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-

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.

The Brain Donation Program at Sun Health Research Institute has been in continual operation since 1987, with over 1000 brains banked. The population studied primarily resides in the retirement communities of northwest metropolitan Phoenix, Arizona. The Institute is affiliated with Sun Health, a nonprofit community-owned and operated health care provider. Subjects are enrolled prospectively to allow standardized clinical assessments during life. Funding comes primarily from competitive grants. The Program has made short postmortem brain retrieval a priority, with a 2.75-h median postmortem interval for the entire collection. This maximizes the utility of the resource for molecular studies; frozen tissue from approximately 82% of all cases is suitable for RNA studies. Studies performed in-house have shown that, even with very short postmortem intervals, increasing delays in brain retrieval adversely affect RNA integrity and that cerebrospinal fluid pH increases with postmortem interval but does not predict tissue viability.