Punit Agrawal

Dopaminergic modulation of semantic priming in Parkinson disease.

ObjectiveOur purpose is to examine the effect of D2/D3 agonists on semantic priming. BackgroundDopamine seems to restrict the semantic network in semantic priming. However, which dopamine receptor mediates this effect is unknown. MethodsTo better understand the receptors involved, 15 nondemented Parkinson disease patients performed a lexical decision task before and 1 hour after they received their first morning medication dose, 8 after D2 and D3 agonists pramipexole or ropinirole, and 7 after L-dopa. Semantic priming was measured for closely, distantly, and unrelated word pairs across a stimulus onset asynchrony of 700 ms. ResultsClosely related pairs were recognized significantly faster than unrelated and distantly related pairs before the drugs, as well as after D2/D3 agents. After L-dopa, closely related pairs remained faster than unrelated, but not faster than distantly related pairs. ConclusionsThis suggests that D1 receptors may mediate the dopaminergic modulation of semantic priming.

Motor performance differentiates individuals with Lewy body dementia, Parkinson’s and Alzheimer’s disease

INTRODUCTION Differential diagnosis of dementia with Lewy bodies (DLB), Parkinsons disease with dementia (PDD), Parkinsons disease (PD) and Alzheimers disease (AD) is challenging. Comparative motor profiles of these neurodegenerative disorders may aid in earlier diagnosis but have not been extensively studied. METHODS Groups were rigorously matched by age, education, and sex. DLB/PDD participants were matched by Mini-Mental State Examination Score to individuals with AD and by Unified Parkinsons Disease Rating Scale motor scores to individuals with PD. Gait, balance, dual task walking and hand dexterity measures were compared between a combined group (n=21) of individuals with Lewy body dementia (LBD) consisting of those with DLB (n=11) and PDD (n=10) to individuals with PD (n=21) or AD (n=21). RESULTS Individuals at the same disease stage with LBD walked significantly slower with shorter stride lengths (p<0.05), demonstrated poorer balance on both the Tinetti and Berg Balance Scale, and poorer performance on dual-task and figure-of-eight walking compared to PD and AD (p<0.05 for all) groups. Upper extremity coordination on the 9-hole peg test differentiated LBD from both PD and AD and was the only motor test in which individuals with AD performed worse than those with PD. Tinetti balance subscores were significantly lower in PDD compared to DLB participants (10.4±2.3 versus 12.8±2.3; p=0.027). CONCLUSIONS Motor features distinguish individuals with LBD from those with AD and PD. Measures of gait, balance and finger dexterity provide an additional means of differentiating individuals with LBD from those with AD and PD.

Paired Studies Comparing Clinical Profiles of Lewy Body Dementia with Alzheimer’s and Parkinson’s Diseases

Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimers disease (AD) and Parkinsons disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea.

Deep Brain Stimulation of Frontal Lobe Networks to Treat Alzheimer’s Disease

The study objective was to evaluate the safety and efficacy of deep brain stimulation (DBS) at the ventral capsule/ventral striatum (VC/VS) region to specifically modulate frontal lobe behavioral and cognitive networks as a novel treatment approach for Alzheimers disease (AD) patients. This is a non-randomized phase I prospective open label interventional trial of three subjects with matched comparison groups. AD participants given DBS for at least 18 months at the VC/VS target were compared on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), our primary outcome clinical measure, to matched groups without DBS from the AD Neuroimaging Initiative (ADNI) cohort. Serial 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) images of AD participants were also compared longitudinally over time. Three AD DBS participants were matched to subjects from the ADNI cohort. All participants tolerated DBS well without significant adverse events. All three AD DBS participants had less performance decline and two of them meaningfully less decline over time on our primary outcome measure, CDR-SB, relative to matched comparison groups from the ADNI using score trajectory slopes. Minimal changes or increased metabolism on FDG-PET were seen in frontal cortical regions after chronic DBS at the VC/VS target. The first use of DBS in AD at a frontal lobe behavior regulation target (VC/VS) was well-tolerated and revealed less performance decline in CDR-SB. Frontal network modulation to improve executive and behavioral deficits should be furthered studied in AD.

