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1.  P50: A candidate ERP biomarker of prodromal Alzheimer’s disease 
Brain research  2015;1624:390-397.
Reductions of cerebrospinal fluid (CSF) amyloid-beta (Aβ42) and elevated phosphorylated-tau (p-Tau) reflect in vivo Alzheimer’s 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.
36 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.
MCI-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.
P50 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 Alzheimer’s pathology.
PMCID: PMC4630129  PMID: 26256251
P50; Alzheimer’s disease (AD); event-related potential (ERP); auditory oddball paradigm; cerebrospinal fluid biomarkers; amyloid-beta
Neurobiology of aging  2015;36(6):2053-2059.
Olfactory dysfunction can be an early sign of Alzheimer’s disease (AD). Since hormone replacement therapy (HRT) may protect against developing AD in postmenopausal women, the question arises as to whether it also protects against olfactory dysfunction in such women. Three olfactory and 12 neurocognitive tests were administered to 432 healthy postmenopausal women with varied HRT histories. Serum levels of reproductive hormones were obtained for all subjects; APOE-ε4 haplotype was determined for 77. National Adult Reading Test and Odor Memory/Discrimination Test (OMT) scores were positively influenced by HRT. Odor identification and OMT test scores were lower for women who scored poorly on a delayed recall test, a surrogate for mild cognitive impairment. WAIS-R NI Spatial Span Backwards Test scores were higher in women receiving estrogen plus progestin HRT and directly correlated with serum testosterone levels, the latter implying a positive effect of testosterone on spatial memory. APOE-ε4 was associated with poorer odor threshold test scores. These data suggest that HRT positively influences a limited number of olfactory and cognitive measures in the menopause.
PMCID: PMC4640930  PMID: 25850354
olfaction; cognition; hormone replacement therapy; estrogen; menopause; endocrinology
3.  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 Parkinson’s 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.
PMCID: PMC4371590  PMID: 25381961
Parkinson’s disease; Mini-Mental State Examination; Montreal Cognitive Assessment; Dementia Rating Scale-2; cognitive screening scales
4.  Neurocognitive development in 22q11.2 Deletion Syndrome: Comparison to youth with developmental delay and medical comorbidities 
Molecular psychiatry  2014;19(11):1205-1211.
The 22q11.2 deletion syndrome (22q11DS) presents with medical and neuropsychiatric manifestations including neurocognitive deficits. Quantitative neurobehavioral measures linked to brain circuitry can help elucidate genetic mechanisms contributing to deficits. To establish the neurocognitive profile and neurocognitive “growth charts”, we compared cross-sectionally 137 individuals with 22q11DS ages 8–21 to 439 demographically matched non-deleted individuals with developmental delay (DD) and medical comorbidities and 443 typically developing (TD) participants. We administered a computerized neurocognitive battery that measures performance accuracy and speed in executive, episodic memory, complex cognition, social cognition and sensorimotor domains. The accuracy performance profile of 22q11DS showed greater impairment than DD, who were impaired relative to TD. Deficits in 22q11DS were most pronounced for face memory and social cognition, followed by complex cognition. Performance speed was similar for 22q11DS and DD, but 22q11DS individuals were differentially slower in face memory and emotion identification. The growth chart, comparing neurocognitive age based on performance relative to chronological age, indicated that 22q11DS participants lagged behind both groups from the earliest age assessed. The lag ranged from less than a year to over three years depending on chronological age and neurocognitive domain. The greatest developmental lag across the age range was for social cognition and complex cognition, with the smallest for episodic memory and sensorimotor speed, where lags were similar to DD. The results suggest that 22q11.2 microdeletion confers specific vulnerability that may underlie brain circuitry associated with deficits in several neuropsychiatric disorders and thereby help identify potential targets and developmental epochs optimal for intervention.
PMCID: PMC4450860  PMID: 24445907
22q11.2 Deletion Syndrome; developmental delay; neurocognition
5.  Meta-Analysis of Olfactory Function in Schizophrenia, First-Degree Family Members, and Youths At-Risk for Psychosis 
Schizophrenia Bulletin  2013;40(1):50-59.
