Neuropsychological and social predictors of participation in a deep brain stimulation study of Parkinson's disease and dystonia.

Objectives: Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson's disease (PD) and dystonia. Methods: Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours. Results: Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped ( b ) CI b =45.0 to 249.0, p b =0.016, and estimate=-95.1, CI b =-159.9 to -49.2, p b =0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed (R 2 =0.284, estimate=67.7, CI b =20.1 to 119.9, p b =0.019). Discussion: Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.

Prefrontal Physiomarkers of Anxiety and Depression in Parkinson's Disease.

Objective: Anxiety and depression are prominent non-motor symptoms of Parkinson's disease (PD), but their pathophysiology remains unclear. We sought to understand their neurophysiological correlates from chronic invasive recordings of the prefrontal cortex (PFC). Methods: We studied four patients undergoing deep brain stimulation (DBS) for their motor signs, who had comorbid mild to moderate anxiety and/or depressive symptoms. In addition to their basal ganglia leads, we placed a permanent prefrontal subdural 4-contact lead. These electrodes were attached to an investigational pulse generator with the capability to sense and store field potential signals, as well as deliver therapeutic neurostimulation. At regular intervals over 3-5 months, participants paired brief invasive neural recordings with self-ratings of symptoms related to depression and anxiety. Results: Mean age was 61 ± 7 years, mean disease duration was 11 ± 8 years and a mean Unified Parkinson's Disease Rating Scale, with part III (UPDRS-III) off medication score of 37 ± 13. Mean Beck Depression Inventory (BDI) score was 14 ± 5 and Beck Anxiety Index was 16.5 ± 5. Prefrontal cortex spectral power in the beta band correlated with patient self-ratings of symptoms of depression and anxiety, with r-values between 0.31 and 0.48. Mood scores showed negative correlation with beta spectral power in lateral locations, and positive correlation with beta spectral power in a mesial recording location, consistent with the dichotomous organization of reward networks in PFC. Interpretation: These findings suggest a physiological basis for anxiety and depression in PD, which may be useful in the development of neurostimulation paradigms for these non-motor disease features.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

Long-term wireless streaming of neural recordings for circuit discovery and adaptive stimulation in individuals with Parkinson's disease.

Neural recordings using invasive devices in humans can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here, we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five individuals with Parkinson's disease (PD) for up to 15 months after implantation. Bilateral four-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 h were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated individual-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation (DBS). This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.

Thalamic deep brain stimulation for acquired dystonia in children and young adults: a phase 1 clinical trial.

OBJECTIVE: The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia. METHODS: Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson's Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety. RESULTS: All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery. CONCLUSIONS: Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia.Clinical trial registration no.: NCT03078816 (clinicaltrials.gov).

Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus.

OBJECTIVE: The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus. METHODS: Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint. RESULTS: The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event. CONCLUSIONS: Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

Parkinson's disease patient preference and experience with various methods of DBS lead placement.

INTRODUCTION: Physiology-guided deep brain stimulation (DBS) surgery requires patients to be awake during a portion of the procedure, which may be poorly tolerated. Interventional MRI-guided (iMRI) DBS surgery was developed to use real-time image guidance, obviating the need for patients to be awake during lead placement. METHODS: All English-speaking adults with PD who underwent iMRI DBS between 2010 and 2014 at our Center were invited to participate. Subjects completed a structured interview that explored perioperative preferences and experiences. We compared these responses to patients who underwent the physiology-guided method, matched for age and gender. RESULTS: Eighty-nine people with PD completed the study. Of those, 40 underwent iMRI, 44 underwent physiology-guided implantation, and five underwent both methods. There were no significant differences in baseline characteristics between groups. The primary reason for choosing iMRI DBS was a preference to be asleep during implantation due to: 1) a history of claustrophobia; 2) concerns about the potential for discomfort during the awake physiology-guided procedure in those with an underlying pain syndrome or severe off-medication symptoms; or 3) non-specific fear about being awake during neurosurgery. CONCLUSION: Participants were satisfied with both DBS surgery methods. However, identification of the factors associated with a preference for iMRI DBS may allow for optimization of patient experience and satisfaction when choices of surgical methods for DBS implantation are available.

