Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Anti-Amyloid Beta Therapy.

Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer's disease trials of anti-amyloid beta (Aß) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aß in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aß therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital.

Diagnosis of Early Alzheimer's Disease: Clinical Practice in 2021.

Alzheimer's disease is a progressive, irreversible neurodegenerative disease impacting cognition, function, and behavior. Alzheimer's disease progresses along a continuum from preclinical disease, to mild cognitive and/or behavioral impairment and then Alzheimer's disease dementia. Recently, clinicians have been encouraged to diagnose Alzheimer's earlier, before patients have progressed to Alzheimer's disease dementia. The early and accurate detection of Alzheimer's disease-associated symptoms and underlying disease pathology by clinicians is fundamental for the screening, diagnosis, and subsequent management of Alzheimer's disease patients. It also enables patients and their caregivers to plan for the future and make appropriate lifestyle changes that could help maintain their quality of life for longer. Unfortunately, detecting early-stage Alzheimer's disease in clinical practice can be challenging and is hindered by several barriers including constraints on clinicians' time, difficulty accurately diagnosing Alzheimer's pathology, and that patients and healthcare providers often dismiss symptoms as part of the normal aging process. As the prevalence of this disease continues to grow, the current model for Alzheimer's disease diagnosis and patient management will need to evolve to integrate care across clinical disciplines and the disease continuum, beginning with primary care. This review summarizes the importance of establishing an early diagnosis of Alzheimer's disease, related practical 'how-to' guidance and considerations, and tools that can be used by healthcare providers throughout the diagnostic journey.

A between-subjects test of the lower-identification/ higher-priming paradox.

An under-recognised U-shaped model states that unconscious and conscious perceptual effects are functionally exclusive and that unconscious perceptual effects manifest themselves only at the objective detection threshold, when conscious perception is completely absent. We tested the U-shaped line model with a between-subjects paradigm. Angry, happy, neutral faces, or blank slides were flashed for 5.5 ms and 19.5 ms before Chinese ideographs in a darkened room. A group of volunteers (n = 84) were asked to rate how much they liked each ideograph and performed an identification task. According to the median identification score two subgroups were composed; one with 50% or < 50% identification scores (n = 31), and one with above 50% identification scores (n = 53). The hypothesised U-shaped line was confirmed by the findings. Affective priming was found only at the two extreme points: the 5.5 ms condition of the low-identification group (subliminal perception) and the 19.5 ms condition of the > 50% high-identification group (supraliminal perception). The two intermediate points (19.5 ms of the low-identification group and 5.5 ms of the high-identification group) did not correspond to significant priming effects. These results confirm that a complete absence of conscious perception is the condition for the deployment of unconscious perceptual effects.

The structure of the corpus callosum in obsessive compulsive disorder.

Abnormal brain connectivity has recently been reported in obsessive compulsive disorder (OCD). However, structural differences in the corpus callosum (CC), the primary structure connecting the two hemispheres, have not been extensively studied. In this case-control study, we recruited 30 patients with OCD and 30 healthy control subjects carefully matched for age, sex and handedness. Combining surface-based mesh-modeling and voxel-based morphometry (VBM), we compared callosal thickness and white matter (WM) density in patients and controls. We investigated associations between callosal structure and cortical gray matter (GM) density, and we related CC measures to neuropsychological performance in OCD. OCD patients showed small anterior and posterior callosal regions compared to healthy control subjects. In the OCD group, anterior callosal thickness was positively correlated with GM density of the right mid-dorso-lateral prefrontal (BA 9/46) area, while posterior callosal thickness was positively correlated with GM density in the left supramarginal gyrus (BA 40). Moreover, posterior callosal WM density was positively correlated with verbal memory, visuo-spatial memory, verbal fluency, and visuo-spatial reasoning performances. Callosal attributes were related to GM density in cortical areas innervated by the CC, and were also related to performance in cognitive domains impaired in the disorder. The CC may therefore be integrally involved in OCD.

WITHDRAWN: The structure of the corpus callosum in obsessive compulsive disorder.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder.

BACKGROUND: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia. METHODS: To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method. RESULTS: In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21). CONCLUSIONS: There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.

Differentiating clinical groups using the serial color-word test (S-CWT).

The present study attempted to differentiate 11 diagnostic groups by means of the Serial Color-Word Test (S-CWT), using multivariate discriminant analysis. Two alternative scoring systems of the S-CWT were outlined. Asample of 514 individuals who had clinical diagnoses of various types and 397 controls who had no diagnostic findings comprised the sample. The first discriminant analysis failed to differentiate the groups adequately. The groups were consequently reduced to four (schizophrenia, bipolar disorders, temporo-mandibular joint pain dysfunction syndrome, and eating disturbances), which gave better reclassification findings for a clinical application of the test. This classification gave over 55% correct assignments. The final four groups had a statistically significant discrimination on the test, which remained stable also in a bootstrap procedure. Implications for treatment indications and outcomes as well as strategies for further studies using the S-CWT are discussed.

