disease by diagnostic category with the use of a 2-way analysis of variance with repeated measures. RESULTS: As expected, the scores in all domains decreased significantly with increasing severity. There was a significant difference in the decline in memory among the diagnostic groups (P = .02) that was mostly attributable to the difference between AD and mixed dementia (P = .03), with the difference between AD and VaD only approaching significance (P = .06). There was a similar finding for praxis. The interaction between diagnosis (AD and VaD) and severity was significant only for memory (P = .02), showing a less severe memory deficit at onset but a proportionately more rapid progression in VaD and arithmetic ability (AD and mixed dementia [P = .03]). CONCLUSIONS: Alzheimer disease, VaD, and mixed dementia evolve similarly as assessed using cognitive domains obtained by subdivision of the ESD in a patient population derived from a memory clinic and by analyzing VaD as a single entity. Only memory impairment evolves differently between AD and VaD, with this depending on the severity. Memory is more severely impaired in the early stage of AD; however, with increasing severity of dementia, memory impairment in VaD accelerates and catches up with AD at the level of moderate impairment. The differences between AD and mixed dementia are greater than those between mixed dementia and VaD, suggesting an important role for the ischemic component of mixed dementia. Simple neuropsychological tools (eg, the ESD) may be incapable of distinguishing between AD and VaD, and more focused instruments may be required. Inherent bias in case selection may prevent extrapolation of these results to VaD in general, but the neuropsychological criteria for VaD may need to vary, depending on the severity.     

Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer's Disease, and Huntington's Disease.

Remote memory was assessed in persons with HIV-associated dementia (HIV-D), probable Alzheimer's disease (AD), and Huntington's disease (HD) and in healthy controls. The clinical groups were similar in overall dementia severity. Each clinical group exhibited impairments on remote memory tests relative to controls; however, temporally graded memory loss with selective preservation of older information was observed in the AD group but not the HD or HIV-D group. Analysis of cued retrieval indicated a preferential cuing benefit for the HIV-D and HD groups relative to the AD group. The similar pattern of remote memory performance demonstrated by the HIV-D and HD groups is a novel finding and suggests a subcortically mediated retrograde amnesia in HIV-D. The temporally graded pattern and the abnormal cued retrieval performance in the AD group are consistent with a consolidation deficit associated with extrahippocampal (cortical) and hippocampal damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory profiling with paired associate learning in Alzheimer's disease, mild cognitive impairment, and healthy aging.

Mild cognitive impairment (MCI) is associated with increased risk of developing Alzheimer's disease (AD), but up to 40% of cases do not develop AD. Examining a case's specific memory profile may help distinguish which MCI cases will progress to AD: An encoding profile is suggestive of incipient AD, whereas a retrieval profile suggests an alternative etiology. Paired associate learning (PAL) tasks are sensitive for preclinical and early detection of AD, but existing tasks do not enable memory profiling. We developed a novel PAL task enabling the differentiation of memory profiles in 19 people with AD, 17 people with amnestic MCI, and 33 normal elderly controls. Unexpectedly, the AD group demonstrated a retrieval profile for PAL using yes-no recognition, although an encoding profile was evident for forced-choice recognition and for the California Verbal Learning Test--Second Edition (Delis, Kramer, Kaplan, & Ober, 2000). There was considerable heterogeneity within the AD and MCI groups as well as intraindividual discordance for memory profiles. The findings challenge the clinical application of memory profiling in the differential diagnosis of AD, and, by extension, question its potential application in the assessment of MCI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Training to criterion in eyeblink classical conditioning in Alzheimer's disease, Down's syndrome with Alzheimer's disease, and healthy elderly.

The cholinergic antagonist scopolamine delays acquisition of eyeblink classical conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms eventually acquire conditioned responses (CRs). Patients with probable Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized that patients with probable AD and DS/AD, like scopolamine-injected organisms, would acquire CRs if given sufficient training. Twelve probable AD patients, 12 DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily 90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the DS-AD, and 100% of the control participants achieved learning criterion. Probable AD, DS/AD, and control participants had statistically significant increases in the percentage of CRs produced over 5 EBCC sessions. The neural substrate for EBCC was not eliminated in probable AD or DS/AD patients, although the learning mechanism was disrupted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An overview of the etiology, diagnosis, and treatment of Alzheimer disease

Alzheimer disease (AD) is the most common form of dementia affecting elderly people. It is the fourth leading cause of death among adults in the United States, following heart disease, cancer, and stroke. The prevalence of AD increases with increasing age. An estimated 10% of people aged 65 years have this progressive, degenerative disease, and this percentage increases to 47.2% for people aged 85 years and older. An early-onset form of AD can affect individuals who are middle-aged, with the youngest documented case being that of a 28-year-old. In the Framingham cohort, women with AD outnumbered men by a ratio of 2.8:1 for those aged 75 years or older. Undoubtedly, as our population continues to age, the increasing prevalence of AD will have an even greater impact on society than it does today. Approximately 4 million Americans have AD, and it is projected that the number will rise to 14 million by the middle of the next century. The financial impact of AD is staggering, with the average lifetime cost for an individual with AD exceeding $170,000. Although the majority of individuals with AD are cared for by family and friends at home, individuals with AD constitute half of all nursing home residents. The average cost of a year of nursing home care for an individual with AD is $42,000, and this cost can exceed $70,000. The purpose of this article is to provide an overview of the etiology of AD, the tools used in the diagnosis of AD, and the treatment of individuals with AD. In addition, the clinical presentation of the various stages of AD is described, and the psychosocial implications of this disease are discussed.     