Subthalamic nucleus deep brain stimulation in isolated dystonia: A 3-year follow-up study.

OBJECTIVE: To report long-term safety and efficacy outcomes of a large cohort of patients with medically refractory isolated dystonia treated with subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS: Twenty patients (12 male, 8 female; mean age 49 ± 16.3 years) with medically refractory isolated dystonia were studied (14 were followed for 36 months). The primary endpoints were change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score at 36 months compared to preoperative baseline. Multiple secondary outcomes were also assessed (ClinicalTrials.gov NCT00773604). RESULTS: Eighteen of 20 patients showed improvement 12 months after STN DBS with sustained benefit persisting for 3 years (n = 14). At 36 months, BFMDRS motor scores improved 70.4% from a mean 17.9 ± 8.5 to 5.3 ± 5.6 (p = 0.0002) and total TWSTRS scores improved 66.6% from a mean 41.0 ± 18.9 to 13.7 ± 17.9 (p = 0.0002). Improvement at 36 months was equivalent to that seen at 6 months. Disability and quality of life measures were also improved. Three hardware-related and 24 stimulation-related nonserious adverse events occurred between years 1 and 3 (including 4 patients with dyskinesia). CONCLUSIONS: This study offers support for long-term tolerability and sustained effectiveness of STN DBS in the treatment of severe forms of isolated dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that STN DBS decreases long-term dystonia severity in patients with medically refractory isolated dystonia.

Clinical outcomes using ClearPoint interventional MRI for deep brain stimulation lead placement in Parkinson's disease.

OBJECTIVE: The ClearPoint real-time interventional MRI-guided methodology for deep brain stimulation (DBS) lead placement may offer advantages to frame-based approaches and allow accurate implantation under general anesthesia. In this study, the authors assessed the safety and efficacy of DBS in Parkinson's disease (PD) using this surgical method. METHODS: This was a prospective single-center study of bilateral DBS therapy in patients with advanced PD and motor fluctuations. Symptom severity was evaluated at baseline and 12 months postimplantation using the change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III "off" medication score as the primary outcome variable. RESULTS: Twenty-six PD patients (15 men and 11 women) were enrolled from 2010 to 2013. Twenty patients were followed for 12 months (16 with a subthalamic nucleus target and 4 with an internal globus pallidus target). The mean UPDRS Part III "off" medication score improved from 40.75 ± 10.9 to 24.35 ± 8.8 (p = 0.001). "On" medication time without troublesome dyskinesia increased 5.2 ± 2.6 hours per day (p = 0.0002). UPDRS Parts II and IV, total UPDRS score, and dyskinesia rating scale "on" medication scores also significantly improved (p < 0.01). The mean levodopa equivalent daily dose decreased from 1072.5 ± 392 mg to 828.25 ± 492 mg (p = 0.046). No significant cognitive or mood declines were observed. A single brain penetration was used for placement of all leads, and the mean targeting error was 0.6 ± 0.3 mm. There were 3 serious adverse events (1 DBS hardware-related infection, 1 lead fracture, and 1 unrelated death). CONCLUSIONS: DBS leads placed using the ClearPoint interventional real-time MRI-guided method resulted in highly accurate lead placement and outcomes comparable to those seen with frame-based approaches.

Identifying preoperative language tracts and predicting postoperative functional recovery using HARDI q-ball fiber tractography in patients with gliomas.

OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

Longitudinal gray matter contraction in three variants of primary progressive aphasia: A tenser-based morphometry study.

