Richard E. Kennedy

Vascular risk factors and cognitive impairment in a stroke-free cohort

Objective: To examine vascular risk factors, as measured by the Framingham Stroke Risk Profile (FSRP), to predict incident cognitive impairment in a large, national sample of black and white adults age 45 years and older. Methods: Participants included subjects without stroke at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with at least 2 cognitive function assessments during the follow-up (n = 23,752). Incident cognitive impairment was defined as decline from a baseline score of 5 or 6 (of possible 6 points) to the most recent follow-up score of 4 or less on the Six-item Screener (SIS). Subjects with suspected stroke during follow-up were censored. Results: During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment. Baseline FSRP score was associated with incident cognitive impairment. An adjusted model revealed that male sex (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.43–1.77), black race (OR = 2.09, 95% CI 1.88–2.35), less education (less than high school graduate vs college graduate, OR = 2.21, 95% CI 1.88–2.60), older age (10-year increments, OR = 2.11, per 10-year increase in age, 95% CI 2.05–2.18), and presence of left ventricular hypertrophy (LVH, OR = 1.29, 95% CI 1.06–1.58) were related to development of cognitive impairment. When LVH was excluded from the model, elevated systolic blood pressure was related to incident cognitive impairment. Conclusions: Total FSRP score, elevated blood pressure, and LVH predict development of clinically significant cognitive dysfunction. Prevention and treatment of high blood pressure may be effective in preserving cognitive health.

Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials

Low cerebrospinal fluid (CSF) amyloid‐β1‐42 concentration and high total‐tau/Aβ1‐42 ratio have been recommended to support the diagnosis of prodromal Alzheimers disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403–13; Dubois et al, Lancet Neurol 2007;6:734–46).

G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons

Pathologic inclusions define α-synucleinopathies that include Parkinsons disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α-synuclein, LRRK2, and the formation of α-synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous α-synuclein into inclusions in response to α-synuclein fibril exposure. This results from the expression of mutant G2019S-LRRK2, as overexpression of WT-LRRK2 not only does not increase formation of inclusions but reduces their abundance. In addition, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its kinase activity. Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of α-synuclein. Knockdown of total α-synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences α-synuclein inclusion formation by altering α-synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological α-synuclein inclusions after the initial formation of α-synuclein pathology by increasing a pool of α-synuclein that is more susceptible to forming inclusions. SIGNIFICANCE STATEMENT α-Synuclein inclusions are found in the brains of patients with many different neurodegenerative diseases. Point mutation, duplication, or triplication of the α-synuclein gene can all cause Parkinsons disease (PD). The G2019S mutation in LRRK2 is the most common known genetic cause of PD. The interaction between G2019S-LRRK2 and α-synuclein may uncover new mechanisms and targets for neuroprotection. Here, we show that expression of G2019S-LRRK2 increases α-synuclein mobility and enhances aggregation of α-synuclein in primary cultured neurons and in dopaminergic neurons of the substantia nigra pars compacta, a susceptible brain region in PD. Potent LRRK2 kinase inhibitors, which are being developed for clinical use, block the increased α-synuclein aggregation in G2019S-LRRK2-expressing neurons. These results demonstrate that α-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of PD-associated pathology.

Evaluation of the Neurobehavioral Functioning Inventory as a depression screening tool after traumatic brain injury.

ObjectiveTo examine the utility of the Neurobehavioral Functioning Inventory (NFI) for diagnosing depression in a rehabilitation setting. DesignIn a prospective study, a structured clinical interview (Structured Clinical Interview for DSM-IV-TR) was used to identify DSM-IV–defined major depressive disorder (MDD) symptoms among patients with traumatic brain injury (TBI). NFI Depression scale items were compared with DSM-IV diagnosis obtained by the Structured Clinical Interview for DSM-IV Axis I Disorders. SettingOutpatient neuropsychology clinic at a university hospital, private outpatient physical medicine and rehabilitation clinic, and a long-term specialized living assistance program. ParticipantsParticipants consisted of 78 patients with TBI who were at least 3 months postinjury and 18 years of age or older. Main Outcome MeasuresStructured Clinical Interview for DSM-IV Axis I Disorders and the NFI. ResultsPsychiatric diagnostic interview with the Structured Clinical Interview for DSM-IV Axis I Disorders indicated that 50% of patients with TBI in our sample had at least one of the following in their lifetime: MDD, MDD due to general medical condition, dysthymia, or adjustment disorder with depressed mood. Thirty percent met diagnostic criteria for current MDD with or without general medical condition. Analyses of the NFI items revealed that individuals with depression endorsed greater levels of problems than did those without depression on 14 of the 32 items related to the DSM-IV symptom domains for depression (P < .00156 with Bonferroni correction). In predicting the diagnosis of depression using individual NFI items, the classification rate based on the Random Forests estimate was 83%. ConclusionFindings indicate that the NFI items differentiated between depressed and nondepressed patients with TBI. Imposing minimal burden on patients and staff, the NFI appears to have good predictive value in diagnosing major depression. In clinical practice and research, the NFI is a potentially valuable screening tool for identifying major depression in persons with TBI.

