Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders.

OBJECTIVE: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. METHODS: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, ß-amyloid (Aß), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. RESULTS: SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F1, 54 = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43-49 = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aß compared to AD (F1, 40-43 = 1.6-2.0, p > 0.1). INTERPRETATION: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases.

PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha-synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta-amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease-modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-ß, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-ß common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-ß (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-ß, α-synuclein and TDP-43.

Arguing against the proposed definition changes of PD.

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Plasma apolipoprotein A1 as a biomarker for Parkinson disease.

OBJECTIVE: To identify plasma-based biomarkers for Parkinson disease (PD) risk. METHODS: In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n = 134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging was performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. RESULTS: One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1; p = 0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards, p < 0.001, hazard ratio = 0.742). The association between plasma ApoA1 levels and age at PD onset was replicated in an independent cohort of PD patients (p < 0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p = 0.037). INTERPRETATION: Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk.

Neuropathologic substrates of Parkinson disease dementia.

OBJECTIVE: A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). METHODS: One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. RESULTS: Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30). INTERPRETATION: CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid ß could potentially improve cognitive performance in PD.

Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease.

OBJECTIVE: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD. METHODS: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients. RESULTS: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8-fold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients. INTERPRETATION: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.

Genetic influences on cognitive decline in Parkinson's disease.

The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥ 10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Expanding applications of deep brain stimulation: a potential therapeutic role in obesity and addiction management.

BACKGROUND: The indications for deep brain stimulation (DBS) are expanding, and the feasibility and efficacy of this surgical procedure in various neurologic and neuropsychiatric disorders continue to be tested. This review attempts to provide background and rationale for applying this therapeutic option to obesity and addiction. We review neural targets currently under clinical investigation for DBS­the hypothalamus and nucleus accumbens­in conditions such as cluster headache and obsessive-compulsive disorder. These brain regions have also been strongly implicated in obesity and addiction. These disorders are frequently refractory, with very high rates of weight regain or relapse, respectively, despite the best available treatments. METHODS: We performed a structured literature review of the animal studies of DBS, which revealed attenuation of food intake, increased metabolism, or decreased drug seeking. We also review the available radiologic evidence in humans, implicating the hypothalamus and nucleus in obesity and addiction. RESULTS: The available evidence of the promise of DBS in these conditions combined with significant medical need, support pursuing pilot studies and clinical trials of DBS in order to decrease the risk of dietary and drug relapse. CONCLUSIONS: Well-designed pilot studies and clinical trials enrolling carefully selected patients with obesity or addiction should be initiated.

Biomarker discovery for Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease.

Ante-mortem diagnosis of neurodegenerative disorders based on clinical features alone is associated with variable sensitivity and specificity, and biomarkers can potentially improve the accuracy of clinical diagnosis. In patients suspected of having Alzheimer's disease (AD), alterations in cerebrospinal fluid (CSF) biomarkers that reflect the neuropathologic changes of AD strongly support the diagnosis, although there is a trade-off between sensitivity and specificity due to similar changes in cognitively healthy subjects. Here, we review the current approaches in using CSF AD biomarkers (total tau, p-tau(181), and Abeta42) to predict the presence of AD pathology, and our recent work using multi-analyte profiling to derive novel biomarkers for biofluid-based AD diagnosis. We also review our use of the multi-analyte profiling strategy to identify novel biomarkers that can distinguish between subtypes of frontotemporal lobar degeneration, and those at risk of developing cognitive impairment in Parkinson's disease. Multi-analyte profiling is a powerful tool for biomarker discovery in complex neurodegenerative disorders, and analytes associated with one or more diseases may shed light on relevant biological pathways and potential targets for intervention.

Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment.

Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer's disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Abeta42, tau and p-tau(181)). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Abeta42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1alpha), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1alpha, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1alpha and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.

A recommended scale for cognitive screening in clinical trials of Parkinson's disease.

Cognitive impairment is common in Parkinson's disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force's evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD.

Longitudinal patterns of semantic and episodic memory in frontotemporal lobar degeneration and Alzheimer's disease.

The longitudinal assessment of episodic and semantic memory was obtained from 236 patients diagnosed with Alzheimer's disease (AD, n = 128) and with frontotemporal lobar degeneration (FTLD, n = 108), including patients with a social comportment/dysexecutive (SOC/EXEC) disorder, progressive nonfluent aphasia (PNFA), semantic dementia (SemD), and corticobasal syndrome (CBS). At the initial assessment, AD patients obtained a lower score on the delayed free recall test than other patients. Longitudinal analyses for delayed free recall found converging performance, with all patients reaching the same level of impairment as AD patients. On the initial evaluation for delayed recognition, AD patients also obtained lower scores than other groups. Longitudinal analyses for delayed recognition test performance found that AD patients consistently produced lower scores than other groups and no convergence between AD and other dementia groups was seen. For semantic memory, there were no initial between-group differences. However, longitudinal analyses for semantic memory revealed group differences over illness duration, with worse performance for SemD versus AD, PNFA, SOC/EXEC, and CBS patients. These data suggest the presence of specific longitudinal patterns of impairment for episodic and semantic memory in AD and FTLD patients suggesting that all forms of dementia do not necessarily converge into a single phenotype.

