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ObjectiveTo determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)–type copathology are more impaired on confrontation naming than those without likely AD-type copathology.MethodsWe selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid1-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD − AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD − AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.ResultsPatients with LBD + AD performed worse on BNT than patients with LBD − AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = −0.28, p < 0.05) and p-tau (ρ = −0.26, p = 0.05) but not Aβ42 (p > 0.1).ConclusionMarkers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

PubMed query for “Parkinson disease” yields more than 2,000 articles per year for each of the last 5 years. That is a daunting pile of bedside reading for even the most diligent neurologist. This review highlights 5 emerging topics that are changing our current understanding and management of Parkinson disease (PD). When using the term PD, we mean Lewy body parkinsonism as defined by the clinical criteria of the United Kingdom Parkinson's Disease Society Brain Bank. Other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, are beyond the scope of this review. Clinicians are frequently faced with the question, posed by a newly diagnosed patient or family member: “Is Parkinson's genetic?” This apparently simple question has a complex answer. In a small minority of cases, there are defined genes that, when mutated, cause PD. For example, mutations in α-synuclein ( SNCA ), leucine-rich repeat kinase-2 ( LRRK2 ), Parkin , PTEN-induced kinase-1 ( PINK1 ), and DJ-1 have been convincingly demonstrated to cause familial PD but often without a typically Mendelian pattern of inheritance. Families with clear autosomal recessive and dominant patterns are rare. Yet the relative risk of developing PD is more than 3 times higher for an asymptomatic individual when a first-degree relative is affected with sporadic PD.1 Even where there is clear familial clustering of cases, a causative gene may not be identified. What is the source of this “missing heritability”? Some insight has come from recent genome-wide association studies2,3 of large numbers of patients. These analyses—essentially case-control studies where “exposures” are defined by genotyping individuals over a large number of sites of variation in the genome—have identified a number of novel “risk genes” that contribute to the overall chance of developing PD. Importantly, some of these were loci already implicated in familial PD ( SNCA, LRRK2 …

Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Results: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex ( p = 0.02), higher Unified Parkinson9s Disease Rating Scale motor score ( p ≤ 0.001), and worse global cognitive score ( p Conclusions: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.

Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.

In Parkinson disease (PD) management, strategies for durable and endogenously regulated dopamine replacement are of significant interest, leading to protocols for transplantation of dopamine-producing cells into brains of patients with PD. Several open label and blinded trials1 have used fetal mesencephalic, autologous adrenal chromaffin cells and, more recently, retinal pigmented epithelial cells (RPE)2 as sources of dopamine production. With each approach, there has been variable, often transient, clinical benefit and some patients developed unexpected complications. Small numbers of these cases have come to autopsy, but a clear and consistent explanation for the limited efficacy of cell-based strategies has not emerged. In this issue of Neurology ®, Farag et al.3 add to this important literature and provide new insights into potential barriers to transplantation by describing the first autopsy from a PD patient implanted with RPE cells in a supportive gelatin matrix. Using morphologic and immunochemical markers, they estimate that only 0.036% …

A 48-year-old woman with a history only of chronic sinus symptoms presented with her first seizure. Coworkers witnessed a staring spell and speech interruption for approximately 30 seconds followed by a generalized convulsion lasting 2 minutes. After brief postictal confusion, her neurologic examination was normal. Laboratory studies showed no abnormalities. There …