Degree Of Clinical Impairment Research Articles

Deciphering the clinico‐radiological heterogeneity of dysexecutive Alzheimer’s disease using unsupervised machine learning techniques

AbstractBackgroundDysexecutive Alzheimer's disease (dAD) is a relatively early‐onset variant of AD primarily degrading core executive functions in the absence of predominant behavioral symptoms. Clinical observations suggest substantial variability in clinical, cognitive and neuroimaging profiles within this syndrome. In this presentation, we will discuss our ongoing work disentangling this heterogeneity using unsupervised machine learning techniques.MethodWe collected clinical, neuropsychological and multimodal imaging (MRI, FDG‐PET, amyloid‐PET, tau‐PET) data on 52 dAD patients assessed in our behavioral neurology clinic at Mayo Clinic Rochester. We first performed a spectral clustering analysis based on FDG‐PET to delineate latent patterns of network degeneration (referred as “eigenbrains”) and assessed the relationships between these eigenbrains and clinical and cognitive symptomatology. We then performed a hierarchical clustering on these eigenbrains to derive data‐driven subtypes of dAD. We compared clinical and cognitive data between subtypes, and then compared the imaging profiles to 52 amyloid‐negative age‐ and sex‐matched controls.ResultSix eigenbrains explained approximatively 48% of the variance in FDG‐PET patterns and primarily reflected heteromodal to primary motor/sensory, left‐right hemispheric asymmetry, and anterior‐to‐posterior gradients of macro‐scale cortical organization (Fig 1). These eigenbrains differentially related to reported age at symptom onset, degree of clinical impairment, and performance on a wide range of cognitive domains (executive functions, episodic memory, and visuospatial). Hierarchical clustering revealed four dAD subtypes (diffuse, biparietal, left‐hemisphere, right‐hemisphere). These subtypes differed in reported age at symptom onset and cognitive profile, where the heteromodal‐diffuse subtype exhibited an overall worse clinical picture and the biparietal had a milder profile compared to other subtypes, which was not explained by disease duration. Additionally, spatial patterns of tau distribution and neurodegeneration overlapped with patterns of FDG‐PET hypometabolism in each subtype, whereas patterns of amyloid deposition were similar across subtypes (Figs 2 & 3).ConclusionAlmost half of the variance in macro‐scale patterns of hypometabolism in this dAD cohort was accounted for by six eigenbrains. These eigenbrains captured the inter‐individual variability in age at symptom onset and cognitive impairment. Four dAD subtypes derived from these eigenbrains revealed meaningful differences in clinical, cognitive, and imaging profiles. Recognizing this heterogeneity has significant clinical implications for diagnosis, prognosis, and symptom monitoring.

Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4)

Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive retrograde degeneration, or “dying-back” phenomenon, of the corticospinal tract’s longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.

Altered topology of large-scale structural brain networks in chronic stroke.

Beyond disruption of neuronal pathways, focal stroke lesions induce structural disintegration of distant, yet connected brain regions via retrograde neuronal degeneration. Stroke lesions alter functional brain connectivity and topology in large-scale brain networks. These changes are associated with the degree of clinical impairment and recovery. In contrast, changes of large scale, structural brain networks after stroke are less well reported. We therefore aimed to analyse the impact of focal lesions on the structural connectome after stroke based on data from diffusion-weighted imaging and probabilistic fibre tracking. In total, 17 patients (mean age 64.5 ± 8.4 years) with upper limb motor deficits in the chronic stage after stroke and 21 healthy participants (mean age 64.9 ± 10.3 years) were included. Clinical deficits were evaluated by grip strength and the upper extremity Fugl-Meyer assessment. We calculated global and local graph theoretical measures to characterize topological changes in the structural connectome. Results from our analysis demonstrated significant alterations of network topology in both ipsi- and contralesional, primarily unaffected, hemispheres after stroke. Global efficiency was significantly lower in stroke connectomes as an indicator of overall reduced capacity for information transfer between distant brain areas. Furthermore, topology of structural connectomes was shifted toward a higher degree of segregation as indicated by significantly higher values of global clustering and modularity. On a level of local network parameters, these effects were most pronounced in a subnetwork of cortico-subcortical brain regions involved in motor control. Structural changes were not significantly associated with clinical measures. We propose that the observed network changes in our patients are best explained by the disruption of inter- and intrahemispheric, long white matter fibre tracts connecting distant brain regions. Our results add novel insights on topological changes of structural large-scale brain networks in the ipsi- and contralesional hemisphere after stroke.