Previous 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.
A 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.
Results 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.
Findings 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.
PMCID: PMC3885295  PMID: 23641047
schizophrenia prodrome; smell; olfaction; schizotypy; psychosis
6.  The Effect of Odor Valence on Olfactory Performance in Schizophrenia Patients, Unaffected Relatives and At-Risk Youth 
Journal of psychiatric research  2013;47(11):1636-1641.
Given the presence of odor identification impairment in individuals with schizophrenia and recent evidence of aberrant odor hedonic processing, the aim of this investigation was to examine the influence of valence and intensity on odor identification in schizophrenia patients, their first-degree family members, and young persons at clinical risk for psychosis. Participants completed the 16-item Sniffin’ Stick Odor Identification Test. A logistic regression was conducted to assess the influence of valence and intensity on odor identification accuracy. Identification performance in the schizophrenia patients and youths at clinical risk for psychosis was significantly influenced by odor valence, but not intensity. Identification accuracy in first-degree family members was not influenced by valence or intensity. These data suggest that abnormalities in odor valence perception may represent an environmentally-mediated marker for hedonic disturbance that could have predictive utility in future conversion to psychosis. Further research examining the utility of odor valence measures as markers for psychosis risk are warranted.
PMCID: PMC4198303  PMID: 23953754
olfaction; anhedonia; emotion; schizophrenia prodrome; smell identification
7.  Comparative accuracies of two common screening instruments for the classification of Alzheimer’s disease, mild cognitive impairment and healthy aging 
To compare the utility and diagnostic accuracy of the MoCA and MMSE in the diagnosis of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) in a clinical cohort.
321 AD, 126 MCI and 140 older adults with healthy cognition (HC) were evaluated using the the MMSE, MoCA, a standardized neuropsychological battery according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD-NB) and an informant based measure of functional impairment, the Dementia Severity Rating Scale (DSRS). Diagnostic accuracy and optimal cut-off scores were calculated for each measure, and a method for converting MoCA to MMSE scores is presented also.
The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared to the more detailed CERAD-NB; however, as a brief cognitive screening measure the MoCA was more sensitive and had higher classification accuracy for differentiating MCI from HC. Complementing the MMSE or the MoCA with the DSRS significantly improved diagnostic accuracy.
The current results support recent data indicating that the MoCA is superior to the MMSE as a global assessment tool, particularly in discerning earlier stages of cognitive decline. In addition, we found that overall diagnostic accuracy improves when the MMSE or MoCA is combined with an informant-based functional measure. Finally, we provide a reliable and easy conversion of MoCA to MMSE scores. However, the need for MCI-specific measures is still needed to increase the diagnostic specificity between AD and MCI.
PMCID: PMC4036230  PMID: 23260866
Alzheimer’s disease; Mild Cognitive Impairment; MMSE; MoCA; Diagnostic accuracy
8.  Olfaction and Apathy in Alzheimer’s Disease, Mild Cognitive Impairment, and Healthy Older Adults 
Aging & mental health  2013;17(5):564-570.
Apathy is a prevalent neuropsychiatric manifestation in individuals with Alzheimer’s 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 Parkinson’s 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.
Participants were administered the Sniffin’ Sticks odor identification test and measures assessing severity of apathy, depression, and overall neuropsychiatric symptomatology.
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 MMSE score.
Collectively, these data suggest that olfactory disturbance and apathy in AD may result from the progression of disease pathology in shared neural substrates.
PMCID: PMC3664659  PMID: 23398350
olfactory; smell; apathy; neuropsychiatry; sex differences
9.  The Influence of Semantic Processing on Odor Identification Ability in Schizophrenia 
Despite the well-documented observation of odor identification deficits in schizophrenia, less is known about where the disruption in the process of correctly identifying an odor occurs. This study aimed to determine the potential moderating effects of semantic processing on the observed olfactory dysfunction in schizophrenia. Schizophrenia patients and healthy comparison subjects completed two versions of the University of Pennsylvania Smell Identification Test (UPSIT): an uncued free-response version and the standard multiple-choice paradigm, as well as three semantic measures: The Boston Naming Test, Animal Naming, and Pyramids and Palm Tree Test. Schizophrenia patients yielded significantly lower scores than the comparison group on the standard UPSIT and on semantic measures. No relationship was observed between olfactory and semantic task performance in patients. These data suggest that odor identification deficits may not be primarily due to semantic processing deficits in schizophrenia.