Midkine, a novel neurotrophic factor, is present in senile plaques of Alzheimer disease

An affinity purified antibody specific for midkine (MK) stained senile plaques in the brain of Alzheimer disease (AD) patients. After formic acid treatment, plaque staining was dramatically enhanced, and almost all beta-amyloid protein (BAP) deposits were also immunoreactive for MK. MK-immunoreactivity was not observed in normal cellular components nor in other pathological lesions including tangles in AD brain. Control brain sections were not immunoreactive for MK. The presence of MK in AD brain but not in control brain was confirmed by Western blotting. MK appears to be involved in the pathological process leading to senile plaque formation.     

Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.     

Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease

Recently, apoptosis has been implicated in the selective neuronal loss of Alzheimer's disease (AD). Apoptosis is regulated by the B cell leukemia-2 gene product (Bcl-2) family (Bcl-2, Bcl-x, Bax, Bak and Bad) and the caspase family (ICH-1 and CPP32), with apoptosis being prevented by Bcl-2 and Bcl-x, and promoted by Bax, Bak, Bad, ICH-1 and CPP32. In the present study, we examined the levels of these proteins in the membranous and cytosolic fractions of temporal cortex in AD and control brain. In the membranous fraction, the levels of Bcl-2 alpha, Bcl-xL, Bcl-x beta, Bak and Bad were increased in AD. In the cytosolic fractions, the level of Bcl-x beta was increased, while Bcl-xL, Bax, Bak, and Bad and ICH-1L were unchanged. CPP32 was not detected in AD or control brain. These findings demonstrate a differential involvement of cell death-regulatory proteins in AD and suggest that Bak, Bad, Bcl-2 and Bcl-x are upregulated in AD brains.     

Emotion experience, expression, and regulation in Alzheimer's disease.

Alzheimer's disease (AD) is associated with intact experience but abnormal expression of emotion. Because emotion regulation is important in determining levels of experienced and expressed emotion, individuals with AD and control participants were asked to watch film clips under conditions of spontaneous expression, suppression, or amplification of emotion. Both groups had difficulties with behavioral amplification that were related to performance on a measure of theory of mind. However, intentional use of suppression was intact even for those with AD, consistent with models of aging that regard some emotion control processes as being relatively more automatic in older adulthood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interdisciplinary forum: from Genetic Diagnosis to Gene Therapy in Oncology. 26 September-1 October, 1996, Madrid, Spain

Alzheimer's disease (AD) represents a heterogeneous disorder, and several factors have been associated with its development. The presence of the apolipoprotein E type (APOE) epsilon 4 allele has been proposed as a risk factor for AD, but how it influences the development of the characteristic hallmarks of the disease remains unknown. In the present study, the neuropathological changes and levels of both core PHF-tau and normal tau protein in 4 neocortical areas, cerebellum and medial temporal cortex were determined in 18 AD cases. The extent of these changes was compared between 10 cases possessing an epsilon 4 allele and 8 cases without. These two groups were indistinguishable in terms of neurofibrillary pathology, whereas cases with an epsilon 4 allele had more diffuse plaques, particularly in the temporal neocortex. Biochemically, there was no difference in the levels of PHF-tau protein between the two groups. These data indicate that APOE epsilon 4 allele may influence deposition of diffuse amyloid, but altered tau protein processing, which underlies the development of the neurofibrillary pathology in AD, is not influenced by this allele.     

Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities

The molecular characteristics of midbrain dopamine (DA) neurons have been extensively studied in Parkinson's disease (PD). No such studies of the characteristics of midbrain DA neurons in Alzheimer's disease (AD) or Alzheimer's disease with parkinsonism (AD/Park) have been published. We examined the levels of tyrosine hydroxylase (TH) protein, and the expression of TH and dopamine transporter (DAT) mRNAs, in midbrain neurons of PD, AD, and AD/Park cases. In PD, the loss of TH protein in the ventral tier of the substantia nigra pars compacta (SNpc) of the PD group in accompanied by severe losses in the number of neurons that express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a shift to higher concentrations of TH mRNA but a shift to lower concentrations of DAT mRNA per cell. Hence, there is evidence that compensation in the remaining neurons can elevate concentrations of TH mRNA and lower DAT mRNA. Alternatively, there may be a predilection for a loss of neurons with high levels of DAT mRNA and low TH mRNA levels within the SNpc of PD cases. There was no change in TH protein but an elevation of TH mRNA concentrations per neuron without any change in concentrations of DAT mRNA in the AD group. The AD/Park group did not exhibit changes in the level of TH protein, but showed a small loss (26%) of neurons in the SNpc and a greater loss in other regions of the midbrain (43-53%). Remaining DA neurons showed a marked shift to lower concentrations of DAT mRNA per neuron and a nonsignificant shift in cellular concentration of TH mRNA to higher levels. This is consistent with our previous work showing that with AD/Park there is a significant reduction in the number of DAT sites located on DA terminals in the striatum, but the midbrain neurons have not died. Our results indicate that the differential regulation of mRNAs encoding TH and DAT is similar in the parkinsonian disorders (PD and AD/Park) even though the degree of cell death is very different. This might suggest that compensatory events occur in these DA neurons in AD/Park that are similar to those in PD and that result in differential effects on mRNAs encoding TH and DAT proteins.     

