The efficiency of the brain connectome is associated with cerebrovascular reactivity in persons with white matter hyperintensities.

The purpose of this study was to determine the relationship between the organization of the brain connectome and cerebrovascular reactivity (CVR) in persons with white matter hyperintensities. Diffusion tensor and CVR mapping 3T MRI scans were acquired in 31 participants with white matter hyperintensities. In each participant, the connectome was assessed by reconstructing all white matter tracts with tractography and segmenting the whole brain into multiple regions. Graph theory analysis was performed to quantify how effectively tracts connected brain regions by measuring the global and local efficiency of the connectome. CVR in white matter and gray matter was correlated with the global and local efficiency of the connectome, while adjusting for age, gender, and gray matter volume. For comparison, white matter hyperintensity volume was also correlated with global and local efficiency. White matter CVR was positively correlated with the global efficiency (coefficient: 23.3, p = .005) and local efficiency (coefficient: 2850, p = .004) of the connectome. Gray matter CVR was positively correlated with the global efficiency (coefficient: 21.3, p < .001) and local efficiency (coefficient: 2670, p < .001) of the connectome. White matter hyperintensity volume was negatively correlated with global efficiency (coefficient: -0.0002, p = .003) and local efficiency (coefficient: -0.024, p = .003) of the connectome. The association between CVR and the brain connectome suggests that impaired cerebrovascular function may be part of the pathophysiology of the disruption of the brain connectome in persons with white matter hyperintensities.

Responsiveness to Change of the Montreal Cognitive Assessment, Mini-Mental State Examination, and SCOPA-Cog in Non-Demented Patients with Parkinson's Disease.

BACKGROUND: Clinical monitoring of patients with Parkinson's disease (PD) for cognitive decline is an important element of care. The Montreal Cognitive Assessment (MoCA) has been proposed to be a sensitive tool for assessing cognitive impairment in PD. The aim of our study was to compare the responsiveness of the MoCA to decline in cognition to the responsiveness of the Mini Mental State Examination (MMSE) and the Scales for Outcomes of Parkinson's disease-cognition (SCOPA-Cog). METHODS: PD patients without dementia were enrolled at 6 North American movement disorders centers between 2008 and 2011. Participants received annual evaluations including the MoCA, MMSE, and SCOPA-Cog followed by formal neuropsychological testing. The gold standard for change in cognition was defined as the change on the neuropsychological test scores over the annual assessments. The Reliable Change Method was used to provide an estimate of the probability that a given difference score would be obtained by chance. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change was quantified using receiver operating characteristics (ROC) curves. RESULTS: One hundred seventeen patients were included in the analysis. Participants were followed at mean intervals of 11 ± 2 months for a median of 2 (maximum 5) visits. According to the reliable change index, 56 intervals of cognitive testing showed a decline in global cognition. ROC analysis of change in MoCA, MMSE, and SCOPA-Cog global scores compared to gold standard testing found an area under the curve (AUC) of 0.55 (95% CI 0.48-0.62), 0.56 (0.48-0.63), and 0.63 (0.55-0.70) respectively. There were no significant differences in the AUCs across the tests. The sensitivity of the MoCA, MMSE, and SCOPA-Cog to change at various thresholds for decline in scores reached a maximum of 71% for a cut-off of 1 point change on the SCOPA-Cog. CONCLUSION: Using neuropsychological testing as a gold standard comparator, the performance of the MoCA, MMSE, and SCOPA-Cog for detecting decline in non-demented PD patients over a 1-year interval is poor. This has implications for clinical practice; stable scores may not be taken as reassurance of the absence of cognitive decline.

Impact of white matter hyperintensities on surrounding white matter tracts.