PMCID: PMC3631780  PMID: 23537559
Schizophrenia; Semantic processing; Olfactory; Olfaction; Smell; Boston naming test
10.  Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis 
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.
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.
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.
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.
PMCID: PMC3922881  PMID: 22070564
olfaction; smell; prodrome; negative symptoms; psychosis prone
12.  Odor Hedonic Capacity and Anhedonia in Schizophrenia and Unaffected First-Degree Relatives of Schizophrenia Patients 
Schizophrenia Bulletin  2011;39(1):59-67.
Objective: There 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. Method: Individuals 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. Results: In 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. Conclusions: Our 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.
PMCID: PMC3523921  PMID: 21616912
smell; olfactory; valence processing; pleasantness; emotion; olfaction
13.  Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker 
Psychiatry research  2012;199(1):8-11.
Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S were hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype.
PMCID: PMC3470780  PMID: 22503356
14.  An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis 
Schizophrenia Research  2012;138(2-3):280-284.
While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3’,5’-monophosphate (cAMP) signaling may contribute to schizophrenia pathology. As cAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor-detection thresholds to two odorants that differ in the degree to which they activate intracellular cAMP were assessed in clinical risk and low-risk participants.
Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n = 17) and controls at low risk for developing psychosis (n = 15). Citralva and lyral are odorants that differ in cAMP activation; citralva is a strong cAMP activator and lyral is a weak cAMP activator.
The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy.
This study extends prior findings of an odor-specific hyposmia implicating cAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of cAMP signaling may be present during the psychosis prodrome.
PMCID: PMC3372687  PMID: 22537567
schizophrenia prodrome; ultra high risk; cAMP; adenosine cyclase; DISC1
15.  Phenylthiocarbamide (PTC) Perception in Patients with Schizophrenia and First-Degree Family Members: Relationship to Clinical Symptomatology and Psychophysical Olfactory Performance 
Schizophrenia research  2007;90(1-3):221-228.
The inability to taste phenylthiocarbamide (PTC; “taste-blindness”) has been associated with a number of medical and neurological illnesses not typically related to taste. We examined PTC sensitivity in 67 schizophrenia patients, 30 healthy controls, and 30 first-degree relatives to determine whether taster status could represent a simple vulnerability marker. A higher prevalence of non-tasters was seen in patients and family members relative to healthy controls. Among patients, non-tasters exhibited increased levels of negative and first-rank symptoms as well as poorer right-nostril odor identification skills relative to PTC tasters. These differences were not explained by age, sex, education, smoking, or intensity differences. Phenotypic variation in PTC sensitivity is thought to be genetic in origin and suggests greater illness risk for those subjects with recessive taster alleles.
PMCID: PMC1862680  PMID: 17208411
Schizophrenia; Family; Taste; Phenylthiocarbamide; PTC; Genetics
16.  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.
PMCID: PMC3662368  PMID: 22189596
Depression; Minor; Elderly; Late-onset; CVLT; Verbal learning and memory
17.  Effects of the Val(158)Met catechol-O-methyltransferase gene polymorphism on olfactory processing in schizophrenia 
Behavioral Neuroscience  2011;126(1):209-215.
