A systematic review and meta-analysis of intellectual, neuropsychological, and psychoeducational functioning in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder frequently associated with cognitive deficits. Despite cognitive deficits being a key feature of NF1, the profile of such impairments in NF1 has been shown to be heterogeneous. Thus, we sought to quantitatively synthesize the extant literature on cognitive functioning in NF1. A random-effects meta-analysis of cross-sectional studies was carried out comparing cognitive functioning of patients with NF1 to typically developing or unaffected sibling comparison subjects of all ages. Analyses included 50 articles (Total NNF1 = 1,522; MAge = 15.70 years, range = 0.52-69.60), yielding 460 effect sizes. Overall moderate deficits were observed [g = -0.64, 95% CI = (-0.69, -0.60)] wherein impairments differed at the level of cognitive domain. Deficits ranged from large [general intelligence: g = -0.95, 95% CI = (-1.12, -0.79)] to small [emotion: g = -0.37, 95% CI = (-0.63, -0.11)]. Moderation analyses revealed nonsignificant contributions of age, sex, educational attainment, and parental level of education to outcomes. These results illustrate that cognitive impairments are diffuse and salient across the lifespan in NF1. Taken together, these results further demonstrate efforts should be made to evaluate and address cognitive morbidity in patients with NF1 in conjunction with existing best practices.

Longitudinal Development of Brain Iron Is Linked to Cognition in Youth.

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8-26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.SIGNIFICANCE STATEMENT Brain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.

A Quantitative Meta-analysis of Olfactory Dysfunction in Epilepsy.

Olfactory dysfunction in epilepsy is well-documented in several olfactory domains. However, the clinical specificity of these deficits remains unknown. The aim of this systematic meta-analysis was to determine which domains of olfactory ability were most impaired in individuals with epilepsy, and to assess moderating factors affecting olfactory ability. Extant peer-reviewed literature on olfaction in epilepsy were identified via a computerized literature search using PubMed, MEDLINE, PsycInfo, and Google Scholar databases. Twenty-one articles met inclusion criteria. These studies included a total of 912 patients with epilepsy and 794 healthy comparison subjects. Included studies measured olfaction using tests of odor identification, discrimination, memory, and detection threshold in patients with different types of epilepsy, including temporal lobe epilepsy (TLE), mixed frontal epilepsy (M-F), and mixed epilepsy (MIX). Olfactory deficits were robust in patients with epilepsy when compared to healthy individuals, with effect sizes in the moderate to large range for several olfactory domains, including odor identification (d = -1.59), memory (d = -1.10), discrimination (d = -1.04), and detection threshold (d = -0.58). Olfactory deficits were most prominent in patients with TLE and M-F epilepsy. Amongst patients with epilepsy, sex, age, smoking status, education, handedness, and age of illness onset were significantly related to olfactory performance. Overall, these meta-analytic findings indicate that the olfactory system is compromised in epilepsy and suggest that detailed neurobiological investigations of the olfactory system may provide further insight into this disorder.

Net Benefits of Recovery High Schools: Higher Cost but Increased Sobriety and Educational Attainment.