SScore: an R package for detecting differential gene expression without gene expression summaries

SUMMARY SScore is an R package that facilitates the comparison of gene expression between Affymetrix GeneChips using the S-score algorithm. The S-score algorithm uses probe level data directly to assess differences in gene expression, without requiring a preliminary separate step of probe set expression summary estimation. Therefore, the algorithm avoids introduction of error associated with the expression summary estimation process and has been demonstrated to improve the accuracy of identifying differentially expressed genes. The S-score produces accurate results even when few or no replicates are available. AVAILABILITY The R package SScore is available from Bioconductor at http://www.bioconductor.org

Community Mobility Among Older Adults With Reduced Kidney Function: A Study of Life-Space

BACKGROUND Life-Space Assessment captures community mobility and social participation and quantifies the distance, frequency, and independence obtained as an older adult moves through his or her environment. Reduced estimated glomerular filtration rate (eGFR) is associated with decline in activities of daily living among older adults, but less is known about the association of eGFR with restrictions in mobility. STUDY DESIGN Prospective observational cohort study. SETTING & PARTICIPANTS Community-dwelling Medicare beneficiaries from the University of Alabama at Birmingham Study of Aging who had serum creatinine measured during a baseline in-home study visit and completed at least one telephone follow-up (N = 390). PREDICTOR eGFR ≥ 60, 45-59, and <45 mL/min/1.73 m(2). OUTCOME Life-space mobility trajectory. MEASUREMENTS Life-space mobility was evaluated by telephone every 6 months for up to 4.5 years using the previously validated Life-Space Assessment. Scores using this tool range from 0-120 (higher scores indicate greater mobility). RESULTS Mean age of the 390 participants was 77.6 ± 5.8 (SD) years, 41% were African American, 50.5% were women; 30.0% had eGFR of 45-59 mL/min/1.73 m(2), and 20.2% had eGFR < 45 mL/min/1.73 m(2). Age-, race-, and sex-adjusted mean baseline life-space mobility scores were 64.8(95% CI, 62.0-67.6), 63.8 (95% CI, 60.3-67.4), and 58.3 (95% CI, 53.8-62.7) among those with eGFR categories ≥ 60, 45-59, and <45 mL/min/1.73 m(2), respectively. Compared with those with eGFRs ≥ 60 mL/min/1.73 m(2), a more rapid decline in life-space mobility was found among those with eGFRs < 45 mL/min/1.73 m(2), though this did not reach statistical significance (P=0.06); a similar effect was not seen among those with eGFRs of 45-59 mL/min/1.73 m(2) (P=0.3). LIMITATIONS Urinary albumin or longitudinal measures of eGFR were not available. CONCLUSIONS eGFR < 45 mL/min/1.73 m(2) was associated with a trend toward a more rapid decline in life-space mobility among community-dwelling older adults. Findings should be confirmed in a larger population.

Impaired financial abilities in Parkinson's disease patients with mild cognitive impairment and dementia

PURPOSE Financial capacity (FC) is an instrumental activity of daily living (IADL) critical to independent functioning and sensitive to cognitive impairment in dementia. Little is known about FC in cognitively impaired patients with Parkinsons disease (PD). The present study investigated FC in PD patients with prodromal and clinical dementia. METHODS Participants were 20 older controls and 35 PD patients who met consensus criteria for either mild cognitive impairment (PD-MCI, n = 18) or PD dementia (PDD, n = 17). FC was assessed using a standardized performance based measure consisting of 9 domain and two global scores (Financial Capacity Instrument; FCI) (1). FCI domain and global performance scores were compared across groups. Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) were calculated for each PD patients domain and global scores. RESULTS Relative to controls, PD-MCI patients were impaired on both FCI global scores and domains of basic monetary skills, financial concepts, and investment decision-making. Relative to both controls and PD-MCI patients, PDD patients were impaired on virtually all FCI variables. With respect to impairment ratings, greater than 50% of PD-MCI patients and greater than 90% of PDD patients were classified as either mild/moderate or severely impaired on the two FCI global scores. CONCLUSIONS Impairment of financial capacity is already present in PD-MCI and is advanced in PDD. Complex cognitively-mediated IADLs such as financial capacity appear to be impaired early in the course of PD dementia.

Life-space mobility declines associated with incident falls and fractures

To determine the effect of falls and fractures on life‐space mobility in a cohort of community‐dwelling older adults.

Evidence for Benefit of Statins to Modify Cognitive Decline and Risk in Alzheimer's Disease

BackgroundDespite substantial research and development investment in Alzheimer’s disease (AD), effective therapeutics remain elusive. Significant emerging evidence has linked cholesterol, β-amyloid and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. However, while some clinical trials evaluating statins in general AD populations have been conducted, these resulted in no significant therapeutic benefit. By focusing on subgroups of the AD population, it may be possible to detect endotypes responsive to statin therapy.MethodsHere we investigate the possible protective and therapeutic effect of statins in AD through the analysis of datasets of integrated clinical trials, and prospective observational studies.ResultsRe-analysis of AD patient-level data from failed clinical trials suggested by trend that use of simvastatin may slow the progression of cognitive decline, and to a greater extent in ApoE4 homozygotes. Evaluation of continual long-term use of various statins, in participants from multiple studies at baseline, revealed better cognitive performance in statin users. These findings were supported in an additional, observational cohort where the incidence of AD was significantly lower in statin users, and ApoE4/ApoE4-genotyped AD patients treated with statins showed better cognitive function over the course of 10-year follow-up.ConclusionsThese results indicate that the use of statins may benefit all AD patients with potentially greater therapeutic efficacy in those homozygous for ApoE4.

Statistical issues in the analysis of DNA Copy Number Variations.

Approaches to assess copy number variation have advanced rapidly and are being incorporated into genetic studies. While the technology exists for CNV genotyping, a further understanding and discussion of how to use the CNV data for association analyses is warranted. We present the options available for processing and analysing CNV data. We break these steps down into choice of genotyping platform, normalisation of the array data, calling algorithm, and statistical analysis.