The present study investigated the pattern of longitudinal changes in cognition and anatomy in three variants of primary progressive aphasia (PPA). Eight patients with the non-fluent variant of PPA (nfvPPA), 13 patients with the semantic variant (svPPA), seven patients with the logopenic variant (lvPPA), and 29 age-matched, neurologically healthy controls were included in the study. All participants underwent longitudinal MRI, neuropsychological and language testing at baseline and at a 1-year follow-up. Tenser-based morphometry (TBM) was applied to T1-weighted MRI images in order to map the progression of gray and white matter atrophy over a 1-year period. Results showed that each patient group was characterized by a specific pattern of cognitive and anatomical changes. Specifically, nfvPPA patients showed gray matter atrophy progression in the left frontal and subcortical areas as well as a decline in motor speech and executive functions; svPPA patients presented atrophy progression in the medial and lateral temporal lobe and decline in semantic memory abilities; and lvPPA patients showed atrophy progression in lateral/posterior temporal and medial parietal regions with a decline in memory, sentence repetition and calculations. In addition, in all three variants, the white matter fibers underlying the abovementioned cortical areas underwent significant volume contraction over a 1-year period. Overall, these results indicate that the three PPA variants present distinct patterns of neuroanatomical contraction, which reflect their clinical and cognitive progression.

Neurocognitive Function in Newly Diagnosed Low-grade Glioma Patients Undergoing Surgical Resection With Awake Mapping Techniques.

BACKGROUND: Low-grade glioma (LGG) patients have increased life expectancy, so interest is high in the treatments that maximize cognition and quality of life. OBJECTIVE: To examine presurgical baseline cognitive deficits in a case series of LGG patients and determine cognitive effects of surgical resection with awake mapping. METHODS: We retrospectively assessed neurological deficits, subjective concerns from patient or caregiver, and cognitive deficits at baseline and postsurgery for 22 patients with newly diagnosed LGG who underwent baseline neuropsychological evaluation and magnetic resonance imaging before awake surgical resection with mapping. Twelve of the 22 patients returned for postoperative evaluation approximately 7 months after surgery. RESULTS: At baseline, 92% of patients/caregivers reported changes in cognition or mood. Neurological examinations and Montreal Cognitive Assessment Scale scores were largely normal; however, on many tests of memory and language, nearly half of individuals showed deficits. After surgery, 45% had no deficits on neurological examination, whereas 55% had only transient or mild difficulties. Follow-up neuropsychological testing found most performances stable to improved, particularly in language, although some patients showed declines on memory tasks. CONCLUSION: Most LGG patients in this series presented with normal neurological examinations and cognitive screening, but showed subjective cognitive and mood concerns and cognitive decline on neuropsychological testing, suggesting the importance of comprehensive evaluation. After awake mapping, language tended to be preserved, but memory demonstrated decline in some patients. These results highlight the importance of establishing a cognitive baseline before surgical resection and further suggest that awake mapping techniques provide reasonable language outcomes in individuals with LGG in eloquent regions.

Effect of subthalamic nucleus deep brain stimulation on dual-task cognitive and motor performance in isolated dystonia.

OBJECTIVE: Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor complications of Parkinson's disease (PD) but may worsen specific cognitive functions. The effect of STN DBS on cognitive function in dystonia patients is less clear. Previous reports indicate that bilateral STN stimulation in patients with PD amplifies the decrement in cognitive-motor dual-task performance seen when moving from a single-task to dual-task paradigm. We aimed to determine if the effect of bilateral STN DBS on dual-task performance in isolated patients with dystonia, who have less cognitive impairment and no dementia, is similar to that seen in PD. METHODS: Eight isolated predominantly cervical patients with dystonia treated with bilateral STN DBS, with average dystonia duration of 10.5 years and Montreal Cognitive Assessment score of 26.5, completed working memory (n-back) and motor (forced-maintenance) tests under single-task and dual-task conditions while on and off DBS. RESULTS: A multivariate, repeated-measures analysis of variance showed no effect of stimulation status (On vs Off) on working memory (F=0.75, p=0.39) or motor function (F=0.22, p=0.69) when performed under single-task conditions, though as working memory task difficulty increased, stimulation disrupted the accuracy of force-tracking. There was a very small worsening in working memory performance (F=9.14, p=0.019) when moving from single-task to dual-tasks when using the 'dual-task loss' analysis. CONCLUSIONS: This study suggests the effect of STN DBS on working memory and attention may be much less consequential in patients with dystonia than has been reported in PD.