PURPOSE: It is unclear how white matter hyperintensities disrupt surrounding white matter tracts. The aim of this tractography study was to determine the spatial relationship between diffusion characteristics along white matter tracts and the distance from white matter hyperintensities. METHODS: Diffusion tensor 3-T MRI scans were acquired in 29 participants with white matter hyperintensities. In each subject, tractography by the fiber assignment by continuous tracking method was used to segment corticospinal tracts. Mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy were measured along corticospinal tracts in relation to white matter hyperintensities. Diffusion characteristics along tracts were correlated with distance from white matter hyperintensities and were also compared between tracts traversing and not traversing white matter hyperintensities. RESULTS: In tracts not traversing through white matter hyperintensities, increasing distance from white matter hyperintensities was associated with decreased mean diffusivity (p = 0.002) and increased fractional anisotropy (p = 0.006). In tracts traversing white matter hyperintensities, compared to tracts not traversing white matter hyperintensites, the mean diffusivity was higher at 6-8 voxels, axial diffusivity higher at 4-8 voxels, and radial diffusivity higher at 7 voxels away from white matter hyperintensities (all p < 0.006). CONCLUSION: White matter hyperintensities are associated with two patterns of altered diffusion characteristics in the surrounding white matter tract network. Diffusion characteristics along white matter tracts improve further away from white matter hyperintensities suggestive of a local penumbra pattern. Also, altered diffusion extends further along tracts traversing white matter hyperintensities suggestive of a Wallerian-type degenerative pattern.

Measuring mild cognitive impairment in patients with Parkinson's disease.

We examined the frequency of Parkinson disease with mild cognitive impairment (PD-MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD-MCI using the new criteria for PD-MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinson's disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD-MCI when impaired performance was based on comparisons with normative scores. Forty-two patients (93%) had multi-domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinson's Disease-Cognition. The Mini-Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD-MCI, and 103 (94%) had multi-domain MCI. We observed dramatic differences in the proportion of patients who had PD-MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD-MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.

Impact of mild cognitive impairment on health-related quality of life in Parkinson's disease.

BACKGROUND/AIMS: To assess the impact of mild cognitive impairment (MCI) or cognitive decline on health-related quality of life (HR-QOL) in Parkinson's disease (PD). METHODS: HR-QOL measured by the Parkinson Disease Quality of Life Questionnaire (PDQ-39), MCI according to Movement Disorder Society Task Force criteria and cognitive decline from premorbid baseline were assessed in non-demented PD patients at 6 movement disorder clinics. RESULTS: Among 137 patients, after adjusting for education, gender, disease duration, and Movement Disorder Society Unified Parkinson's Disease Rating Scale total score, MCI was associated with worse scores within the PDQ-39 dimension of communication (p = 0.008). Subjects were divided into tertiles of cognitive decline from premorbid level. Scores in the dimension of stigma were worst in the second tertile of cognitive decline (p = 0.03). MCI was associated with worse social support scores in the second tertile of cognitive decline (p = 0.008). CONCLUSION: MCI and cognitive decline from premorbid baseline are associated with reduced HR-QOL in communication, stigma, and social support domains. The cognitive decline from premorbid baseline modifies the association between MCI and HR-QOL in PD and knowing both will allow a better appreciation of difficulties patients face in daily life.

The pill questionnaire in a nondemented Parkinson's disease population.

We assessed the Pill Questionnaire as a screen for mild cognitive impairment in nondemented Parkinson's disease patients. The relationship between ability to remember medications for Parkinson's disease in the Pill Questionnaire, mild cognitive impairment, and deficits on neuropsychological tests performed 2-3 weeks later blind to Pill Questionnaire results was assessed in movement disorders clinic patients. In 109 subjects, inaccurate medication reporting on the Pill Questionnaire was associated with lower scores on the Montreal Cognitive Assessment, Scales for Outcomes in Parkinson's Disease-Cognition and with deficits in memory, attention, executive function-inhibitory control, processing speed, visuospatial function, and language. Inaccurate medication reporting was also associated with an adjusted odds ratio of 2.4 (95% CI, 0.91-5.88; P = .06) for mild cognitive impairment, with a specificity of 80% and sensitivity of 41%. The Pill Questionnaire is neither sensitive nor specific enough to be used as the sole screening or diagnostic tool for mild cognitive impairment. However, inaccurate medication reporting is associated with deficits spanning many cognitive domains and should alert a clinician to a higher likelihood of cognitive impairment.