Referential failures and affective reactivity of language in schizophrenia and unipolar depression.

Reference failures, and their increase in affectively negative conditions (known as affective reactivity of speech), are more frequently observed in schizophrenia patients than in normal controls, but no information is available comparing schizophrenia with depression, ie, a mental disorder closely linked to the concept of affective reactivity. To address this gap in the literature, the present study compared 24 schizophrenia inpatients, 21 unipolar depression inpatients and 21 normal controls. Two 10-minute conversational speech samples (1 on negative and 1 on positive memories) were collected from each patient. The transcripts of the audiotaped interviews were analyzed blindly for frequencies of 6 types of referential failures, employing the Communication Disturbances Index, adapted for use with Italian. The schizophrenia patients made more frequent total reference failures and, specifically, more missing information references than the depression patients. The depression patients made more frequent reference failures than the normal controls, overall, and on most of the specific types of failures. Affective reactivity of speech was observed only for the schizophrenia sample and was greatest for missing information references. This study supports the viability of reference failure analysis as a measure of communication disturbance in a language other than English. The findings indicate that schizophrenia and depression both are associated with high levels of referential failures but that affective reactivity of speech is present only in schizophrenia and not in depression.

Quetiapine fumarate for schizophrenia and bipolar disorder in young patients.

During the past decade, there has been a substantial increase in the prescribing of antipsychotics to young patients for a variety of pediatric psychiatric disorders. Quetiapine (Seroquel®) received its initial indication from the U.S. Food and Drug Administration for treatment of schizophrenia in 1997, and it received its second indication for the treatment of mania-associated bipolar disorder in 2004. Currently, in young patients, authorized quetiapine indications are schizophrenia in individuals aged 13 or older and manic episodes associated with bipolar I disorder in children 10 to 17 years old. Quetiapine has different pharmacological actions and acts as an antagonist for following receptors: D(2) receptor, serotonin 5-HT(2A) also known as α(1)-adrenoceptor, histamine 1 receptor and muscarinic acetylcholine receptor. Several studies have shown its favorable profile of effectiveness and tolerability in young bipolar and schizophrenic patients. However, the current data make it very clear that the risks and benefits of this drug need to be weighed individually for each patient.

BDNF Val66Met polymorphism is associated with aggressive behavior in schizophrenia.

Brain-derived neurotrophic factor (BDNF) gene variants may potentially influence behaviour. In order to test this hypothesis, we investigated the relationship between BDNF Val66Met polymorphism and aggressive behaviour in a population of schizophrenic patients. Our results showed that increased number of BDNF Met alleles was associated with increased aggressive behaviour.

A comparative study of axis I antecedents before age 18 of unipolar depression, bipolar disorder and schizophrenia.

BACKGROUND: Despite a large scientific literature on early clinical precursors of schizophrenia, bipolar disorder and unipolar depression, few data are available on axis I disorders preceding the adult onset of these illnesses. SAMPLING AND METHODS: Disorders before the age of 18 years were retrospectively assessed with a structured interview in 3 groups of consecutive adult inpatients with DSM-IV diagnoses of schizophrenia (n = 197), major depressive disorder (n = 287) and bipolar disorder (n = 132). Only patients with adult onset of schizophrenia and of mania/hypomania were included. A sample of the general population served as control group (n = 300). RESULTS AND CONCLUSION: The clinical groups significantly outnumbered the control sample on the majority of early axis I diagnoses. Schizophrenia was significantly associated (1) with attention deficit hyperactivity disorder (ADHD), ADHD inattentive subtype, ADHD hyperactive subtype and primary nocturnal enuresis, compared to unipolar depression, and (2) with social phobia and ADHD inattentive subtype, compared to bipolar disorder. Oppositional defiant disorder was significantly associated with bipolar disorder, compared to the other clinical and control groups. The ADHD hyperactive subtype predicted the adult onset of bipolar disorder compared to unipolar depression. Externalizing disorders seem of special importance as regards the clinical pathways toward schizophrenia.

Allelic frequencies of 3' Ig heavy chain locus enhancer HS1,2-A associated with Ig levels in patients with schizophrenia.

