Longitudinal Neuropsychiatric Predictors of Death in Alzheimer's Disease.

Characteristics associated with life expectancy in Alzheimer's disease (AD) are still far from known. Here we aimed at examining the ability of baseline/longitudinal clinical variables to predict time to death. One-hundred fifty AD outpatients underwent diagnostic, neuropsychiatric, and functional assessment at baseline (when ApoE ɛ4 was also investigated) and at each subsequent annual visit. A random effects joint modeling approach was used to simultaneously model the baseline and longitudinal trajectory of each factor and predict the time to death, adjusting for demographic covariates. An ancillary analysis of ApoE ɛ4 status as a predictor was also conducted. Kaplan-Meier survival curves were constructed to elucidate the relationship between each factor and the estimated probability of death over time. Shorter survival was associated with male gender, higher education, older age, lower cognition, and worse functioning in daily life, but not ApoE ɛ4 status. Longitudinal trajectories increased predictive power over using just baseline levels highlighting apathy, and secondarily aberrant motor behaviors and sleep disorders, as a highly reliable predictor for mortality. Apathy was the strongest neuropsychiatric predictor of time to death, which supports its role in the pathogenesis of the disorder. An increased knowledge of factors modulating survival in AD is a strategic prerequisite to plan therapeutic interventions.

Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease.

OBJECTIVES: Neuropsychiatric symptoms are common in patients with Alzheimer disease (AD). Treatment for both AD and psychiatric disturbances may affect the clinical observed pattern and comorbidity. The authors aimed to identify whether particular neuropsychiatric syndromes occur in untreated patients with AD, establish the severity of syndromes, and investigate the relationship between specific neuropsychiatric syndromes and AD disease severity. DESIGN: Cross-sectional, multicenter, clinical study. PARTICIPANTS: A total of 1,015 newly diagnosed, untreated outpatients with AD from five Italian memory clinics were consecutively enrolled in the study from January 2003 to December 2005. MEASUREMENTS: All patients underwent thorough examination by clinical neurologists/geriatricians, including neuropsychiatric symptom evaluation with the Neuropsychiatric Inventory. RESULTS: Factor analysis revealed five distinct neuropsychiatric syndromes: the apathetic syndrome (as unique syndrome) was the most frequent, followed by affective syndrome (anxiety and depression), psychomotor (agitation, irritability, and aberrant motor behavior), psychotic (delusions and hallucinations), and manic (disinhibition and euphoria) syndromes. More than three quarters of patients with AD presented with one or more of the syndromes (N = 790, 77.8%), and more than half exhibited clinically significant severity of symptoms (N = 603, 59.4%). With the exception of the affective one, all syndromes showed an increased occurrence with increasing severity of dementia. CONCLUSIONS: The authors' study supports the use of a syndrome approach for neuropsychiatric evaluation in patients with AD. Individual neuropsychiatric symptoms can be reclassified into five distinct psychiatric syndromes. Clinicians should incorporate a thorough psychiatric and neurologic examination of patients with AD and consider therapeutic strategies that focus on psychiatric syndromes, rather than specific individual symptoms.

Delusion symptoms and response to antipsychotic treatment are associated with the 5-HT2A receptor polymorphism (102T/C) in Alzheimer's disease: a 3-year follow-up longitudinal study.

Although the etiology of psychotic symptoms (hallucinations and delusions) in Alzheimer's disease is still not known, alterations in serotonergic neurotransmission have been proposed. In a 3-year follow-up study, we evaluated the association of serotonin (5-HT) receptor 5-HT2a 102T/C polymorphism (allelic variants CC, CT and TT) with psychotic symptom severity and response to treatment with atypical antipsychotics (risperidone, olanzapine and quietapine) in 80 patients with a diagnosis of probable Alzheimer's disease. The Neuropsychiatric Inventory (NPI) was administered to determine the frequency and severity (FxS) of psychotic and other behavioral symptoms. There was a significant difference in the NPI FxS delusion score among the three variants of the 5-HT2a 102T/C polymorphism, with patients carrying the TT genotype the most delusional during the follow-up period. In particular, NPI FxS delusion score was higher in TT than in CC genotype at year 2. Moreover, patients with delusion symptoms carrying the CT and TT genotypes were resistant to the treatment with antipsychotic drugs. Thus our study, although at preliminary level, suggests that the presence of T allele of the 102T/C polymorphism in patients with Alzheimer's disease is associated with both increased presence of delusion symptoms and treatment-resistance to second generation antipsychotic drugs.