Method for the affinity purification of covalently linked peptides following cyanogen bromide cleavage of proteins.

The low resolution structure of a protein can sometimes be inferred from information about existing disulfide bridges or experimentally introduced chemical crosslinks. Frequently, this task involves enzymatic digestion of a protein followed by mass spectrometry-based identification of covalently linked peptides. To facilitate this task, we developed a method for the enrichment of covalently linked peptides following the chemical cleavage of a protein. The method capitalizes on the availability of homoserine lactone moieties at the C-termini of cyanogen bromide cleavage products which support selective conjugation of affinity tags. The availability of two C-termini within covalently linked peptides allows for the conjugation of two distinct affinity tags and thereby enables subsequent removal of unmodified peptides by tandem affinity chromatography. Here, we demonstrate the stepwise implementation of this method using a polyhistidine tag and a biotin tag for the selective two-step purification of covalently linked cyanogen bromide fragments from increasingly complex protein samples. The method is independent of the nature of the covalent bond, is adaptable to fully denaturing conditions, and requires only low picomole quantities of starting material.

Melanocortin-4 Receptor Deficiency Phenotype with an Interstitial 18q Deletion: A Case Report of Severe Childhood Obesity and Tall Stature.

Childhood obesity is a growing health concern, associated with significant physical and psychological morbidity. Childhood obesity is known to have a strong genetic component, with mutations in the melanocortin-4 receptor (MC4R) gene being the most common monogenetic cause of obesity. Over 166 different MC4R mutations have been identified in persons with hyperphagia, severe childhood obesity, and increased linear growth. However, it is unclear whether the MC4-R deficiency phenotype is due to haploinsufficiency or dominant-negative effects by the mutant receptor. We report the case of a four-and-a-half-year-old boy with an interstitial deletion involving the long arm of chromosome 18 (46,XY,del(18)(q21.32q22.1)) encompassing the MC4R gene. This patient presented with tall stature and hyperphagia within his first 18 months of life leading to significant obesity. This case supports haploinsufficiency of MC4-R as it describes a MC4-R deficiency phenotype in a patient heterozygous for a full MC4R gene deletion. The intact functional allele with MC4-R haploinsufficiency has the potential to favor a therapeutic response to gastric surgery. Currently, small molecule MC4-R agonists are under development for pharmacologic therapy.

Altered Superficial White Matter on Tractography MRI in Alzheimer's Disease.

BACKGROUND/AIMS: Superficial white matter provides extensive cortico-cortical connections. This tractography study aimed to assess the diffusion characteristics of superficial white matter tracts in Alzheimer's disease. METHODS: Diffusion tensor 3T magnetic resonance imaging scans were acquired in 24 controls and 16 participants with Alzheimer's disease. Neuropsychological test scores were available in some participants. Tractography was performed by the Fiber Assignment by Continuous Tracking (FACT) method. The superficial white matter was manually segmented and divided into frontal, parietal, temporal and occipital lobes. The mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AxD) and fractional anisotropy (FA) of these tracts were compared between controls and participants with Alzheimer's disease and correlated with available cognitive tests while adjusting for age and white matter hyperintensity volume. RESULTS: Alzheimer's disease was associated with increased MD (p = 0.0011), increased RD (p = 0.0019) and increased AxD (p = 0.0017) in temporal superficial white matter. In controls, superficial white matter was associated with the performance on the Montreal Cognitive Assessment, Stroop and Trail Making Test B tests, whereas in Alzheimer's disease patients, it was not associated with the performance on cognitive tests. CONCLUSION: Temporal lobe superficial white matter appears to be disrupted in Alzheimer's disease.

Correlating quantitative tractography at 3T MRI and cognitive tests in healthy older adults.

