Paul J. Moberg

Meta-Analysis of Olfactory Function in Schizophrenia, First-Degree Family Members, and Youths At-Risk for Psychosis

BACKGROUNDnPrevious research has provided compelling support for olfactory dysfunction in schizophrenia patients, their first-degree relatives, and youth at-risk for psychosis. A previous meta-analysis revealed large effect sizes across olfactory tasks but was limited to 2 olfactory tasks and did not examine moderator variables. Thus, the current meta-analysis was undertaken to incorporate additional studies, risk cohorts, olfactory test domains, and moderator variable analyses.nnnMETHODnA meta-analysis was conducted on 67 publications examining olfactory function in schizophrenia patients and 15 publications examining olfactory functioning in youth at-risk for psychosis, first-degree relatives of schizophrenia patients, and individuals with schizotypy.nnnRESULTSnResults revealed medium-to-large olfactory deficits in schizophrenia patients though significant heterogeneity was evident. Several variables moderated overall study effects. At-risk youths similarly demonstrated medium-to-large effect sizes, whereas first-degree relatives and individuals with schizotypy showed small effects.nnnCONCLUSIONSnFindings suggest robust olfactory deficits in schizophrenia and at-risk youths. In schizophrenia, several variables had significant impact on these deficits and warrant consideration in prospective studies. Our findings also indicate that olfactory measures may be a useful marker of schizophrenia risk status.

Conversion Between Mini-Mental State Examination, Montreal Cognitive Assessment, and Dementia Rating Scale-2 Scores in Parkinson’s Disease

Cognitive impairment is one of the earliest, most common, and most disabling non‐motor symptoms in Parkinsons disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale‐2 (DRS‐2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS‐2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS‐2 using equipercentile equating and log‐linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients.

Facial emotion perception differs in young persons at genetic and clinical high-risk for psychosis

A large body of literature has documented facial emotion perception impairments in schizophrenia. More recently, emotion perception has been investigated in persons at genetic and clinical high-risk for psychosis. This study compared emotion perception abilities in groups of young persons with schizophrenia, clinical high-risk, genetic risk and healthy controls. Groups, ages 13-25, included 24 persons at clinical high-risk, 52 first-degree relatives at genetic risk, 91 persons with schizophrenia and 90 low risk persons who completed computerized testing of emotion recognition and differentiation. Groups differed by overall emotion recognition abilities and recognition of happy, sad, anger and fear expressions. Pairwise comparisons revealed comparable impairments in recognition of happy, angry, and fearful expressions for persons at clinical high-risk and schizophrenia, while genetic risk participants were less impaired, showing reduced recognition of fearful expressions. Groups also differed for differentiation of happy and sad expressions, but differences were mainly between schizophrenia and control groups. Emotion perception impairments are observable in young persons at-risk for psychosis. Preliminary results with clinical high-risk participants, when considered along findings in genetic risk relatives, suggest social cognition abilities to reflect pathophysiological processes involved in risk of schizophrenia.

Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis

Abstract Objectives. While deficits in odor identification and discrimination have been reported in schizophrenia, few studies have examined the relative specificity of these deficits in patients and at-risk youth. Method. Sniffin’ Sticks odor identification and discrimination were assessed in schizophrenia outpatients and non-ill first-degree relatives (Study One), as well as youth at clinical (CR) or genetic (GR) risk for schizophrenia (Study Two). Scores were z-transformed, using the performance of a demographically-matched adult or adolescent comparison group. Results. Patients and relatives were impaired on odor identification, but odor discrimination impairment was limited to the patient group. A similar pattern of impairment emerged in at-risk youth. GR youth were impaired on odor identification but not discrimination, while CR youth were impaired on both tasks. In patients, olfactory impairment was correlated with negative symptomatology. Conclusions. To our knowledge, this is the first study to show that CR youth are impaired on both olfactory tasks, as observed in adult schizophrenia patients. GR youth were impaired only on odor identification like their adult counterparts. These data suggest that odor identification impairment, in isolation, may represent a genetic marker of vulnerability for schizophrenia, while odor discrimination deficits may be a biomarker associated with the development of psychosis.

Odor Hedonic Capacity and Anhedonia in Schizophrenia and Unaffected First-Degree Relatives of Schizophrenia Patients