Effect of frequency on subthalamic nucleus deep brain stimulation in primary dystonia.

BACKGROUND: Subthalamic nucleus deep brain stimulation (DBS) is an alternative target choice for treating primary dystonia, but little is known about the most effective programming parameters. OBJECTIVE: Here we prospectively evaluate the effect of low versus high frequency subthalamic nucleus DBS in patients with predominantly cervical or upper extremity primary dystonia. METHODS: Seven patients were stimulated at low frequency stimulation (60 Hz) for the first three months and then switched to high frequency stimulation (130 Hz) until month six. Severity of dystonia was determined by a blinded rater (unaware of the patient's pre or post-operative status) who scored the Burke Fahn Marsden dystonia rating scale movement score (BFMDRS-M) and the Toronto Western Spasmodic Torticollis Rating Scale severity score (TWSTRS-S) preoperatively, three, six, and twelve months post-surgery. RESULTS: Patients had a lower mean improvement of 16.6% in BFMDRS-M and 9.5% in TWSTRS-S at three months using low frequency stimulation compared to a 52.3% (p = 0.018) and 45.2% (p = 0.028), respectively, noted at six months using high frequency stimulation. At 12 months (using 130 Hz), the BFMDRS-M and TWSTRS-S improved by 51.8% (p = 0.022) and 56% (p = 0.034). Patients developed transient dyskinesia (during low and high frequency stimulation) which improved with programming adjustments. CONCLUSION: This study offers further support of the effectiveness of subthalamic nucleus DBS in the treatment of primary dystonia and finds that high frequency stimulation was more effective than low frequency stimulation.

Rivastigmine is associated with restoration of left frontal brain activity in Parkinson's disease.

The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinson's disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age- and sex-matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low-frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance-related normalization in the left frontal cortex function.

Cognitive processing speed in older adults: relationship with white matter integrity.

Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55-87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.

C-reactive protein is related to memory and medial temporal brain volume in older adults.

Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community-dwelling older adults with detectable (n=76) and undetectable (n=65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.

Dementia=(MC)2: a 4-item screening test for mild cognitive impairment and dementia.

To develop a practical informant-based screening tool that reliably identifies patients with mild cognitive impairment (MCI) and dementia, we analyzed data from a sample of patients and normal controls seen in a memory clinic. All patients were evaluated with the Clinical Dementia Rating scale. Individual Clinical Dementia Rating responses were dichotomized and entered into a forward stepwise multivariable logistic regression model. Four independent predictors of MCI and dementia thus identified were combined into a prediction rule that was validated in a separate cohort drawn from the same clinic. Using a cut point of 2 or more positive responses to the 4 questions, the final prediction rule had sensitivity of 95% (95% confidence interval (CI): 92-97%) for MCI or dementia, and a specificity of 91% (95% CI: 86-95%). When applied to the validation cohort, the sensitivity for MCI or dementia was 96% (95% CI: 94-98%), and the specificity was 96% (95% CI: 92-98%). Using both cohorts, the positive likelihood ratio for MCI or dementia was 15.6 (95% CI: 14.0-17.3) and the negative likelihood ratio was 0.05 (95% CI: 0.04-0.07). This tool has the potential to identify patients who warrant further cognitive evaluation in busy outpatient or emergency department settings.

Heterogeneous patterns of tissue injury in NARP syndrome.

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual-spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.