BACKGROUND: Recovery high schools (RHS) provide a supportive educational and therapeutic environment for students subsequent to treatment for substance use disorders (SUDs). Most students served by RHSs have concurrent mental health disorders and are at risk for school failure or dropout and substance use relapse. AIMS OF THE STUDY: The central question addressed is whether RHSs are economically efficient alternatives to other high school settings for students in recovery. The aim is to estimate the incremental cost-benefit of RHSs. METHODS: A quasi-experimental non-equivalent pretest-posttest comparison group design was used. We compared substance use and educational outcomes for adolescents who had received specialty SUD treatment; 143 who enrolled in an RHS were compared to 117 who enrolled in a non-RHS school. Groups were balanced by use of a propensity score to drop students who were not similar to those in the other group. The propensity score was also used as a covariate in multiple regression to estimate cost and outcome parameters and standard errors. To take account of uncertainties in impacts and shadow prices, we used Monte Carlo simulations to estimate the distribution of incremental benefits of RHS relative to non-RHS schooling. RESULTS: Two beneficial impacts of statistical and substantive importance were identified: increased probability of high school graduation and increased sobriety. RHS students had significantly (p<.05) less substance use during the study period -- at 12-month follow-up, 55% of RHS and 26% of comparison students reported 3 month abstinence from alcohol and drugs. Urinalysis confirmed abstinence from THC (cannabis) for 68% of RHS versus 37% of comparison students. RHS students' high school graduation rates were 21 to 25 percentage points higher than comparison students. Adopting a societal perspective, incremental benefits of RHSs were estimated by monetizing the increased probability of high school graduation and comparing it to incremental costs. Mean net benefits ranged from USD16.1 thousand to USD51.9 thousand per participant; benefit-to-cost ratios ranged from 3.0 to 7.2. DISCUSSION: Monetizing the benefits and the incremental costs of RHS relative to conventional schooling show substantial positive net benefits from RHS participation. Two factors lend credibility to the results. First, the RHS improvement in substance use indicates a mechanism through which the increased probability of high school graduation can plausibly occur. Second, the estimated increases in the probability of high school graduation were large and statistically significant. As the productivity gains from high school graduation are also large, the dominant benefit category is very plausible. Limitations include the non-randomized design; selection bias into the study conditions not fully controlled by the propensity scores; generalizability only to young people with treated behavioral health disorders; lack of estimates for direct monetization of reduced substance use among adolescents; possible attenuation of the value of education among individuals with behavioral health issues; and uncertainty in calculation of school costs. IMPLICATIONS FOR BEHAVIORAL HEALTH POLICIES: This research provides evidence that the recovery high school model provides cost beneficial support for high school students after primary SUD treatment. The students who enroll in RHSs typically have co-occurring mental health and substance use disorders, adding complexity to their continuing care. Funding policies recognizing the multiple systems of care (behavioral health, education, child and family services, juvenile justice) responsible for these young people are called for.

Neurocognitive Functioning in Patients with 22q11.2 Deletion Syndrome: A Meta-Analytic Review.

The 22q11.2 deletion syndrome (22q11.2DS) is a known risk factor for development of schizophrenia and is characterized by a complex neuropsychological profile. To date, a quantitative meta-analysis examining cognitive functioning in 22q11.2DS has not been conducted. A systematic review of cross-sectional studies comparing neuropsychological performance of individuals with 22q11.2DS with age-matched healthy typically developing and sibling comparison subjects was carried out. Potential moderators were analyzed. Analyses included 43 articles (282 effects) that met inclusion criteria. Very large and heterogeneous effects were seen for global cognition (d = - 1.21) and in specific neuropsychological domains (intellectual functioning, achievement, and executive function; d range = - 0.51 to - 2.43). Moderator analysis revealed a significant role for type of healthy comparison group used (typically developing or siblings), demographics (age, sex) and clinical factors (externalizing behavior). Results revealed significant differences between pediatric and adult samples, with isolated analysis within the pediatric sample yielding large effects in several neuropsychological domains (intellectual functioning, achievement, visual memory; d range = - 0.56 to - 2.50). Large cognitive deficits in intellectual functioning and specific neuropsychological variables in individuals with 22q11.2DS represent a robust finding, but these deficits are influenced by several factors, including type of comparison group utilized, age, sex, and clinical status. These findings highlight the clinical relevance of characterizing cognitive functioning in 22q11.2DS and the importance of considering demographic and clinical moderators in future analyses.

Olfactory processing in bipolar disorder, major depression, and anxiety.

OBJECTIVES: Although olfactory abnormalities are well established in schizophrenia, considerably less work has examined olfactory performance in other neuropsychiatric conditions. In the current study, we examined odor identification, odor discrimination, detection threshold, and odor hedonic processing performance in individuals with bipolar I disorder (n = 43; n = 13 with psychotic features), bipolar II disorder (n = 48), major depressive disorder (MDD) (n = 134), anxiety (n = 48), and no mental disorder (n = 72) who participated in a community-based family study. METHODS: Best estimate DSM-IV diagnoses were based on in-depth personal interviews as well as interviews with family members. Olfactory tests were administered during an in-person clinical visit and were compared using robust linear regression adjusting for age, sex, and psychiatric medication use, as well as nicotine use when necessary. RESULTS: Compared to controls, odor identification performance was lower among individuals with MDD (b = -1.37, 95% confidence interval [CI]: -2.50, -0.24) and bipolar I disorder (b = -1.79, 95% CI: -3.51, -0.67). Among the latter group, performance was only reduced among those with psychotic features (b = -3.49, 95% CI: -6.33, -0.65), particularly for pleasant odors (b = -1.46, 95% CI: -2.51, -0.42). Those with MDD showed lower identification accuracy for neutral odors (b = -0.63, 95% CI: -1.20, -0.06). Performances on measures of odor discrimination and detection threshold did not differ by diagnostic group. CONCLUSIONS: Collectively, these findings indicate that odor identification difficulties may exist in mood disorders, especially when psychotic features are present. In contrast, the global olfactory dysfunction observed in schizophrenia may not be a feature of other neuropsychiatric conditions.