Inferior frontal white matter volume and suicidality in schizophrenia.

The neurobiology of suicidality in schizophrenia is largely unknown. We therefore assessed gray and white matter volumes associated with past suicidality and current self-aggression in schizophrenia. Fifty-five outpatients with schizophrenia (n=55) and healthy controls (n=55), matched for age, gender and handedness, were recruited. Ten patients had a life-time history of one or more suicide attempts. Current self-aggression was assessed using the Modified Overt Aggression Scale. High resolution structural magnetic resonance images were analyzed by voxel-based morphometry. We found significantly larger inferior frontal white matter volumes bilaterally in patients with a previous suicide attempt as compared with those patients without a history of suicidality. No other significant white or gray matter volume differences were observed. White matter volume in these regions did not differ between healthy controls and those patients without a previous suicide attempt. Furthermore, among patients, the level of current self-aggression showed a significant positive correlation with white matter volume in the same regions. Inferior frontal white matter alterations in fronto-temporo-limbic circuits may be associated with suicidality and self-aggression in schizophrenia.

Facial emotion recognition deficit in amnestic mild cognitive impairment and Alzheimer disease.

OBJECTIVES: A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine whether a deficit in facial emotion recognition is present in a-MCI phase and whether this is intensity dependent. A secondary aim was to investigate relationships between facial emotion recognition and cognitive performances. DESIGN: Case-control study. SETTING: Memory clinic. PARTICIPANTS: Fifty a-MCI patients, 50 mild AD patients, and 50 comparison subjects (COM) were enrolled. MEASUREMENTS: Information about facial emotion recognition was obtained from Penn Emotion Recognition Test. The Mental Deterioration Battery was used to measure cognitive impairment. RESULTS: Mild AD patients were more impaired in the recognition of almost all emotional stimuli of all intensities than a-MCI and COM subjects. However, there was an increased progression only in low-intensity facial emotion recognition deficit from COM to a-MCI to mild AD patients. In particular, a-MCI subjects differed significantly from COM in low-intensity fearful face recognition performance. This deficit in a-MCI patients was explained by the short-term verbal memory impairment, whereas the same deficit in mild AD patients was explained by the long-term verbal memory impairment. CONCLUSIONS: Emotion recognition progresses from a deficit in low-intensity fearful facial recognition in a-MCI phase to a deficit in all intensities and emotions in mild AD. This could be an effect of the progressive degeneration of brain structures modulating emotional processing. An early detection of emotional impairment in MCI phases of dementia may have clinical implications.

Interleukin-18 produced by peripheral blood cells is increased in Alzheimer's disease and correlates with cognitive impairment.

A body of evidence indicates that inflammation plays a pivotal role in AD pathogenesis. IL-18 is a pro-inflammatory cytokine produced in the brain, emerging to be implicated in AD. Although no differences in circulating IL-18 levels were measured between AD patients and controls, a significant increased production of IL-18 was obtained from stimulated blood mononuclear cells of AD patients. This was true particularly in AD subjects carrying the C/C genotype at the -607 position of IL-18 gene promoter. Furthermore, a significant correlation between IL-18 production and cognitive decline was observed in AD patients. Overall, these data indicate that IL-18-related inflammatory pathways, probably also in virtue of polymorphic IL-18 gene influence, are exacerbated in AD patients, and that this cytokine may indeed participate in pathogenic processes leading to dementia.

Glutathione S-transferase P1 and T1 gene polymorphisms predict longitudinal course and age at onset of Alzheimer disease.

OBJECTIVE: Oxidative stress has been suggested as a contributor of Alzheimer disease (AD) neurodegeneration, particularly in those patients with late-onset AD (LOAD). Therefore, the authors studied the effect of glutathione S-transferase (GST) P1-M1-T1 gene polymorphisms and their interactions with the apolipoprotein E (ApoE) epsilon4 allelic variant on the three-year longitudinal course of AD. METHODS: Global cognitive level as measured by the Mini-Mental State Exam, basic activities of daily living (BADLs) as measured by the Physical Self-Maintenance Scale, and behavior as measured by the Neuropsychiatric Inventory, were assessed at baseline and after 1, 2, and 3 years in a sample of 99 LOAD patients. These subjects were drug naive and had undergone the first clinical examination for the diagnosis of AD. RESULTS: A multiple regression analysis indicated that the presence of ApoE epsilon4 allelic variant or GSTT1 null phenotype predicted the faster age at onset of the illness (F = 5.76, df = 2, 96, p = 0.0043). Carriers of GSTP1 *C allelic variant had a faster decline in cognitive functions (repeated measures analysis of variance [ANOVA]: F = 4.00, df = 3, 285, p = 0.008) and in BADLs (repeated measures ANOVA: F = 5.27, df = 3, 285, p = 0.001). This faster decline was independent from ApoE epsilon4 allele possession. No effect of GST P1-M1-T1 polymorphisms was found on behavioral symptom severity. CONCLUSION: These data are in line with the hypotheses that oxidative damage is a prominent feature in the clinical progression and the age at onset of LOAD.

Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease.

BACKGROUND AND AIM: Inflammation has been extensively implicated in the pathogenesis of Alzheimer's disease (AD). Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine interleukin (IL)-18 has not been associated with AD. The aim of this study was to investigate the impact of two polymorphisms of the human IL-18 gene promoter at positions -607 (C/A) and -137 (G/C) on both susceptibility to and progression of AD. RESULTS: The results revealed that the genotype distribution of the -607 (C/A) polymorphism was different between patients with AD and control subjects (chi2 = 7.99, df = 2, p = 0.0184). In particular, carriers of the CC genotype were at increased risk of developing AD (OR 2.33; 95% CI 1.29 to 4.22; p = 0.0052). The observed genotypes were in Hardy-Weinberg equilibrium, as for the -607 polymorphism, whereas the -137 polymorphism appeared in Hardy-Weinberg disequilibrium only in the patient group (p = 0.0061). Finally, in a 2 year follow-up study, the -137 CC genotype was strongly and specifically associated with a faster cognitive decline (F = 4.024; df = 4,192; p = 0.0037 for time by IL-18 -137 G/C group interaction) with no interaction effect with the apolipoprotein E epsilon4/non-epsilon4 allele presence. CONCLUSION: As IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.

Glutathione S-transferase P1 *C allelic variant increases susceptibility for late-onset Alzheimer disease: association study and relationship with apolipoprotein E epsilon4 allele.

BACKGROUND: Oxidative stress and neuronal cell death have been implicated in the pathogenesis of Alzheimer disease (AD). Considering that the glutathione transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress, we aimed at determining the various GSTP1, GSTM1, and GSTT1 polymorphisms and ApoE genotypes to investigate their role as susceptibility genes for late-onset AD (LOAD). METHODS: We included 210 LOAD patients and 228 healthy controls matched for age, sex, and educational level in our case-control genetic association study. GSTM1 and GSTT1 genotypes were studied by conventional PCR, whereas GSTP1 and ApoE genotypes were determined by real-time PCR on the LightCycler. RESULTS: We found a significant association between LOAD and the GSTP1*C allelic variant [odds ratio (OR) = 1.9; P < 0.05], but no association between the GSTM1 and GSTT1 deleted genotypes and LOAD. In addition, a preliminary result suggested that carriers of both the GSTP1*C and ApoE epsilon4 allelic variants were at increased risk of LOAD (OR = 19.98; P < 0.0001). CONCLUSION: The GSTP1*C allelic variant should be considered a candidate for LOAD, particularly in persons having the ApoE epsilon4 allelic variant, because the GSTP1 and ApoE gene products are implicated in oxidative stress and apoptosis processes leading to beta-amyloid-mediated neurodegeneration.

Chronic schizophrenia as a brain misconnection syndrome: a white matter voxel-based morphometry study.

It has been hypothesized that schizophrenia could be due to a defect of neural circuitry, that is a misconnection between different cerebral areas, particularly those involved in language processing and production. A group of 28 patients with chronic schizophrenia were investigated in order to detect differences in locations of white matter voxel signal intensity in comparison with a control group of 28 normal subjects matched for age, gender and educational level. Voxel-based morphometry was used to assess the white matter of the brain. Significant voxel signal hypointensity was identified in schizophrenic patients bilaterally (mainly in the left hemisphere) in the post-central gyrus and superior temporal gyrus and unilaterally (in the left hemisphere) in the inferior frontal gyrus-pars triangularis and pars pretriangularis, the medial orbital gyrus, the lateral orbital gyrus and the rectus gyrus. Thus, the white matters of these cerebral areas were structurally modified particularly in the left hemisphere and in those structures that control language and hearing processes.