The catechol-O-methyltransferase (COMT) val158met polymorphism has received attention in schizophrenia due to its role in prefrontal dopamine catabolism. Given the rich dopaminergic innervations of the olfactory bulb and the influence of dopamine on the transmission of olfactory signals, we examined the influence of COMT genotype status on the olfactory processing impairment observed in schizophrenia. The University of Pennsylvania Smell Identification Test was administered unirhinally to individuals with schizophrenia (n = 42) and a demographically-matched sample of healthy controls (n = 30). Individuals were genotyped for the COMT val158met polymorphism. A statistically significant interaction of diagnosis and COMT genotype was observed, such that schizophrenia heterozygotes and Met homozygotes showed impaired odor identification accuracy relative to Val158 homozygotes. These findings could not be explained by factors such as antipsychotic medication status, clinical symptomatology, or demographic and illness characteristics. Notably, the schizophrenia Val158 homozygotes’ odor identification performance was comparable to that of the control group. These data indicate that odor identification impairments observed in schizophrenia are influenced by the COMT val158met polymorphism. This relationship is consistent with specific dopaminergic modulation of primary olfactory sensory afferents, rather than a broader effect on cognitive processes. Future studies examining the olfactory processing deficit in schizophrenia with respect to other olfactory measures and COMT haplotypes is warranted.
PMCID: PMC3269516  PMID: 22148860
dopamine; olfaction; smell; COMT; genetics
18.  Computerized Neurocognitive Test Performance in Schizophrenia: A Lifespan Analysis 
Computerized neurocognitive batteries based on advanced behavioral neuroscience methods are increasingly used in large-scale clinical and genomic studies. Favorable construct validity in younger schizophrenia patients has been reported, but not in older patients. New variables afforded by computerized assessments were used to clarify age-associated cognitive impairment across the lifespan.
624 patients with schizophrenia and 624 healthy comparison (HC) subjects aged 16–75 completed a 1–2 hour computerized neurocognitive battery (CNB) that assessed abstraction and mental flexibility, attention, working memory, recognition memory (verbal, facial, spatial), language, visuospatial and emotion processing. Linear mixed effects models tested for group differences in accuracy, response time, and efficiency scores. Contrasts were stratified by age.
91% of older (45+) and 94% of younger (<45) groups provided “good” data quality. After controlling for parental education and project, there were significant three-way interactions for diagnosis x domain x age group on all three outcome variables. Patients performed worse than HC across all neurocognitive domains, except in the oldest group of 60+ patients. Age-stratified analyses did not show differences between younger (16–45) and older patients (45–60, 60+), except for the attention domain. Older patients’ reduced working memory efficiency was due to worse speed, not accuracy. Older patients were quicker than younger patients in processing emotions.
Computerized assessments are feasible in large cohorts of schizophrenia patients. There is stable and generalized neurocognitive dysfunction across the lifespan in schizophrenia, albeit with fewer differences in some domains between older patients and HC after age 60. Speed-accuracy tradeoff strategies suggest deceleration of some frontal networks and improvements in speed of emotional processing.
PMCID: PMC3243946  PMID: 22183011
Schizophrenia; neuropsychology; aging
19.  An Odor-Specific Threshold Deficit Implicates Abnormal Intracellular Cyclic AMP Signaling in Schizophrenia 
The American journal of psychiatry  2008;166(2):226-233.
Although olfactory deficits are common in schizophrenia, their underlying pathophysiology remains unknown. Recent evidence has suggested that cAMP signaling may be disrupted in schizophrenia. Since cAMP mediates signal transduction in olfactory receptor neurons, this could contribute to the etiology of observed olfactory deficits. This study was designed to test this hypothesis by determining odor detection threshold sensitivities to two odorants that differ in their relative activations of this intracellular cAMP signaling cascade.
Thirty schizophrenia patients, 25 healthy comparison subjects, and 19 unaffected first-degree relatives of schizophrenia patients were studied. Odor detection threshold sensitivities were measured for the two odorants citralva and lyral. Although both have fruity/floral scents, citralva strongly activates adenylyl cyclase to increase cAMP levels, while lyral is a very weak activator of adenylyl cyclase.
There was a significant group-by-odor interaction. Both schizophrenia patients and unaffected first-degree relatives were impaired in their ability to detect lyral versus citralva. Comparison subjects were equally sensitive to both odorants. This selective deficit could not be explained by differences in age, sex, smoking, clinical symptom profile, or medication use.