A quantitative meta-analysis of olfactory dysfunction in mild cognitive impairment.

BACKGROUND: The connection between Alzheimer's disease (AD) and olfactory deficits is well documented and further, alterations in olfactory functioning may signal declines in functions associated with dementia. The aim of the present comprehensive meta-analysis was to investigate the nature of olfactory deficits in mild cognitive impairment (MCI). METHODS: Articles were identified through computerised literature search from inception to 30 June 2016 using PubMed, MEDLINE and PsychInfo databases. In order to control for differences in sample size during effect size computation, studies were weighted according to their inverse variance estimates. RESULTS: 31 articles (62 effects) were identified, which included 1993 MCI patients and 2861 healthy older adults (HOA). Included studies contrasted odour identification, discrimination, detection threshold and/or memory between cases and controls. Moderate to large and heterogeneous effects were seen for olfactory deficits in MCI relative to HOA (d=-0.76, 95% CI -0.87<δ<-0.64). Moderator analysis revealed that tests of odour identification yielded larger effect sizes than those of odour detection threshold or memory. In addition, a potential interaction between age and sex was observed, with male patients carrying a larger burden of olfactory deficit and older female patients performing better on olfactory tests. CONCLUSIONS AND RELEVANCE: Olfactory deficits are present and robust in MCI. Odour identification is most impaired in MCI, which parallels the most prominent sensory deficit seen in AD. As such, a simple-to-administer test of odour identification warrants inclusion in the screening of individuals at risk for developing AD.

Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression.

BACKGROUND: We report the neuropsychological outcome of 25 patients with treatment-resistant major depressive disorder (TRD) who participated in an Institutional Review Board (IRB)-approved randomised double-blind trial comparing active to sham deep brain stimulation (DBS) in the anterior limb of the ventral capsule/ventral striatum (VC/VS). METHODS: Participants were randomised to active (n=12) versus sham (n=13) DBS for 16 weeks. Data were analysed at the individual and group levels. Group differences were analysed using repeated measures ANOVAs. Relationships between depression severity and cognition were examined using partial correlations. The false discovery rate method controlled for multiple analyses. RESULTS: No significant interactions comparing active versus sham stimulation over time were evident. Change in depression was unrelated to change in neuropsychological measures. Twenty patients declined by ≥1 SD on at least one measure (41.3% of declines occurred in active group participants; 63.0% in older participants regardless of stimulation status). Twenty-two patients exhibited improvements >1 SD on neuropsychological measures (47.7% in the active group; 63.1% in younger participants). CONCLUSIONS: These data suggest that VC/VS DBS in patients with TRD does not significantly affect neuropsychological function. Age at surgery, regardless of stimulation status, may be related to cognitive outcome at the individual patient level. TRIAL REGISTRATION NUMBER: NCT00837486; Results.

Bridging cognitive screening tests in neurologic disorders: A crosswalk between the short Montreal Cognitive Assessment and Mini-Mental State Examination.

INTRODUCTION: To provide a crosswalk between the recently proposed short Montreal Cognitive Assessment (s-MoCA) and Mini-Mental State Examination (MMSE) within a clinical cohort. METHODS: A total of 791 participants, with and without neurologic conditions, received both the MMSE and the MoCA at the same visit. s-MoCA scores were calculated and equipercentile equating was used to create a crosswalk between the s-MoCA and MMSE. RESULTS: As expected, s-MoCA scores were highly correlated (Pearson r = 0.82, P < .001) with MMSE scores. s-MoCA scores correctly classified 85% of healthy older adults and 91% of individuals with neurologic conditions that impair cognition. In addition, we provide an easy to use table that enables the conversion of s-MoCA score to MMSE score. DISCUSSION: The s-MoCA is quick to administer, provides high sensitivity and specificity for cognitive impairment, and now can be compared directly with the MMSE.

Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease.

INTRODUCTION: Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings. METHODS: Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease. RESULTS: 8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items. DISCUSSION: Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min.

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.

