Donald J. Connor

Defining mild cognitive impairment in Parkinson's disease

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinsons disease (PD) (PD‐MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimers 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.

Longitudinal Modeling of Age-Related Memory Decline and the APOE ε4 Effect

BACKGROUND The APOE epsilon4 allele is associated with the risk of late-onset Alzheimers disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Unified Staging System for Lewy Body Disorders: Correlation with Nigrostriatal Degeneration, Cognitive Impairment and Motor Dysfunction

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 ten 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.

The role of cholinergic projections from the nucleus basalis in memory

The behavioral effects of lesions of the nucleus basalis magnocellularis (NBM) are reviewed, focusing on the anatomical extent of the lesion, the involvement of neurotransmitter systems and the alterations in memory processes. Most behavioral deficits after NBM lesions can be attributed to damage to the NBM itself, although during spontaneous or pharmacologically induced recovery, other brain structures might play a role. The neurochemical deficit underlying the behavioral impairments is most likely the decrease in cholinergic functioning, since, for example, enhancement of cholinergic functioning is sufficient for behavioral improvement. However, since the lesions are not specific for cholinergic neurons, the extent to which noncholinergic damage causes behavioral deficits is still unclear. Finally, lesions of the NBM impair memory, but affect also other behavioral processes, such as discrimination and habituation. A common process underlying these various impairments could be that of insufficiently focused processing of stimuli.

The Sun Health Research Institute Brain Donation Program: description and experience, 1987-2007.

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.

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

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 Alzheimers disease (AD) pathology.

Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles

The role of intracranial atherosclerosis in Alzheimer’s disease (AD) has been a subject of debate since the first decade of the last century. The initial “vascular hypothesis” of AD was rejected after a series of mid-twentieth century gross anatomical postmortem studies that showed an inconstant relationship between intracranial atherosclerosis and senile dementia. These early studies did not utilize statistical methods, however, and the investigators did not appear to consider the possibility that intracranial atherosclerosis might have a probabilistic, rather than an absolute, effect on AD risk. Recent studies by three independent groups have found a significant statistical association between postmortem measures of circle of Willis atherosclerosis and AD. The present study was undertaken to further address the validity of this association in a large autopsy series, including cases diagnosed neuropathologically with vascular dementia (VaD) and non-AD dementias. Postmortem gross anatomical grading of circle of Willis atherosclerosis was performed in 397 subjects classified by neuropathological diagnosis, including 92 non-demented elderly controls, 215 with AD, 30 with VaD and 60 with non-AD dementias. Circle of Willis atherosclerosis was more severe in subjects with AD and VaD than in control subjects, while it was equivalent between control subjects and subjects with non-AD dementias. Increasing atherosclerotic grade increased the odds ratios (OR) for the diagnoses of both AD and VaD and also increased the ORs for both increased neuritic plaque density and higher Braak neurofibrillary tangle stage. The significance of these associations was retained after consideration of the effects of age, gender and the apolipoprotein E-ε4 allele. The results suggest that the statistical association between intracranial atherosclerosis and AD is not an artifact of diagnostic misclassification or of unequal distribution of the apolipoprotein E-ε4 allele.

Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders

Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson’s disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer’s disease with LTS (ADLS), Alzheimer’s disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson’s Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Parkinson disease with dementia: comparing patients with and without Alzheimer pathology.

Subjects with Parkinson disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer disease (AD). The objective is to identify clinical and neuropathologic differences between Parkinson disease with dementia (PDD) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD−AD (N=23) and PDD+AD (N=28). A small subset of subjects with PDD−AD and PDD+AD had received at least 1 standardized neuropsychologic assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms before the onset of dementia. Education, responsiveness of L-dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, and mean Mini-Mental State Examination, Global Deterioration Scale, Functional Assessment Staging, and Unified Parkinson Disease Rating Scale scores did not differ significantly between the 2 groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared with PDD−AD. This study suggests that it is difficult to distinguish PDD+AD and PDD−AD on the basis of movement, clinical, and neuropsychologic assessment. PDD−AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathologic diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.

Reduced risk of incident AD with elective statin use in a clinical trial cohort.

Statins have been reported to reduce the risk and be of benefit in the treatment of Alzheimers disease (AD). Individuals enrolling in the randomized controlled trial testing two anti-inflammatory agents for primary prevention of AD (Alzheimers Disease Anti-inflammatory Prevention Trial; ADAPT) were allowed the elective use of statins. Our objective was to assess whether statin use is associated with reduced risk of incident AD among ADAPT participants. In primary ADAPT study , participants were assessed annually for cholesterol levels and cognitive status. If impairment in cognition was noted, a dementia evaluation was performed. Onset of mild cognitive impairment (MCI) or AD was taken as the date of this evaluation. Time-to-onset was analyzed in six-month intervals following enrollment. Without knowledge of primary treatment assignment in ADAPT, participants were grouped by their self-reported use of lipid-lowering agents (LLA). In the current ancillary ADAPT study we found that elective statin use was associated with significantly reduced risk of incident AD after adjustment for age, gender, education and Apolipoprotein E (ApoE) genotype. The findings were similar when comparing all LLA use (statin and non-statin LLA) to non-LLA use. Cholesterol levels were lower among statin users compared with non-LLA users, but the MMSE scores were equivalent. The data suggest that statin therapy may be of benefit in reducing the risk of AD.