This study establishes the presence of an odor-specific hyposmia that may denote a disruption of cAMP-mediated signal transduction in schizophrenia. The presence of a parallel deficit in the patients’ unaffected first-degree relatives suggests that this deficit is genetically mediated. Although additional physiological studies are needed to confirm the underlying mechanism, these results offer strong inferential support for the hypothesis that cAMP signaling is dys-regulated in schizophrenia.
PMCID: PMC3524831  PMID: 19074977
20.  Olfactory Receptor Neuron Dysfunction in Schizophrenia 
Olfactory impairments are a common feature of schizophrenia. Impairments in odor detection and odor identification are present early in the course of illness and among those at risk for the disorder. These behavioral impairments have been linked to both physiological and anatomical abnormalities in the neural substrates subserving olfaction, including relatively peripheral elements of the olfactory system. The location of olfactory receptor neurons in the nasal epithelium allows noninvasive access to these neurons in living subjects. This offers a unique opportunity to directly assess neuronal integrity in vivo in patients. The peripheral olfactory receptor neuron response to odor stimulation was assessed in 21 schizophrenia patients and 18 healthy comparison subjects. The electroolfactogram, representing the electrical depolarization of the olfactory receptor neurons, was recording following stimulation with different doses and durations of hydrogen sulfide, a pure olfactory nerve stimulant. Schizophrenia patients had abnormally large depolarization responses following odor stimulation, independent of clinical symptomatology, antipsychotic medication dosage or smoking history. Although the precise pathophysiological mechanism is unknown, this olfactory receptor neuron abnormality is consistent with several lines of evidence suggesting altered proliferation or maturation of olfactory receptor neuron cell lineages in schizophrenia. It is also consistent with emerging evidence of disruptions of cyclic AMP-mediated intracellular signaling mechanisms, and may be a marker of these disruptions. It unambiguously demonstrates that neurophysiological disturbances in schizophrenia are not limited to cortical and subcortical structures, but rather include even the most peripheral sensory neurons.
PMCID: PMC3524971  PMID: 18754006
schizophrenia; olfaction; olfactory receptor neuron; olfactory epithelium; electroolfactogram; signal transduction
21.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
PMCID: PMC3290902  PMID: 22159053
22.  Neuropsychological Performance in Older Patients With Schizophrenia: A Meta-Analysis of Cross-sectional and Longitudinal Studies 
Schizophrenia Bulletin  2010;37(6):1318-1326.
Objective: Cognitive deficits are among the most reliable predictors of functional impairment in schizophrenia and a particular concern for older individuals with schizophrenia. Previous reviews have focused on the nature and course of cognitive impairments in younger cohorts, but a quantitative meta-analysis in older patients is pending. Method: A previously used search strategy identified studies assessing performance on tests of global cognition and specific neuropsychological domains in older patients with schizophrenia and age-matched comparison groups. Both cross-sectional and longitudinal studies were included. Potential methodological, demographic, and clinical moderators were analyzed. Results: Twenty-nine cross-sectional (2110 patients, 1738 comparison subjects) and 14 longitudinal (954 patients) studies met inclusion criteria. Patients were approximately 65 years old, with 11 years of education, 53% male and 79% Caucasian. Longitudinal analysis (range 1–6 years) revealed homogeneity with small effect sizes (d = −0.097) being observed. Cross-sectional analyses revealed large and heterogeneous deficits in global cognition (d = −1.19) and on specific neuropsychological tests (d = −0.7 to −1.14). Moderator analysis revealed a significant role for demographic (age, sex, education, race) and clinical factors (diagnosis, inpatient status, age of onset, duration of illness, positive and negative symptomology). Medication status (medicated vs nonmedicated) and chlorpromazine equivalents were inconsequential, albeit underrepresented. Conclusions: Large and generalized cognitive deficits in older individuals with schizophrenia represent a robust finding paralleling impairments across the life span, but these deficits do not decline over a 1–6 year period. The importance of considering demographic and clinical moderators in cross-sectional analyses is highlighted.
