Summary Background Idiopathic Parkinson's disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain ...imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders. Methods Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2·6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis. Findings 167 patients were assessed. Image-based classification for idiopathic Parkinson's disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV). Interpretation Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials. Funding National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.
Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show ...associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals.
In silico
modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.
•No significant reduction in brain glial activation measured by PBR28-PET SUVR.•No significant reduction in serum neurofilament light levels over 36–40 weeks.•Adverse event related dose ...reductions/discontinuations common.
Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by 11CPBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks.
In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12–24 weeks and (b) serum NfL over 36–40 weeks. The secondary safety and tolerability endpoints were collected through Week 40.
The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (−0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (−1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60–80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events.
The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12–24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36–40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.
•The study assessed imaging biomarkers to identify pwMS at risk for CI and CW in a real-world setting.•This was an international, multi-center, longitudinal, retrospective, real-word study of 332 ...relapsing-remitting pwMS.•This study confirms the feasibility of using thalamic atrophy and dysconnectivity as MRI biomarkers for CI in pwMS.•PwMS with thalamic atrophy and worse thalamic dysconnectivity presented more frequently with CI and experienced greater CW.
Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient.
To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting.
This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed.
332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model.
PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.
Background
Dementia associated diseases (DAD) refers to clinical conditions characterized by progressive cognitive impairment (CI) that interferes with ability to function independently. However, ...cognitive impairments can vary in degree and combination of cognitive deficits across multiple cognitive domains. Traditional history and cognitive assessments in clinic are insufficient to identify these varied combinations. Therefore, a clinician may be unaware of these variations and impact on patient QOL and decision‐making. Effective quantitative analysis of cognitive function can be obtained in routine care by a validated, examiner‐independent, sensitive, and reliable computerized cognitive assessment battery (CAB‐NT). Patient reported outcomes (PRO) provide information regarding patient perception of ability across clinically relevant concerns. The BRIEF Health Literacy survey (BHL) PRO is used to find the degree to which one can read, understand, exchange, and use health information and resources. Comparison to computerized cognitive testing has not been explored in this population.
Method
Retrospective cross‐sectional analysis of patients with DAD (PwDAD) who completed both PRO BHL and CAB in routine care on the same day. CAB‐NT included 7 cognitive domains: memory (Mem), executive function (Exe), attention (Att), information processing speed (Inf), visual‐spatial (Vis), verbal function (Ver), motor skills (Mot) and global cognitive summary score (GCS). Linear regression analysis was explored with significance (p<0.05).
Result
329 PwDaD, average age of 70±13 years, 63.2% female. Linear regression was used to analyze trends between BHL and CAB. Significant correlations (p = 0.05) were found for CAB‐NT vs: BHL: GCS‐r = 0.42, Vis‐r = 0.36, Mem‐r = 0.31, Exe‐r = 0.39, Ver‐r = 0.25, Mot‐r = 0.22, Inf‐r = 0.32, and Att‐r = 0.28. One‐way ANOVA was performed between BHL (inadequate, marginal, and adequate) and the cognitive domains of the CAB‐NT. Significant differenced (p = 0.05) were found between the three BHL groups within each cognitive domain.
Conclusion
Patient centric DAD performances on CAB‐NT is related to patient‐reported health literacy. The more impaired the CAB‐NT scores, the poorer patient‐perceived health literacy reported. Patient centric recognition of CI can enhance clinician’s recognition of those people who may require additional information for health‐care decisions or incorporate health‐care proxy for effective shared decision making in routine care. Incorporation of this patient centric information can potentially lead to improved outcomes and satisfaction.
Background
Dementia associated diseases (DAD) refer to a group of disorders clinically characterized by progressive cognitive impairment (CI). CI may reflect abnormalities across multiple cognitive ...domains (CD) to varying degrees and combinations and interfere with the ability to carry out activities of daily living (ADL). Determination of driving ability in routine care relies on patient, family, and clinician shared‐decision making, as availability of routine on‐road driving assessment might be limited. Incorporation of patient reported outcomes (PRO) in routine care has increased, becoming more important for patient care and treatment decisions. Neuro‐QoL Cognitive Function Questionnaire (CF) provides an opportunity to assess self‐reported cognition routinely. The relationship of CF to objective computerized multi‐domain cognitive testing and self‐reported driving has not been explored. Providing easily available objective screening might be of great value for all involved in the decision to continue or stop driving in view of the profound impact loss of driving has on independence.
Method
A retrospective review of PwDAD who provided self‐reported driving status and completed both objective and subjective cognitive function (CF) measures. Subjective CF was measured by CF score which pertaining to comprehension, cognition, attention, and learning. The validated computerized cognitive assessment battery (CAB‐NT), includes 7 cognitive domains: memory(Mem), executive function(Exe), attention(Att), information processing speed(Inf), visual‐spatial(Vis), verbal function(Ver), motor skills(Mot) and a global cognitive summary score(GCS). T‐tests and regression analysis was utilized for analysis assuming both equal and unequal variances, with significance (p< 0.05).