Vasculopathy associated with peripheral neuropathy in gait parameters of diabetic people

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus when glycemic levels are poorly controlled. Sometimes DPN is accompanied by vasculopathy (DPV), which can worsen the clinical prognosis. The aim of this study was to analyze the gait parameters of nondiabetic individuals and diabetic individuals with DPN with or without DPV. METHOD The study included 68 individuals (50 to 65 years old) divided into three groups: people without diabetes mellitus (n = 33), diabetic patients with DPN (n = 18), and diabetic patients with both DPN and DVP (n = 17). The participants underwent a gait evaluation using electronic baropodometry to obtain the single and double support, velocity, and pressure-time integral. RESULTS The pressure-time integral, velocity, and single support variables were lower, and the double support and double support/single support ratio were higher in the diabetic neuropathy and vasculopathy group. The velocity was lower the greater the degree of impairment of the diabetic foot. Some correlations were identified with velocity. CONCLUSION In diabetic individuals, there was a significant worsening of the gait parameters analyzed according to increasing degree of clinical impairment.

Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution.

Management of unruptured arteriovenous malformations (AVMs) is controversial. In the first randomized trial of unruptured AVMs (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [ARUBA]), medically managed patients had a significantly lower risk of death or stroke and had better outcomes. The University of California, San Francisco (UCSF) was one of the participating ARUBA sites. While 473 patients were screened for eligibility, only 4 patients were enrolled in ARUBA. The purpose of this study is to report the treatment and outcomes of all ARUBA-eligible patients at UCSF. The authors compared the treatment and outcomes of ARUBA-eligible patients using prospectively collected data from the UCSF brain AVM registry. Similar to ARUBA, they compared the rate of stroke or death in observed and treated patients and used the modified Rankin Scale to grade outcomes. Of 74 patients, 61 received an intervention and 13 were observed. Most treated patients had resection with or without preoperative embolization (43 [70.5%] of 61 patients). One of the 13 observed patients died after AVM hemorrhage. Nine of the 61 treated patients had a stroke or died. There was no significant difference in the rate of stroke or death (HR 1.34, 95% CI 0.12-14.53, p = 0.81) or clinical impairment (Fisher's exact test, p > 0.99) between observed and treated patients. The risk of stroke or death and degree of clinical impairment among treated patients was lower than reported in ARUBA. The authors found no significant difference in outcomes between observed and treated ARUBA-eligible patients at UCSF. Results in ARUBA-eligible patients managed outside that trial led to an entirely different conclusion about AVM intervention, due to the primary role of surgery, judicious surgical selection with established outcome predictors, and technical expertise developed at high-volume AVM centers.

Use of quantitative EEG in infants with port-wine birthmark to assess for Sturge–Weber brain involvement

Many infants born with a facial port-wine (PW) birthmark will not develop brain involvement of Sturge-Weber syndrome (SWS). Previous studies have shown asymmetry in quantitative EEG (qEEG) correlates with degree of clinical impairment in children and adults with known SWS. We hope to determine if quantitative qEEG can be used as a method to predict which infants are most likely to develop SWS brain involvement on MRI. The current study looks at the ability of qEEG to differentiate between infants with radiographically demonstrated SWS and those without. We first performed an observational study of qEEG results on eight infants with facial PW birthmark (four had SWS brain involvement). We recorded standard clinical EEGs and then derived a measure of asymmetry. We subsequently validated this threshold through a study of an additional nine infants with PW birthmark (five with SWS brain involvement). Quantitative EEG correctly identified infants with SWS brain involvement in all cases in the Validation cohort. This technique was at least as good as a pediatric electroencephalographer with extensive experience reading SWS EEGs. This study demonstrates the ability for qEEG to discriminate between those infants with SWS brain involvement and those with neurologically asymptomatic PW birthmark. This study represents an important step toward the development of a qEEG technique able to predict which infants with PW birthmark will develop SWS brain involvement.

Soft tissue injury protocol (STIP) using motion MRI for cervical spine trauma assessment

The purpose of this study was to establish a noninvasive scoring method, using motion MRI, to determine the degree of clinical impairment in traumatized cervical spines. This method is called the soft tissue injury protocol (STIP) scoring method. The cervical spines of 100 adult accident victims were evaluated prospectively using motion MRI at 12 weeks following hyperflexion/hyperextension injury from rear, low-impact motor vehicle collisions. Subjects were scored for degree of functional impairment based on an eight-point scale derived from the following clinical criteria: hypolordosis, motion restriction, disk herniation, and spinal stenosis. Five classes of impairment, ranging from normal to severe impairment, were identified as a basis for therapeutic management. Using the STIP scoring method, 94% of patients (94 of 100) were determined to have nonsurgical injuries. Class 1 and 2 injuries indicated mild impairment and were found in 68% of patients, who were considered to have reached maximum medical improvement at 12 weeks after injury. A Class 3 injury indicated moderate impairment and was found 26% of patients, who required an additional 12 weeks of rehabilitative and medical treatment to achieve maximum medical improvement. Class 4 and 5 injuries indicated severe impairment; these were identified in 6% of patients and required surgical intervention. Five of the six patients requiring surgery (83%) achieved maximum medical improvement at 36 weeks after injury. The STIP scoring method is a practical, noninvasive method of determining the degree of clinical impairment, as a basis for distinguishing injury requiring medical treatment from injury requiring surgical treatment, in cases of subacute cervical spine trauma.