Infectious and autoimmune pathogenic hypotheses of schizophrenia have been proposed, prompting searches for antibodies against viruses or brain structures, and for altered levels of immunoglobulins. Previous experiments have shown that allele frequencies of the Ig heavy chain 3' enhancer HS1,2*A are associated with several autoimmune diseases, suggesting a possible correlation between HS1,2 alleles and Ig production. To test this, we analyzed levels of serum Igs and HS1,2*A genotypes in two independent cohorts, one of 88 schizophrenic inpatients (24 women) and a second of 133 healthy subjects (59 women). Both groups were similar in the frequency of individuals with altered serum concentration of Ig classes and IgG subclasses (schizophrenia panel-80 percent; controls-68 percent). With the possible exception of a stabilizing effect of olanzapine, no psychopharmacological drug consumed during the month prior to serum sampling in the schizophrenia group significantly affected Ig levels. In both patient and control cohorts, an increased frequency of the HS1,2*2A allele corresponded to increased Ig plasma levels, while an increased frequency of the HS1,2*1A allele corresponded to decreased Ig plasma levels. EMSA analysis with nuclear extracts from human B cells showed that the transcription factor SP1 bound to the polymorphic region of both HS1,2*1A and HS1,2*2A while NF-kB bound only to the HS1,2*2A. We predict that differences in transcription factor binding sites in the two allelic variants of the 3' IgH enhancer HS1,2 may provide a mechanism by which differences in Ig expression are affected.

Early adverse experiences in schizophrenia and unipolar depression.

To study the prevalence of early adversities in schizophrenia and unipolar depression, 2 groups of consecutive adult-onset inpatients with DSM-IV diagnoses of schizophrenia (n = 173) and unipolar depression (n = 305) were compared with an unscreened control group of volunteers from the general population (n = 310), with respect to their association with 4 types of childhood abuse and with early parental adversities (discord, separation, death, psychiatric caseness). Compared with general population, most types of early adversities (except sexual abuse and parental death) were significantly associated with both clinical groups. Compared with depression, all early adversities with the same 2 exceptions were significantly associated with schizophrenia; both frequency of abuse and number of types of abuse increased the risk of schizophrenia in a dose-response pattern, suggesting causality. These findings stress the role of social developmental factors in the etiology of schizophrenia.

Personality differences between depressed melancholic and non-melancholic inpatients.

OBJECTIVE: The aim of the present study was to confirm that non-melancholic depression corresponds to a higher degree of personality dysfunction compared to melancholia. METHOD: A total of 188 inpatients, with a main DSM-IV diagnosis of major depressive disorder, were classified as melancholic and non-melancholic according to CORE system, DSM-IV, Research Diagnostic Criteria (RDC) Retarded Depression, and RDC Agitated Depression. Personality was assessed by means of the Temperament and Personality Questionnaire (T&P). Only patients at the nadir of their episode were included. RESULTS: Compared to non-melancholic depressives, patients with CORE melancholia scored lower on social avoidance and higher on effectiveness and cooperativeness; patients with RDC Retarded Depression scored lower on Anxious-Worrying and Cooperativeness; patients with RDC Agitated Depression scored lower on Social Avoidance, Rejection Sensitivity and Anxious-Worrying, and higher on Effectiveness; while patients with DSM-IV melancholia scored higher on Irritability and lower on Cooperativeness. Both CORE and RDC Agitated Depression were associated with higher scores of Perfectionism. CONCLUSIONS: The hypothesis of an association of melancholic depression with less marked personality dysfunction was confirmed for CORE melancholia and RDC Agitated Depression, and not supported for DSM-IV melancholia. Mixed evidence was obtained for RDC Retarded Depression. Personality of melancholic depressives seems to be characterized not only by less dysfunction but also by perfectionism, akin to the features of Tellenbach's typus melancholicus.

The defense mechanism test-separation theme in two anxiety disorders.

Two groups of 26 age- and sex-matched outpatients, with DSM-IV diagnoses of obsessive-compulsive disorder and panic disorder with agoraphobia, were compared on the Defense Mechanism Test-Separation Theme. A stimulus portraying a mother figure who is leaving a room where a baby lies alone on the floor was presented 22 times at increasing exposure durations in a single-view tachistoscope. Participants were asked to describe what they perceived at each step, according to the method of the Defense Mechanism Test. As predicted, reports of the mother seen as an inanimate object (phobic repression) were statistically significantly associated with agoraphobia, while reports of the mother entering the room or doing something other than leaving the baby (reaction formation) and reports of the baby as an angel (intellectualization) were associated with obsessive-compulsive disorder.

Patterns of adaptation in obsessive-compulsive disorder: multivariate indicators of greater variability and linear change compared to controls.