Results
496 PwDAD, average age 73.4±8.9, 61.2% female. T‐test showed significant differences between driving status yes/no for both CF and all CAB‐NT domains. However, regression analysis showed a small effect size between CF and CAB‐NT cognitive domains scores.
Conclusion
Self‐reported driving status in PwDAD corresponds to both perceived/subjective CF and objective measures of cognitive function. However, the relationship between subjective and objective cognitive function measures is problematic. With various CDs involved in the safe effective operation of a motor vehicle, it is necessary to objectively assess this risk with objective measures. Evidence of incongruent relationship between objective and subjective cognitive function enhances the importance of incorporating objective measures of cognitive ability to safely maintain an active driving status.
Background
Dementia associated diseases (DAD) refers to a heterogeneous group of disorders that are clinically characterized by progressive cognitive impairment (CI) that ultimately adversely ...influences an individual’s ability to function independently. CI may reflect abnormalities across multiple cognitive domains to varying degrees and combinations across various cognitive domains (CD). Identifying treatment needs and discussing treatment options requires ongoing communication between patient and provider over the disease continuum; communication capacity may be compromised but underappreciated. Impaired verbal and episodic memory function in people with DAD (PwDAD) can adversely impact communication abilities. Maintaining an effective long‐term treatment plan requires consistent monitoring of both performance ability and patient perspective (patient reported outcomes, PRO) across a continuum of patient needs (health, safety, and QoL).
Method
Retrospective review of information obtained in the course of routine care including driving status, Neuro QOL‐Anxiety Short‐Form (A‐SF); Neuro QOL‐Communication Short‐Form (C‐SF); validated multi‐domain computerized cognitive assessment battery (CAB). CAB Domain Score of Verbal Function (CAB‐V) and Memory Function (CAB‐M). CAB and PRO were completed without provider influence.
Result
530 PwDAD (62% female, average age 71.9 +/‐ 14.3 years) was used to compare patient driving status with A‐SF, C‐SF, NT‐V, NT‐M scores. T‐Tests assuming both equal and unequal variances comparing multiple PRO scores to driving status determined significance at (p<0.01). Statistically significant relationships were identified between driving status and: A‐SF, C‐SF, CAB‐V, and CAB‐M.
Conclusion
Self‐reported anxiety and ability to communicate, objective impairment in verbal, and memory function are related to driving status in PwDAD. Appreciation of disease impact, whether perceived or performance ability, across a continuum should be incorporated in routine care and monitoring of dementia disorders to optimize care and outcome by identifying issues of concern that have both visible and invisible impact both patients and clinicians to design an effective plan of care to accommodate patient centric impairment and needs. Standardized methods of routine PRO collection concerning various aspects of real‐world health outside of a clinic encounter are important to building an effective holistic treatment plan.
Background
Dementia associated diseases (DAD) refers to several clinical conditions that are characterized by progressive cognitive impairment that interferes with an individual’s ability to function ...independently. Cognitive impairments (CI) can vary in degree and combination across multiple cognitive domains (CD) that routine care or tests (MMSE, MOCA) might not adequately identify. Therefore, a clinician may not recognize these varied types of CI or change in CD scores effectively. Enhanced recognition of patient centric CI in routine care can be accomplished improved analytics by incorporating a validated, examiner independent computerized cognitive assessment battery (CAB‐NT). Patient self‐reported outcome measures (PRO) are concurrently incorporated with CAB‐NT to gauge associated disability progression. Ability and participation in social roles and activities and communication ability can adversely affect quality of life (QoL) for people with Dementia associated diseases (PwDAD) and are likely related to CI and other factors.
Method
Retrospective review of consecutive PwDAD who completed both CAB‐NT and PRO (SSRA, APSRA, and C‐SF) on the same day in the course of routine care. CAB‐NT included 7 cognitive domains: memory (Mem), executive function (Exe), attention (Att), information processing speed (Inf), visual spatial (Vis), verbal function (Ver), motor skills (Mot) as well as a global cognitive summary score (GCS).
Results
312 PwDaD, 64.74% female, average age 66 +/‐ 17 years. Simple linear regression analyses were performed with significant correlations (p = <0.05): CAB‐NT vs SSRA: GCS r = 0.2, Exe r = 0.3, Mot r = 0.2, and Att r = 0.3. CAB‐NT vs APSRA: Exe r = 0.3, Att r = 0.2. CAB‐NT vs C‐SF: Exe r = 0.2.
Conclusion
Social roles and communication in PwDAD are most impacted by CI associated with executive functioning and attention. Impairment in these domains are associated with increased difficulty for PwDaD to effectively interact with others and may lead to reduced QoL for these patients. Identifying the degree and combination of such CI precisely might allow for early and effective targeted proactive behavioral and/or medicinal intervention to improve QOL of these patients.
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