OBJECTIVEnThere is increasing evidence that schizophrenia patients have difficulties in the hedonic appraisal of odors. In a prior study, we assessed olfactory hedonic perception birhinally and found that males with schizophrenia failed to attach the appropriate hedonic valence to a pleasant odor, despite correctly perceiving changes in odor intensity. Female patients, in contrast, exhibited normal responses. The current study extends this work by examining odor valence processing in unaffected first-degree relatives of schizophrenia patients, to determine the extent to which this abnormality may be genetically mediated. We also examine odor valence processing unirhinally, rather than birhinally, to probe possible lateralized differences in patients hedonic processing deficits.nnnMETHODnIndividuals with schizophrenia (n = 54), first-degree unaffected family members (n = 22), and demographically matched controls (n = 45) were administered the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test.nnnRESULTSnIn contrast to family members and controls, both male and female schizophrenia probands underevaluated the hedonic characteristics of amyl acetate at lower concentrations and overevaluated its pleasantness at concentrations perceived as unpleasant by both controls and relatives. These patient-specific differences could not be explained by differences in smoking habit, medication use, or subjective ratings of odor intensity. However, they were associated with increased levels of anhedonia/asociality and negative symptomatology.nnnCONCLUSIONSnOur findings suggest that both male and female schizophrenia patients have difficulties in the unirhinal appraisal of hedonic valence. Normal responses in unaffected first-degree relatives suggest that this is an environmentally, rather than genetically, mediated abnormality denoting negative symptomatology.

Medication Management and Neuropsychological Performance in Parkinson's Disease

Medication non-adherence is associated with chronic disease and complex medication schedules, and Parkinsons disease (PD) patients also frequently have cognitive impairments that may interfere with effective medication management. The current study quantitatively assessed the medication management skills of PD patients and probed the neurocognitive underpinnings and clinical correlates of this skill. A total of 26 men with PD completed a neuropsychological battery and a modified version of the Hopkins Medication Schedule (HMS), a standard test of a persons ability to understand and implement a routine prescription medication. Estimated adherence rates from performance on the HMS were low. Memory, executive functioning, and processing speed were strongly related to different components of the HMS. A range of neuropsychological abilities is associated with the ability to understand and implement a medication schedule and pillbox in individuals with PD.

Olfaction and apathy in Alzheimer's disease, mild cognitive impairment, and healthy older adults

Objectives: Apathy is a prevalent neuropsychiatric manifestation in individuals with Alzheimers disease (AD) that is associated with decreased social functioning and increased caregiver burden. Olfactory deficits are also commonly observed in AD, and prior work has indicated a link between increased apathy and olfactory dysfunction in individuals with Parkinsons disease. Here, we examined odor identification performance in patients with probable AD (n = 172), individuals with mild cognitive impairment (MCI; n = 112), and neurologically and psychiatrically healthy older adults (n = 132) and its relation to apathy, depression, and overall psychopathology. Method: Participants were administered the Sniffin’ Sticks odor identification test and measures assessing severity of apathy, depression, and overall neuropsychiatric symptomatology. Results: Consistent with previous research, AD and MCI patients were significantly worse at identifying odors than healthy older adults. Additionally, a sex by diagnosis interaction was observed. AD patients had significantly higher levels of apathy relative to MCI and control participants. Of note, across the entire sample odor identification deficits were correlated with level of apathy at the level of p < 0.01, but not with depression or neuropsychiatric symptom severity, when controlling for Mini-Mental State Examination (MMSE) score. Conclusion: Collectively, these data suggest that olfactory disturbance and apathy in AD may result from the progression of disease pathology in shared neural substrates.

Verbal Learning and Memory in Older Adults with Minor and Major Depression

Late-life minor depression (miD) is a prevalent but poorly understood illness. Verbal learning and memory profiles have commonly been used to characterize neuropsychiatric disorders. This study compared the performance of 27 older adults with miD on the California Verbal Learning Test (CVLT) with 26 age-matched individuals with Major Depressive Disorder (MDD) and 36 non-depressed controls. Results revealed that the miD group performed comparably with controls and significantly better than the MDD group on several CVLT indices. Moreover, cluster analysis revealed three distinct groups, consistent with theoretical representations of normal, subcortical, and cortical verbal learning and memory profiles. The majority of the miD group showed normal profiles (74%), whereas most individuals with MDD displayed subcortical profiles (54%). The findings suggest that depression in the elderly is a heterogeneous entity and that the CVLT may be a useful tool for characterizing learning and memory in late-onset depressive disorders.