Computer-vision analysis of craniofacial dysmorphology in 22q11.2 deletion syndrome and psychosis spectrum disorders.

BACKGROUND: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders. METHODS: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features. RESULTS: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements. CONCLUSIONS: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development.

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

OBJECTIVES: 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. 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.

Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging.

BACKGROUND: The aim of this study was to compare the utility and diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in the diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a clinical cohort. METHODS: Three hundred twenty-one AD, 126 MCI, and 140 older adults with healthy cognition (HC) were evaluated using the MMSE, the MoCA, a standardized neuropsychologic 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. RESULTS: The MMSE and MoCA offer reasonably good diagnostic and classification accuracy as compared with 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. CONCLUSION: The findings 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.

Gender and ethnic/racial diversity in clinical neuropsychology: Updates from the AACN, NAN, SCN 2020 practice and "salary survey".

OBJECTIVE: Examination of gender and diversity issues within clinical neuropsychology, using data from the 2020 professional practice and "salary survey." METHODS: Clinical neuropsychologists in the U.S. and Canada were invited to participate in an online survey. The final sample consisted of 1677 doctoral-level practitioners. RESULTS: Approximately, 60% of responding neuropsychologists are women and 53.8% of those women identify as early career psychologists (ECPs). Conversely, a majority of men in the sample are advanced career psychologists (ACPs). Both genders work predominantly in institutions, but more men than women work in private practice. ACP men produce a greater number of peer-reviewed publications and conference presentations. Across all work settings, women earn significantly less than men, and are less satisfied with their incomes. Establishing and maintaining family life is the biggest obstacle to attaining greater income and job satisfaction for both genders. Ethnic/racial minority status was identified in 12.9% of respondents, with 59.2% being ECPs. Job satisfaction and hostility in the workplace vary across ethnic/racial minority groups. Hispanic/Latino(a) and White neuropsychologists report higher incomes, but there were no statistically significant differences between any of the groups. CONCLUSIONS: Income and select practice differences persist between female and male neuropsychologists. There is a slow rate of increased ethnic/racial diversity over time, which is much more apparent among early career practitioners. Trajectories and demographics suggest that the gender income gap is unlikely to be improved by the next survey iteration in 2025, whereas it is very likely that ethnic/racial diversity will continue to increase gradually.

Computerized neurocognitive test performance in schizophrenia: a lifespan analysis.

OBJECTIVE: 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. METHODS: 624 patients with schizophrenia and 624 healthy comparison (HC) subjects age 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. RESULTS: 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. CONCLUSIONS: 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.

International consensus statement on allergy and rhinology: Olfaction.

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.

Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease.

OBJECTIVE: Olfactory dysfunction is common in Alzheimer disease (AD) and other neurodegenerative diseases. Paired helical filament (PHF)-tau, alpha-synuclein, and amyloid-beta lesions occur early and severely in cerebral regions of the olfactory system, and they have also been observed in olfactory epithelium (OE). However, their frequency, abundance, and disease specificity, and the relationships of OE pathology to brain pathology have not been established. METHODS: We investigated the pathological expression of amyloid-beta, PHFtau, alpha-synuclein, and TDP-43 in postmortem OE of 79 cases with AD, 63 cases with various other neurodegenerative diseases, and 45 neuropathologically normal cases. RESULTS: Amyloid-beta was present as punctate and small patchy aggregates in 71% of AD cases, compared with 22% of normal cases and 14% of cases with other diseases, and in greater amounts in AD than in either of the other 2 diagnostic categories. PHFtau was evident in dystrophic neurites in 55% of cases with AD, 34% with normal brains, and 39% with other neurodegenerative diseases, also at higher densities in AD. alpha-Synuclein was present in dystrophic neurites in 7 cases, 6 of which also had cerebral Lewy bodies. Pathological TDP-43 inclusions were not observed in the OE in any cases. Amyloid-beta and to a lesser degree, PHFtau ratings in OE significantly correlated with cortical Abeta and PHFtau lesion ratings in the brain. INTERPRETATION: These data demonstrate that AD pathology in the OE is present in the majority of cases with pathologically verified AD and correlates with brain pathology. Future work may assess the utility of amyloid-beta and PHFtau measurement in OE as a biomarker for AD.

Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson's disease.

Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinson's disease, but how they are related remains unclear. We investigated the relationship between olfactory dysfunction and neuropsychiatric manifestations and 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 nonmotor symptoms.