This study used diffusion tensor imaging tractography at 3 T MRI to relate cognitive function to white matter tracts in the brain. Brain T2 fluid attenuated inversion recovery-weighted and diffusion tensor 3 T MRI scans were acquired in thirty-three healthy participants without mild cognitive impairment or dementia. They completed a battery of neuropsychological tests including the Montreal Cognitive Assessment, Stroop test, Trail Making Test B, Wechsler Memory Scale-III Longest span forward, Wechsler Memory Scale-III Longest span backward, Mattis Dementia Rating Scale, California Verbal Learning Test Version II Long Delay Free Recall, and Letter Number Sequencing. Tractography was generated by the Fiber Assignment by Continuous Tracking method. The corpus callosum, cingulum, long association fibers, corticospinal/bulbar tracts, thalamic projection fibers, superior cerebellar peduncle, middle cerebellar peduncle and inferior cerebellar peduncle were manually segmented. The fractional anisotropy (FA) and mean diffusivity (MD) of these tracts were quantified. We studied the association between cognitive test scores and the MD and FA of tracts while controlling for age and total white matter hyperintensities volume. Worse scores on the Stroop test was associated with decreased FA of the corpus callosum, corticospinal/bulbar tract, and thalamic projection tracts. Scores on the other cognitive tests were not associated with either the FA or MD of measured tracts. In healthy persons the Stroop test appears to be a better predictor of the microstructural integrity of white matter tracts measured by DTI tractography than other cognitive tests.

Cognitive Function and 3-Tesla Magnetic Resonance Imaging Tractography of White Matter Hyperintensities in Elderly Persons.

BACKGROUND/AIMS: This study used 3-Tesla magnetic resonance imaging (MRI) tractography to determine if there was an association between tracts crossing white matter hyperintensities (WMH) and cognitive function in elderly persons. METHODS: Brain T2-weighted fluid-attenuated inversion recovery (FLAIR) and diffusion tensor MRI scans were acquired in participants above the age of 60 years. Twenty-six persons had WMH identified on T2 FLAIR scans. They completed a battery of neuropsychological tests and were classified as normal controls (n = 15) or with Alzheimer's dementia (n = 11). Tractography was generated by the Fiber Assignment by Continuous Tracking method. All tracts that crossed WMH were segmented. The average fractional anisotropy and average mean diffusivity of these tracts were quantified. We studied the association between cognitive test scores with the average mean diffusivity and average fractional anisotropy of tracts while controlling for age, total WMH volume and diagnosis. RESULTS: An increased mean diffusivity of tracts crossing WMH was associated with worse performance on the Wechsler Memory Scale-III Longest Span Forward (p = 0.02). There was no association between the fractional anisotropy of tracts and performance on cognitive testing. CONCLUSION: The mean diffusivity of tracts crossing WMH measured by tractography is a novel correlate of performance on the Wechsler Memory Scale-III Longest Span Forward in elderly persons.

Longitudinal quantitative MRI in multiple system atrophy and progressive supranuclear palsy.

OBJECTIVE: MRI has been used in parkinsonism to assess atrophy, tissue water diffusivity, and mineral deposition but usually at a single time-point. However, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are progressive diseases. This study assessed the value of longitudinal MRI in characterizing the time course of the degenerative process. METHODS: Two serial MRIs (mean 23 months apart) were retrospectively analyzed in 12 MSA, 6 PSP, and 18 age and sex matched controls. Assessment included selected cross-sectional areas, regional apparent diffusion coefficient (ADC) and gradient echo (GRE) intensity ratios of the lateral ventricles, caudate, putamen, middle cerebellar peduncle, pons and midbrain. RESULTS: On follow-up imaging, there was a larger ADC increase in the putamen in PSP over time compared to controls (p = 0.02). In MSA there was greater volume loss in the pons over time compared to controls (p = 0.002). In MSA the changes in middle cerebellar peduncle ADC were correlated with motor symptom severity according to the Unified Parkinson's Disease Rating Scale Part III (p = 0.005). CONCLUSIONS: Evidence of progressive neurodegeneration can be observed on MRI in MSA and PSP within two years consisting of increasing putaminal ADC in PSP and pontine atrophy in MSA.

Reluctance to start medication for Parkinson's disease: a mutual misunderstanding by patients and physicians.

