The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type α-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of 10 brain regions from 417 subjects stained immunohistochemically for α-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson's disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer's disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson's Disease Rating Scale Part 3. Additionally there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases. KeywordsParkinson's disease; parkinsonism; dementia with Lewy bodies; Alzheimer's disease; incidental Lewy bodies; α-synuclein; olfactory bulb; amgydala; limbic; brainstem; neocortex NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIt has been almost two centuries since the first description (73,74) of Parkinson's disease (PD) and almost one century since the subsequent discovery of its characteristic microscopic lesion, the Lewy body (61,47,82). The intervening years have provided a wealth of detail on its clinical manifestations and pathology. The presenting syndromes are dementia, motor parkinsonism or both. Since Kosaka's delineation of "diffuse Lewy body disease" associated with dementia in 1976(55), followed by the alternative concepts of "senile dementia of the Lewy body type" (78) and "Lewy body variant of Alzheimer's disease" (41), those presenting with dementia are now termed dementia with Lewy bodies (DLB), the definition of which has undergone two major iterations (66,67). In both PD and DLB, aggregation, phosphorylation and nitration of α-synuclein, an abundant synaptic protein, have been suggested to be critical processes leading to Lewy body formation and clinical symptomatology (36,80,28,39,4) .Investigations that have mapped the topographical distribution and density of Lewy bodies and their associated abnormal neurites have indicated that these are spread much more widely throughout the neuraxis than formerly appreciated (22,2...

Objective Age-related cognitive decline trajectories were compared in apolipoprotein E (APOE) e4 homozygotes (HMZ), heterozygotes (HTZ), and noncarriers (NC) in the absence of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). Background At how young an age memory decline diverges from that of noncarriers in healthy people with elevated genetic risk for late-onset AD due to APOE e4 is unknown. Methods Cognitively normal participants age 21-97 years were recruited with local ads, grouped using an APOE e4 enrichment paradigm, and had longitudinal neuropsychological testing. Anyone who developed MCI or dementia during followup was excluded. Acceleration of the rates of decline for predetermined cognitive measures were compared between APOE e4/4 HMZ, e3/4 HTZ, and e4 NC using a mixed model for longitudinal change with age. Results 79 e4 HMZ, 238 HTZ and 498 NC were included. APOE e4 carriers were younger (mean 58.0 vs 61.4 years, p<0.001) and had more years of followup (5.3 v 4.7 years, p=0.01), with equivalent education (15.4 years) and gender (69% women). With accelerating declines beginning prior to age 60 in e4 carriers, longitudinal decline in memory in e4 carriers accelerated more than in NC (p=0.0253) with a possible e4 gene-dose effect (p=0.0231) in which longitudinal decline in e4 HMZ accelerated more than in NC (p=0.0087). Weaker similar effects were also found on a visuospatial and general mental status measure. Conclusions Age-related memory decline in APOE e4 carriers diverges from NC prior to age 60 and appears most severe in HMZ despite ongoing normal clinical status.

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinson's disease (PD) (PD-MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimer's disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD-CogNL), PD-MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD-D) using DSM-IV criteria. Twenty-one percent of our PD sample met criteria for PD-MCI, 62% were PD-CogNL, and 17% had PD-D. The mean duration of PD and MMSE scores of the PD-MCI group were intermediate and significantly different from both PD-CogNL and PD-D. The cognitive domain most frequently abnormal in PD-MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD-MCI was more common than PD-MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD-CogNL and PD-D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD-MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention.

Background-We evaluated the amounts of amyloid-beta (Aβ) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.

Background: Laboratory evidence of cholesterol-induced production of amyloid ␤ as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder.Objective: To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease.Design: Pilot intention-to-treat, proof-of-concept, doubleblind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment.Participants: Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable. Main Outcome Measures:The primary outcome measures were change in Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global Impres-