Extent, pattern, and correlates of remote memory impairment in Alzheimer's disease and Parkinson's disease.

Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Semantic memory in Alzheimer's disease: Representativeness, ontologic category, and material.

Alzheimer's disease (AD) patients with semantic memory difficulty and AD patients with relatively preserved semantic memory named pictures and judged the category membership of words and pictures of natural kinds and manufactured artifacts that varied in their representativeness. Only semantically impaired patients were insensitive to representativeness in their category judgments. AD subgroup judgments did not differ for natural kinds compared to manufactured artifacts nor for words compared to pictures. AD subgroup differences could not be explained by dementia severity, memory, reading, and visuoperception. The similarity process for relating coordinate members of a taxonomic category contributes to the normal appreciation of word and picture meaning, and this process is compromised in AD patients with semantic difficulty. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The apolipoprotein E gene, attention, and brain function.

The ε4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ε4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ε4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ε4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Semantic fluency in Alzheimer's, Parkinson's, and Huntington's disease: Dissociation of storage and retrieval failures.

Patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and normal controls were compared on 2 versions of a semantic fluency task: a standard, uncued version and a version in which Ss were cued with subordinate categories. All patients were impaired relative to controls on the standard version. On the cued version, PD and HD patients improved significantly, but AD patients did not. AD patients' fluency, but not PD or HD patients', correlated significantly with confrontation naming ability. Impairment exhibited by PD and HD patients on standard semantic fluency tasks may be due to a retrieval deficit, whereas that of AD patients may be due to degradation of semantic memory stores. In addition, the pattern of performance exhibited by a nonaphasic patient with bilateral frontal lobe lesions suggests that the retrieval functions involved may depend on integrity of the prefrontal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mannan-binding lectin in human serum, cerebrospinal fluid and brain tissue and its role in Alzheimer's disease

Mannan-Binding lectin (MBL) is a serum lectin which can activate the classical complement pathway. Complement proteins of the classical pathway have been found in the brains of patients with Alzheimer's disease (AD) in association with AD brain pathology. To investigate the role for MBL in AD we have looked for its presence in the brain by immunohistochemistry and determined the levels of MBL in paired samples of cerebrospinal fluid and serum from AD patients and controls. MBL was detected in association with blood vessels in the brain tissue of both AD patients and control subjects. There was no apparent difference in the distribution of MBL in the brain tissue between the two groups. The mean concentration of MBL in the CSF was 44% lower in AD patients than in controls (AD 154 +/- 35 pg/ml, n = 19; non-AD 276 +/- 50 pg/ml, n = 15, p < 0.05). The levels of MBL in serum were not significantly different in the two groups. Thus, this study shows that MBL is associated with blood vessels in the brains of both AD and control subjects. Moreover, CSF levels of MBL appear to be lower in AD patients than in control subjects which may indicate a higher degree of MBL consumption connected with complement activation in the AD patients.     

A prospective evaluation of Bass, Bionator and Twin Block appliances. Part I--The hard tissues

A prospective clinical study with a random allocation of 47 adolescent patients to three different functional appliance groups was established and compared with an untreated control group over a 9-month period. Treatment was undertaken with either a Bionator, Twin Block, or Bass appliance. Pre- and post-treatment cephalograms were used to quantify the skeletal and dentoalveolar changes produced by the appliances and compared with those observed in the control group as a result of growth. Both the Bionator and Twin Block appliances demonstrated a statistically significant increase in mandibular length (3.9 +/- 2.7 mm; 3.7 +/- 2.1 mm, respectively) compared with the control group (P < 0.05), with an anterior movement of pogonion and point B. Highly statistically significant increases (P < 0.01) were seen in lower face heights for all the appliance groups compared with the control group. The Twin Block group showed the least forward movement of point A due to a change in the inclination of the maxillary plane. The Bionator and Twin Block groups showed statistically significant reductions in the inclination of the upper incisors to the maxillary plane (P < 0.05). The Bass group showed minimal change in the inclination of the lower labial segment to the mandibular plane. The Bionator group demonstrated the greatest proclination of the lower labial segment (4.0 +/- 3.6 degrees). Clinically important changes were measured in all the appliance groups when compared with the control group. Differences were also identified between the functional appliance groups. The Twin Block appliance and, to a lesser extent, the Bionator appeared the most effective in producing sagittal and vertical changes.