Abstract Objective Cognitive intra-individual variability (IIV) is a sensitive predictor of cognitive decline and disease severity in Alzheimer’s disease (AD). Despite its sensitivity, whether IIV is merely a psychometric artifact or disease pathology biomarker remains unknown. The present study evaluated the association between IIV and cerebrospinal fluid (CSF) biomarkers of AD. Method Participants included 422 individuals from the National Alzheimer’s Coordinating Center Unified Dataset 3.0 who completed baseline neuropsychological assessment and had CSF data. All participants were adult monolingual English speakers. Participants with vision or hearing impairments were excluded. Cases were stratified into cognitively normal (n = 267) and AD groups (n = 155; mild cognitive impairment = 50, dementia = 105). Cross-sectional IIV was calculated by obtaining the individual standard deviation (iSD) of ten cognitive tests. Finally, the coefficient of variation (CoV) was computed by dividing iSD by the participant’s overall test battery mean. Non-parametric Spearman-rank correlations were used to assess the relation between CoV and CSF biomarkers, including beta-amyloid 1–42, total tau (t-tau), and phosphorylated tau (p-tau181). Results In the AD group, CoV was positively correlated with p-tau181 (r = 0.285, p = 0.003) and t-tau (r = 0.241, p = 0.009), and negatively correlated with beta-amyloid 1–42 (r = −0.314, p < 0.001). Correlations between CoV and CSF biomarkers were not significant in the cognitively normal group for beta-amyloid 1–42 (r = 0.076, p = 0.215), p-tau181 (r = −0.014, p = 0.840), and t-tau (r = −0.046, p = 0.485). Conclusions In people with mild cognitive impairment and dementia of presumed AD etiology, cognitive IIV is associated with CSF biomarkers. These findings provide preliminary evidence that IIV is not merely a statistical artifact, but is associated with AD neuropathology.
Abstract Objective Olfactory dysfunction is well-documented in epilepsy. We recently found that olfactory assessment may have clinical utility in identifying surgical candidates with intractable epilepsy who benefit from magnetic resonance–guided laser interstitial thermal therapy (MRgLiTT). However, the demographic, clinical, and cognitive correlates of olfaction in epilepsy remain unclear and could aid in understanding its potential utility in clinical examinations. Method We identified 60 outpatients with epilepsy (mean age = 38.22 ± 13.84 years; 50% male; 89.3% right-handed; seizure location: 45.0% left, 33.3% right, 13.3% bilateral, 8.3% unspecified) referred for neuropsychological evaluation in the Johns Hopkins Division of Medical Psychology Clinic. Neuropsychological evaluation included the 16-item Sniffin’ Sticks Odor Identification Test. Linear regression models were used to examine associations between 1) olfaction and demographic/clinical characteristics (age, sex, education, duration of illness, seizure laterality) and 2) olfaction and cognition (processing speed, language, auditory-verbal and visuospatial memory, executive functioning; adjusted for demographic/clinical characteristics). Results Olfactory performance was not significantly associated with demographic or clinical characteristics. Across all participants, better olfactory performance was associated with better auditory-verbal memory (B = 5.04, t(46) = 4.16, p < 0.001) and visual confrontation naming (B = 1.53, t(45) = 4.11, p < 0.001) with correction for multiple comparisons. In a subset with lateralizing epilepsy (n = 47), better odor identification performance remained a significant predictor of the aforementioned cognitive measures with adjustment for demographic and clinical characteristics. Conclusions Consistent with work in other neurologic conditions, our preliminary findings indicate that olfactory function is associated with verbally-mediated neuropsychological measures in epilepsy. Future studies utilizing pre-surgical neuroimaging will examine the association between olfaction, cognition, and radiographic markers of tissue integrity in epilepsy.
Abstract We examined the association of olfaction with incident dementia and characterized this relationship by key demographic subgroups and APOE-ε4 genotype in the ARIC study. We further examined how change in olfaction was associated with dementia incidence. Olfaction was evaluated using the 12-item Sniffin’ Sticks test in 4470 ARIC participants in 2011-2013 (visit 5) and in 2658 participants in 2016-2017 (visit 6). We defined olfaction as good (score 11-12), moderate (9-10), hyposmia (7-8), and anosmia (0-6). Dementia status was ascertained from 2011-2013 through 2020. Of the 4470 participants at baseline (age:75±5 years, 21% Black race, 60% women), 17% developed dementia over 10 years. In multivariable Cox models, moderate olfaction (hazard ratio (HR):1.5, 95%CI:1.3-1.9), hyposmia (HR:2.2, 95%CI:1.8-2.8), and anosmia (HR:3.5, 95%CI:2.8-4.3) were associated with higher dementia rate in a linear, monotonic manner relative to good olfaction. Findings were similar across subgroups of age, sex, race, and APOE-ε4 genotype. We also used logistic regression to estimate marginal dementia probability. We found that, on the risk difference scale, the absolute risk difference between anosmia and good olfaction was higher in APOE-ε4 carriers (0.29, 95%CI:0.20-0.37) compared to that in non-carriers (0.16, 95%CI:0.11-0.21); jointly, APOE-ε4 carriers with anosmia had the greatest cumulative dementia probability. Further, compared to participants who maintained good olfaction from visit 5 to visit 6, those with stable anosmia (HR:5.6, 95%CI:2.7-11.6) and a decline from good to anosmia (HR:4.5, 95%CI:2.2-9.4)) showed comparable associations with dementia incidence. Our study provides important data about how simple noninvasive olfaction tests may inform future dementia risk.