Best surgical practices: a stepwise approach to the University of Pennsylvania deep brain stimulation protocol.

Deep brain stimulation (DBS) is the treatment of choice for otherwise healthy patients with advanced Parkinson disease who are suffering from disabling dyskinesias and motor fluctuations related to dopaminergic therapy. As DBS is an elective procedure, it is essential to minimize the risk of morbidity. Further, precision in targeting deep brain structures is critical to optimize efficacy in controlling motor features. The authors have already established an operational checklist in an effort to minimize errors made during DBS surgery. Here, they set out to standardize a strict, step-by-step approach to the DBS surgery used at their institution, including preoperative evaluation, the day of surgery, and the postoperative course. They provide careful instruction on Leksell frame assembly and placement as well as the determination of indirect coordinates derived from MR images used to target deep brain structures. Detailed descriptions of the operative procedure are provided, outlining placement of the stereotactic arc as well as determination of the appropriate bur hole location, lead placement using electrophysiology, and placement of the internal pulse generator. The authors also include their approach to preventing postoperative morbidity. They believe that a strategic, step-by-step approach to DBS surgery combined with a standardized checklist will help to minimize operating room mistakes that can compromise targeting and increase the risk of complication.

Long-term efficacy of rasagiline in early Parkinson's disease.

This study was designed to follow the long-term efficacy, safety, and tolerability of rasagiline for Parkinson's disease (PD) with data collected from all patients who had ever taken rasagiline during the 12-month TEMPO monotherapy trial (N = 398) and subsequent open-label extension. Patients were followed for up to 6.5 years with a mean of 3.5 +/- 2.1 years. After 12 months, additional PD medications were added as required. Of patients remaining in the trial at 2 years, 46% were maintained on rasagiline monotherapy. The majority of patients received a dopamine agonist prior to levodopa as the first additional dopaminergic agent. Analysis using a Kaplan-Meier method indicated that by 5.4 years only 25% of patients progressed to Hoehn & Yahr stage III. Rasagiline was well tolerated, with 11.3% of patients (45/398) withdrawing because of an adverse event. Rasagiline therapy for PD was effective, well tolerated, and safe in this long-term trial.

Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations.

Mutations in LRRK2 are the single most common known cause of Parkinson's disease (PD). Two new PD patients with LRRK2 mutation were identified from a cohort with extensive postmortem assessment. One of these patients harbors the R793M mutation and presented with the typical clinical and pathological features of PD. A novel L1165P mutation was identified in a second patient. This patient had the classical and pathological features of PD, but additionally developed severe neuropsychological symptoms and dementia associated with abundant neurofibrillary tangles in the hippocampal formation; features consistent with a secondary diagnosis of tangle-predominant dementia. alpha-Synuclein-containing pathological inclusions in these patients also were highly phosphorylated at Ser-129, similar to other patients with idiopathic PD. These two PD patients also were characterized by the presence of occasional cytoplasmic TDP-43 inclusions in the temporal cortex, a finding that was not observed in three other patients with the G2019S mutation in LRRK2. These findings extend the clinical and pathological features that may be associated with LRRK2 mutations.

Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease.

The purpose of this study to compare the long-term clinical outcome of early versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects (N = 404) were randomly assigned to initial treatment with rasagiline (early-start group) or placebo for 6 months followed by rasagiline (delayed-start group) in the TEMPO study. Subjects who chose to participate in an open-label extension (N = 306) continued to receive rasagiline as well as other PD medications as needed. Average (+/-SD) duration in the study was 3.6 +/- 2.1 years; 177 subjects received rasagiline for > or =5.0 years. Over the entire 6.5-year follow-up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P = 0.006) in favor of the early-start versus delayed-start rasagiline group. Although the interaction between treatment and time was significant, values for the early-start group were better than the delayed-start group across all time points. Significantly less worsening (percent change) in total UPDRS scores was observed in the early-start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of rasagiline provided long-term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD.

Validation of the questionnaire for impulsive-compulsive disorders in Parkinson's disease.

As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson's disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism, and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored. The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling = 0.95, sexual behavior = 0.97, buying = 0.87, eating = 0.88, punding = 0.78, hobbyism = 0.93, walkabout = 0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling = 0.95, sexual behavior = 0.96, buying = 0.87, eating = 0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96 and 94%, respectively. Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.