Patterns of adaptation to conflict in persons with Obsessive-Compulsive Disorder were assessed with the Serial Color-Word Test. Obsessive-Compulsive patients (n=50) were compared with an age- and sex-matched group of nonclinical volunteers. Measures of linear and nonlinear change in reading times during each of the five consecutive trials of the test were compared between groups by means of a multivariate model with doubly repeated measures. The multivariate analysis yielded a significant between-groups result (Wilks Lambda = .76, p < .001), mainly supported by higher values of nonlinear change in the Obsessive-Compulsive group. Thus, the discriminative ability of the Serial Color-Word Test was confirmed when individual differences were removed from the error term.

Expression of protease-activated receptor-1 and -2 in orofacial granulomatosis.

OBJECTIVE: Orofacial granulomatosis (OFG) is a rare condition characterized by non-caseating granulomas in the orofacial region. Protease-Activated Receptors (PARs) play a role in inflammatory diseases in diverse human tissues. The aim of the study was to investigate the expression of PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 in tissues taken from OFG patients. METHODS: PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn's disease (five cases), Melkersson-Rosenthal syndrome (MRS) (six cases), cheilitis granulomatosa (five cases) and normal oral mucosa (five cases). RESULTS: PAR-1 was observed in mononuclear inflammatory cells in edematous/lichenoid lesions, whereas a strong PAR-2 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions, irrespective of the clinical features (Crohn vs MRS). MMPs and COX-2 were expressed in the inflammatory component of edematous/lichenoid lesions and markedly overexpressed in granulomatous lesions. COX-1 was weakly and variably expressed in both edematous/lichenoid and granulomatous lesions. CONCLUSION: Thus, PAR-1 and PAR-2 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion. Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes.

Signs of defense in obsessive-compulsive disorder: a validation study of the Defense Mechanism Test.

A group of 31 patients with Obsessive-Compulsive Disorder was compared with an age and sex-matched group of 31 nonclinical volunteers on the Defense Mechanism Test, a tachistoscopic paradigm which confronts the subject with anxiety-arousing stimuli at increasing durations from subliminal levels until complete recognition. It was hypothesized that distortions of the stimuli coded as Isolation or Reaction Formation would be more frequent in the obsessive-compulsive sample. Reaction Formation and one variant of Isolation (Barrier Isolation) were significantly associated with the obsessive-compulsive diagnosis.

Patterns of adaptation to conflict and schizoid personality scale scores.

A previous investigation gave no evidence of a significant relationship of patterns of adaptation to conflict, as measured with the Serial Color-Word Test, with the Schizoid Personality Scale of the Coolidge Axis II Inventory. As a new scoring algorithm has subsequently been proposed for the latter scale, a replication was done with the modified schizoid scale. A group of 75 consecutive nonpsychotic women outpatients was given the Serial Color-Word Test and Coolidge's inventory. Both multiple and logistic regressions selected two significant predictors of schizoid personality, corresponding to high values of linear change in reading times during Trials 3 and 5 of the Serial Color-Word Test, i.e., to an increasingly rigid and inflexible style of the adaptive process. A multivariate analysis of variance yielded an effect size of .22 (partial eta2).

Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment.

BACKGROUND/AIM: Osteonecrosis of the jaws is being increasingly reported in patients with bone metastasis from a variety of solid tumours and disseminated multiple myeloma receiving intra-venous bisphosphonates. The signs and symptoms that may occur before the appearance of clinical evident osteonecrosis include changes in the health of periodontal tissues, non-healing mucosal ulcers, loose teeth and unexplained soft-tissue infection. A series of nine periodontally involving patients showing osteonecrosis of the jaws that appeared following the intra-venous use of bisphosphonates is reported. MATERIAL AND METHODS: Nine consecutive patients with osteonecrosis of the jaws were prospectically studied. Patients' past medical histories and the drugs that they had received for their malignant disease were systematically documented. Clinical, histopathological and radiographic features and proposal for treatment modalities of osteonecrosis are also reported. RESULTS: Of the nine patients (six women and three men) observed, all had osteonecrosis in the mandible; two had maxillary involvement as well. All nine patients had a history of extraction of periodontally hopeless teeth preceding the onset of osteonecrosis. In two patients, the lesions also appeared in edentulous areas spontaneously. All the patients had received intra-venous bisphosphonates as treatment for their disseminated haematological neoplasms or metastatic bone disease. The duration of bisphosphonate therapy at presentation ranged from 10 to 70 months (median: 33 months). CONCLUSIONS: Jaw osteonecrosis appears to be associated with the intra-venous use of bisphosphonates. Dental professionals should be aware of this potentially serious complication in periodontal patients receiving long-term treatment with bisphosphonates.