Abstract Treatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy, from a first episode psychosis cohort that includes 138 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a significant reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a significant reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC GSH, HP and SFG volumes, and age at onset could potentially be trait biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.
ABSTRACT Objective To investigate hemispheric effects of directional versus ring subthalamic nucleus (STN) deep brain stimulation (DBS) surgery on cognitive function in patients with advanced Parkinson’s disease (PD). Methods We examined 31 PD patients (Left STN n = 17; Right STN n = 14) who underwent unilateral subthalamic nucleus (STN) DBS as part of a NIH-sponsored randomized, cross-over, double-blind (ring vs directional) clinical trial. Outcome measures were tests of verbal fluency, auditory-verbal memory, and response inhibition. First, all participants were pooled together to study the effects of directional versus ring stimulation. Then, we stratified the groups by surgery hemisphere and studied the longitudinal changes in cognition post-unilateral STN DBS. Results Relative to pre-DBS cognitive baseline performances, there were no group changes in cognition following unilateral DBS for either directional or ring stimulation. However, assessment of unilateral DBS by hemisphere revealed a different pattern. The left STN DBS group had lower verbal fluency than the right STN group ( t (20.66 = -2.50, p = 0.02). Over a period of eight months post-DBS, verbal fluency declined in the left STN DBS group ( p = 0.013) and improved in the right STN DBS group over time ( p < .001). Similarly, response inhibition improved following right STN DBS ( p = 0.031). Immediate recall did not significantly differ over time, nor was it affected by implant hemisphere, but delayed recall equivalently declined over time for both left and right STN DBS groups (left STN DBS p = 0.001, right STN DBS differ from left STN DBS p = 0.794). Conclusions Directional and ring DBS did not differentially or adversely affect cognition over time. Regarding hemisphere effects, verbal fluency decline was observed in those who received left STN DBS, along with the left and right STN DBS declines in delayed memory. The left STN DBS verbal fluency decrement is consistent with prior bilateral DBS research, likely reflecting disruption of the basal-ganglia-thalamocortical network connecting STN and inferior frontal gyrus. Interestingly, we found an improvement in verbal fluency and response inhibition following right STN DBS. It is possible that unilateral STN DBS, particularly in the right hemisphere, may mitigate cognitive decline.
We demonstrate significant structural abnormalities in the OB, primary and secondary olfactory brain regions in early PD patients measured by high resolution MRI at 7T. The MRI measures showed significant correlations with behavioral olfactory deficits in the participants.
Cognitive impairment amongst Parkinson’s disease (PD) patients is highly prevalent and associated with an increased risk of dementia. There is growing evidence that altered cerebrovascular functions contribute to cognitive impairment. Few studies have compared cerebrovascular changes in PD patients with normal and impaired cognition and those with mild-cognitive-impairment (MCI) without movement disorder. Here, we investigated arteriolar-cerebral-blood-volume (CBVa), an index reflecting the homeostasis of the most actively regulated segment in the microvasculature, using advanced MRI in various brain regions in PD and MCI patients and matched controls. Our goal is to find brain regions with altered CBVa that are specific to PD with normal and impaired cognition, and MCI-without-movement-disorder, respectively. In PD patients with normal cognition (n = 10), CBVa was significantly decreased in the substantia nigra, caudate and putamen when compared to controls. In PD patients with impaired cognition (n = 6), CBVa showed a decreasing trend in the substantia nigra, caudate and putamen, but was significantly increased in the presupplementary motor area and intracalcarine gyrus compared to controls. In MCI-patients-without-movement-disorder (n = 18), CBVa was significantly increased in the caudate, putamen, hippocampus and lingual gyrus compared to controls. These findings provide important information for efforts towards developing biomarkers for the evaluation of potential risk of PD dementia (PDD) in PD patients. The current study is limited in sample size and therefore is exploratory in nature. The data from this pilot study will serve as the basis for power analysis for subsequent studies to further investigate and validate the current findings.
Background Olfactory dysfunction has been reproducibly reported in patients with psychosis, including first episode psychosis (FEP) patients. Consistently, structural abnormalities in the olfactory bulb (OB), a key region of the peripheral olfactory system, have also been reported in psychotic disorders. Meanwhile, air pollution and viral infections in the upper respiratory tract, including those of SARS-CoV-2, are reportedly risk factors for brain dysfunction and mental disorders. These risk factors can disturb the olfactory epithelium (OE) that is located adjacent to the OB and connected via direct neuronal projections. Nevertheless, it is unknown how a disturbance of the OE possibly affects the OB in the pathophysiological context of psychotic disorders. Methods We examined the volume of the OB in FEP patients and healthy controls from 3 Tesla magnetic resonance imaging and molecular expression profiles of olfactory neuronal cells (ONCs) enriched from freshly biopsied OE. Results We observed a reduction of the OB volume in FEP patients compared with healthy controls. We also observed a significant alteration in gene expression profiles in the ONCs from FEP patients, supporting the pathological changes in the OE. Among such molecular changes, immune-related molecules and pathways were underscored in association with the OB volume changes in FEP patients. Conclusions Our data support the OB and OE pathologies in FEP patients. Immune-related molecular changes in the OE can biologically link adverse factors in the nasal cavity, such as air pollution and viral infection, with the OB structural change, both of which have been reported for psychotic disorders.