PMCID: PMC3196956  PMID: 20547571
schizophrenia; neuropsychology; meta-analysis; elderly
23.  Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson’s disease 
Hyposmia, psychiatric disorders and cognitive problems are common non-motor manifestations in Parkinson's Disease but how they are related remains unclear.
To investigate the relationship between olfactory dysfunction and neuropsychiatric manifestations we performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London-Drexel and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification test.
There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%, p<0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean(standard deviation) 6.2(3.2) vs. 8.4(2.8), p<0.001) and executive performance (Tower of London total moves, 52(38) vs. 34(21), p<0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex and disease characteristics in logistic regression models.
The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common non-motor symptoms.
PMCID: PMC3168697  PMID: 21611985
Parkinson's Disease; olfaction; non-motor symptoms; psychiatric symptoms; cognitive symptoms
24.  Identification of pleasant, neutral, and unpleasant odors in schizophrenia 
Psychiatry research  2011;187(1-2):30-35.
Recent work on odor hedonics in schizophrenia has indicated that patients display abnormalities in hedonic judgments of odors in comparison to healthy comparison participants. In the current study, identification accuracy for pleasant, neutral, and unpleasant odors in individuals with schizophrenia and healthy controls was examined. Thirty-three schizophrenia patients (63% male) and thirty-one healthy volunteers (65% male) were recruited. The groups were well matched on age, sex, and smoking status. Participants were administered the University of Pennsylvania Smell Identification Test, which was subsequently divided into 16 pleasant, 15 neutral, and 9 unpleasant items. Analysis of identification z-scores for pleasant, neutral, and unpleasant odors revealed a significant diagnosis by valence interaction. Post-hoc analysis revealed that schizophrenia participants made more identification errors on pleasant and neutral odors compared to healthy controls, with no differences observed for unpleasant odors. No effect was seen for sex. The findings from the current investigation suggest that odor identification accuracy in patients is influenced by odor valence. This pattern of results parallels a growing body of literature indicating that patients display aberrant pleasantness ratings for pleasant odors and highlights the need for additional research on the influence of odor valence on olfactory identification performance in individuals with schizophrenia.
PMCID: PMC3073768  PMID: 21239063
olfaction; olfactory; hedonics; anhedonia; pleasantness
25.  The Relationship of Bipolar Disorder Lifetime Duration and Vascular Burden to Cognition in Older Adults 
Bipolar disorders  2010;12(8):851-858.
We describe the cognitive function of older adults presenting with Bipolar Disorder (BD) and mania. We examine whether longer lifetime duration of BD is associated with greater cognitive dysfunction. We also examine whether there are negative, synergistic effects between lifetime duration of BD and vascular disease burden on cognition.
87 non-demented individuals with BD I ages 60 years and older, experiencing manic, hypomanic, or mixed episodes, were assessed with the Dementia Rating Scale (DRS) and the Framingham Stroke Risk Profile (FSRP) as a measure of vascular disease burden.
Subjects had a mean (SD) age of 68.7 (7.1) years and 13.6 (3.1) years of education; 50.6% (n=44) were females; 89.7% (n=78) white and 10.3% (n=9) black. They presented with overall and domain-specific cognitive impairment: in memory, visuospatial ability, and executive function, compared to age-adjusted norms. Lifetime duration of BD was not related to DRS total score, any other subscale scores, or vascular disease burden. FSRP scores were related to the DRS memory subscale scores, but not total scores or any other domain scores. A negative interactive effect between lifetime duration of BD and FSRP was only observed with the DRS construction subscale.
In this study, lifetime duration of BD had no significant relationship with overall cognitive function in older non-demented adults. Greater vascular disease burden was associated with worse memory function. There was no synergistic relationship between lifetime duration of BD and vascular disease burden on overall cognition function. Addressing vascular disease, especially early on in the course of BD, may mitigate cognitive impairment in older age.
PMCID: PMC3038329  PMID: 21176032
Bipolar Disorder; Cognition; Aged

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