Olfaction and schizophrenia clinical risk status: Just the facts

Dear Editors, n nThe recent meta-analysis by Cohen et al. (2012) offered a review of the evidence regarding olfactory dysfunction in both schizophrenia patients and individuals at risk for the illness. Their analysis supported the presence of a robust olfactory identification deficit in patients. However, concerning the study of at-risk individuals, they concluded as follows: “Overall, the present findings failed to find evidence that olfaction identification deficits are a meaningful vulnerability marker of schizophrenia pathology..(We) believe that conducting further studies…is not a particularly promising endeavor.” It is our opinion that this assertion could have an unwarranted and unfortunate chilling effect on future research, as it does not accurately reflect the current status of the field. In reviewing 16 studies purported to examine schizophrenia risk status, the authors conflate three very different categories of risk. Five were studies of otherwise-healthy individuals who scored high on a psychometric scale of schizotypal features (e.g. Schizotypal Personality Questionnaire). Nine were studies of unaffected family members of schizophrenia patients. Only two were studies of “ultra-high risk” individuals in the sub-psychotic or prodromal state, as assessed by the Structured Interview for Prodromal Syndromes (SIPS). The incidence of future conversion to overt psychosis is very different in these sub-categories. Grouping them together presents a distorted picture that can lead to erroneous conclusions. n nConversion rates among prodromal individuals with symptoms severe enough to prompt clinical referral have been reported as approximately 35% within 2.5 years (Cannon et al., 2008). Unaffected first-degree relatives of schizophrenia patients, in contrast, have a lifetime psychosis incidence of approximately 10% (Karlsson, 1982). Since most of the published family studies were of older adults (i.e., parents and siblings of schizophrenia probands), many of whom were already past the peak ages of illness onset, the actual incidence in this group was likely substantially lower. In the two existing large-scale longitudinal studies of individuals with psychometrically defined schizotypy, one reported zero cases of psychosis among 91 “at-risk” subjects after 5 years (Gooding et al., 2005). The other reported 10 cases of psychosis among 182 subjects (5.5%) after 10 years (Chapman et al., 1994). Clearly, the risk for psychosis among ultra-high risk subjects greatly exceeds the risk among individuals in the other two categories. A sensitive and specific marker of disease vulnerability should, ideally, reflect this heightened risk profile. Indeed, any vulnerability marker that cannot distinguish among these three groups has very little predictive utility. The results for odor identification, as reported by Cohen, are entirely consistent with these expectations regarding an ideal vulnerability marker. He determined the effect size for the ultra-high risk group to be −0.67 (a moderate to large effect), whereas the effect sizes for unaffected family members and psychometrically defined schizotypals were −0.21 and −0.14, respectively (small to insignificant effects). n nThe facts regarding olfaction and clinical high-risk status are the following. There have been a total of three published studies of olfactory deficits in clinical high-risk subjects relative to demographically comparably healthy individuals (Brewer et al., 2003; Kamath et al., 2012; Woodberry et al., 2010). The overall effect size in the Brewer study was −0.48 (Woods, S.J. Personal communication). The effect size, as listed in the Woodbury manuscript, was −0.89 (not −0.84 as reported by Cohen). The effect sizes in the Kamath study — which was not included in Cohen’s review due to its recent publication — were −1.26 for odor identification and −1.11 for odor discrimination. A meta-analysis of all available data from these three studies yields a composite effect size of −0.77, rather than −0.67. n nImportantly, the Brewer and Woodberry studies also included longitudinal follow-ups of their clinical high-risk participants, which allowed them to examine separately the baseline data from those subjects who subsequently became psychotic. The effect sizes for these future-psychosis subsamples were substantially higher than for the high-risk groups as a whole, −0.68 and −1.32, respectively. Brewer’s future-psychosis sample was large enough to be further parsed into those who developed schizophrenia and those who developed other psychotic illnesses. The effect size for odor identification deficits in those who subsequently developed schizophrenia was −1.12; for those who developed other psychoses, it was −0.24. n nSo the facts, as opposed to the fiction, regarding olfaction and clinical high-risk status are these. There have been three independent studies to date, with three sets of positive findings, a large composite effect, and initial evidence to suggest that this impairment is indicative of a future schizophrenia-spectrum psychotic disorder. The magnitude, consistency and predictive potential of this deficit collectively establish olfactory impairment as one of the most viable biomarkers of the psychosis clinical high-risk state yet identified. Our confidence in making this assertion would, of course, be greater if it were based on a greater number of studies, and it may ultimately be proven false. But to conclude, based on current evidence, that further study is unwarranted would be a truly egregious error.

P50: A candidate ERP biomarker of prodromal Alzheimer's disease

INTRODUCTIONnReductions of cerebrospinal fluid (CSF) amyloid-beta (Aβ42) and elevated phosphorylated-tau (p-Tau) reflect in vivo Alzheimers disease (AD) pathology and show utility in predicting conversion from mild cognitive impairment (MCI) to dementia. We investigated the P50 event-related potential component as a noninvasive biomarker of AD pathology in non-demented elderly.nnnMETHODSn36 MCI patients were stratified into amyloid positive (MCI-AD, n=17) and negative (MCI-Other, n=19) groups using CSF levels of Aβ42. All amyloid positive patients were also p-Tau positive. P50s were elicited with an auditory oddball paradigm.nnnRESULTSnMCI-AD patients yielded larger P50s than MCI-Other. The best amyloid-status predictor model showed 94.7% sensitivity, 94.1% specificity and 94.4% total accuracy.nnnDISCUSSIONnP50 predicted amyloid status in MCI patients, thereby showing a relationship with AD pathology versus MCI from another etiology. The P50 may have clinical utility for inexpensive pre-screening and assessment of Alzheimers pathology.