Successful subthalamic nucleus deep brain stimulation therapy after significant lead displacement from a subdural hematoma

A 57-year-old man with a 21 year history of Parkinsons disease underwent bilateral subthalamic nucleus deep brain stimulation (DBS) placement. One week postoperatively he developed an acute left subdural hematoma from a fall with significant displacement of the DBS leads. It was promptly evacuated, the patient slowly recovered neurologically, and the leads again moved near to the original position. Six months of stimulation therapy attained 50% reduction in symptoms. This case report demonstrates the movement of DBS leads due to brain shift and their ability to come back to previous location once the brain shift is corrected.

Prospective Tractography-Based Targeting for Improved Safety of Focused Ultrasound Thalamotomy

BACKGROUND Focused ultrasound thalamotomy (FUS-T) was recently approved for the treatment of refractory essential tremor (ET). Despite its noninvasive approach, FUS-T reinitiated concerns about the adverse effects and long-term efficacy after lesioning. OBJECTIVE To prospectively assess the outcomes of FUS-T in 10 ET patients using tractography-based targeting of the ventral intermediate nucleus (VIM). METHODS VIM was identified at the intercommissural plane based on its neighboring tracts: the pyramidal tract and medial lemniscus. FUS-T was performed at the center of tractography-defined VIM. Tremor outcomes, at baseline and 3 mo, were assessed independently by the Tremor Research Group. We analyzed targeting coordinates, clinical outcomes, and adverse events. The FUS-T lesion location was analyzed in relation to unbiased thalamic parcellation using probabilisitic tractography. Quantitative diffusion-weighted imaging changes were also studied in fiber tracts of interest. RESULTS The tractography coordinates were more anterior than the standard. Intraoperatively, therapeutic sonications at the tractography target improved tremor (>50% improvement) without motor or sensory side effects. Sustained improvement in tremor was observed at 3 mo (tremor score: 18.3 ± 6.9 vs 8.1 ± 4.4, P = .001). No motor weakness and sensory deficits after FUS-T were observed during 6-mo follow-up. Ataxia was observed in 3 patients. FUS-T lesions overlapped with the VIM parcellated with probablisitic tractography. Significant microstructural changes were observed in the white matter connecting VIM with cerebellum and motor cortex. CONCLUSION This is the first report of prospective VIM targeting with tractography for FUS-T. These results suggest that tractography-guided targeting is safe and has satisfactory short-term clinical outcomes.

Memory profiles differ between parkinsonian dementia syndromes and Alzheimer's disease

efits, and general ethics of disclosing apolipoprotein (APOE) genotype to older adults. Knowledge that one carries the APOE e 4 allele risk factor for Alzheimer’s disease (AD) was recently found to have little short-term psychological risk. However, the impact of this knowledge on subjective ratings of memory and objective memory test performance of older adults is unknown. Methods:We administered objective verbal and visual memory tests, and self-rating scales of memory function, to 144 older adults (ages 52-89) with known APOE genotype who knew (e 4+: n 1⁄4 25; e 4-: n 1⁄4 49) or did not know (e 4+: n 1⁄4 25; e 4-: n 1⁄4 45) their genotype and genetic risk for AD prior to neuropsychological evaluation. Results: Although APOE genotype did not have an overall main effect on subjective self-ratings or objective memory scores, we observed significant genotype X disclosure interaction effects on several memory rating scales and tests of immediate and delayed verbal recall (all p’s<.05). Older adults who knew their e 4+ genotype tended to judge their memory more harshly and performed worse on an objective verbal memory test than did e 4+ adults who did not know. In contrast, older adults who knew their e 4genotype judged their memory more positively than did e 4adults who did not know, but these groups did not differ in objective memory test performance. The participant groups did not differ significantly in age, level of education, gender distribution, global ratings of depression (i.e., Geriatric Depression Scale) or global cognitive performance (i.e., Mini-Mental State Exam, Mattis Dementia Rating Scale). Conclusions: These results indicate that informing older adults that they have an APOE genotype associated with increased risk of AD can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. Therefore, clinicians and researchers should consider knowledge of genotype when evaluating older adults who may or may not be at risk for developing dementia. Similar implications can be drawn for those individuals who have knowledge of AD related risk based on neuroimaging or cerebrospinal fluid biomarkers.