Relation between interstitial myocardial collagen and the degree of clinical impairment in Chagas’ disease

Cardiac performance is negatively associated with interstitial collagen in Chagas' cardiomyopathy. The magnitude of dysfunction is related to the degree of collagen, and this association seems to exhibit a threshold above it if definite cardiac deterioration occurs.

Neuronal ceroid-lipofuscinosis: preferential metabolic alterations in thalamus and posterior association cortex demonstrated by PET.

Regional brain glucose utilisation was investigated with positron emission tomography (PET) and fluorodeoxyglucose (FDG) in four siblings with neuronal ceroid-lipofuscinosis. A consistent pattern was found, namely a decrease of glucose utilisation in all grey structures but more marked at the level of the thalamus and posterior association cortex. The severity of metabolic anomalies was correlated with the degree of clinical impairment and with disease duration; they were the most severe in the oldest patient, who was also the most affected clinically, intermediate in two others, and minimal in the subject with the shortest period of development of the disease. These observations suggest that PET is useful for the definition of anatomical targets of metabolic diseases and for the investigation of their pathophysiology.

Idiopathic pulmonary fibrosis. Pretreatment bronchoalveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy.

Analysis of bronchoalveolar lavage cellular constituents has been recommended as a valuable method for the characterization of the inflammatory cellular population and for studying cellular interactions in the lower respiratory tract of patients with idiopathic pulmonary fibrosis (IPF). However, the clinical relevance of the enumeration of cells in bronchoalveolar lavage fluid (BALF) from patients with IPF remains controversial. We therefore examined the correlations between BALF cellular constituents and both the histopathologic abnormalities and the subsequent clinical response to corticosteroid therapy in 26 newly diagnosed, untreated patients with IPF. The BALF lymphocytosis was associated with moderate-to-severe alveolar septal inflammation (p less than 0.0005) and with a relative lack of histologic honeycombing (p less than 0.05). On the other hand, BALF neutrophil and eosinophil contents did not significantly correlate with any of eleven particular histopathologic abnormalities, and BALF neutrophil and lymphocyte contents did not correlate with the degree of clinical impairment (quantitated by a composite score based on dyspnea, radiographic abnormalities, and physiologic impairment) upon presentation. However, BALF eosinophil content correlated significantly with the severity of clinical impairment, higher eosinophil counts being associated with more severe initial clinical impairment (p less than 0.01). Neither pretreatment BALF neutrophil nor eosinophil content was related to the frequency or magnitude of subsequent clinical change in 20 patients evaluated before and after 1 yr of corticosteroid therapy. In contrast, pretreatment BALF lymphocytosis was associated with significant subsequent clinical improvement (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of psychoeducational diagnosis to educational placement

This study was designed to investigate the relationship between diagnostic classifications and educational placement recommendations utilized by educational psychologists in the evaluation of psychoeducational reports completed on a select group of boys referred to a Child Psychiatric Outpatient Department. In the present study, 45 reports were evaluated for clinical consensus in five input areas: Developmental History, School History, Cognitive Functioning, Sensorimotor-Perceptual Functioning, and Academic Achievement. In addition, one of four educational recommendations was identified for each subject: No Educational Placement Intervention Necessary, Special Tutoring or Remediation, Special Class Placement, and Special School Placement. There was interrater agreement at a greater than chance level ( p≤.01) for three of the input areas, and agreement at a greater than chance level ( p≤.05) for one of the input areas. Using the maximum rating given by the evaluators on each variable, subjects were classified into six discrete clusters based on their clinical characteristics. A chi square test determined that there was no significant association ( p >.05) between cluster membership and specific educational placement recommendations. However, more global relationships between degree of clinical impairment and the need for some educational placement were found.

Glycosidases in serum of cystic fibrosis patients

In a study of eight glycosidases in serum samples from 72 cystic fibrosis patients, 85 cystic fibrosis parents and 34 healthy and diseased controls, significant elevations of mean α-glucosidase levels were found in cystic fibrosis patients. All other glycosidases did not show any significant change. Mean α-glucosidase levels in obligate heterozygotes were the same as in control individuals. Moreover, α-glucosidase levels in cystic fibrosis patients correlated with the degree of clinical impairment as measured by the Schwachman score.