Reluctance to start medication has never been investigated before in PD. We studied reluctance to start medication for PD motor symptoms, namely its prevalence, underlying reasons, drug-specificity, and associated delay in the start of PD medication. A cross-sectional observational international study was conducted. Patients with a clinical diagnosis of PD advised to start antiparkinsonian medication in the previous 5 years were invited to complete a questionnaire in three centers located in North America and Europe. An electronic online survey was sent to physicians through the mailing list of the Movement Disorder Society. 469 participants (201 PD patients, 268 physicians). 40.2% (n = 82) of the patients reported reluctance to start medication, but 88.6% (n = 234/264) of the physicians estimated that ≤20% of their patients with PD had been reluctant to start medication. The most common reasons reported by patients were the fear of side effects (n = 35, 55.6%), followed by non-acceptance of diagnosis (n = 23, 36.5%); fear of a temporally limited benefit was more commonly selected by physicians (n = 92/267, 34.5%). Patients indicated reluctance to start DAs more frequently compared with L-DOPA (OR: 2.22, 95% CI: 1.30, 9.03; p = 0.013) while physicians perceived L-DOPA to be associated with more reluctance (OR: 4.7, 95% CI: 3.41; 6.59; p < 0.0001). Patients with PD and physicians have a different perspective on the issue of reluctance to start medication. There is a need to bring physicians and patients with PD closer to a shared vision of the problem reluctance to start medication.

The ZIP5 ectodomain co-localizes with PrP and may acquire a PrP-like fold that assembles into a dimer.

The cellular prion protein (PrP(C)) was recently observed to co-purify with members of the LIV-1 subfamily of ZIP zinc transporters (LZTs), precipitating the surprising discovery that the prion gene family descended from an ancestral LZT gene. Here, we compared the subcellular distribution and biophysical characteristics of LZTs and their PrP-like ectodomains. When expressed in neuroblastoma cells, the ZIP5 member of the LZT subfamily was observed to be largely directed to the same subcellular locations as PrP(C) and both proteins were seen to be endocytosed through vesicles decorated with the Rab5 marker protein. When recombinantly expressed, the PrP-like domain of ZIP5 could be obtained with yields and levels of purity sufficient for structural analyses but it tended to aggregate, thereby precluding attempts to study its structure. These obstacles were overcome by moving to a mammalian cell expression system. The subsequent biophysical characterization of a homogeneous preparation of the ZIP5 PrP-like ectodomain shows that this protein acquires a dimeric, largely globular fold with an α-helical content similar to that of mammalian PrP(C). The use of a mammalian cell expression system also allowed for the expression and purification of stable preparations of Takifugu rubripes PrP-1, thereby overcoming a key hindrance to high-resolution work on a fish PrP(C).

LIV-1 ZIP ectodomain shedding in prion-infected mice resembles cellular response to transition metal starvation.

We recently documented the co-purification of members of the LIV-1 subfamily of ZIP (Zrt-, Irt-like Protein) zinc transporters (LZTs) with the cellular prion protein (PrP(C)) and, subsequently, established that the prion gene family descended from an ancestral LZT gene. Here, we begin to address whether the study of LZTs can shed light on the biology of prion proteins in health and disease. Starting from an observation of an abnormal LZT immunoreactive band in prion-infected mice, subsequent cell biological analyses uncovered a surprisingly coordinated biology of ZIP10 (an LZT member) and prion proteins that involves alterations to N-glycosylation and endoproteolysis in response to manipulations to the extracellular divalent cation milieu. Starving cells of manganese or zinc, but not copper, causes shedding of the N1 fragment of PrP(C) and of the ectodomain of ZIP10. For ZIP10, this posttranslational biology is influenced by an interaction between its PrP-like ectodomain and a conserved metal coordination site within its C-terminal multi-spanning transmembrane domain. The transition metal starvation-induced cleavage of ZIP10 can be differentiated by an immature N-glycosylation signature from a constitutive cleavage targeting the same site. Data from this work provide a first glimpse into a hitherto neglected molecular biology that ties PrP to its LZT cousins and suggest that manganese or zinc starvation may contribute to the etiology of prion disease in mice.