Michael Donohue

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Personal ViewTracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization.

Background: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally. Objective: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures. Methods: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials. Results: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimers Disease Assessment Scale–Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Aβ-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures. Conclusion: The Alzheimers Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.

The A4 Study: Stopping AD Before Symptoms Begin?

A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline. A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.

Clinical core of the Alzheimer's disease neuroimaging initiative: Progress and plans

The Clinical Core of the Alzheimers Disease Neuroimaging Initiative (ADNI) has provided clinical, operational, and data management support to ADNI since its inception. This article reviews the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow‐up of more than 800 subjects in the three original cohorts: healthy controls, amnestic mild cognitive impairment (now referred to as late MCI, or LMCI), and mild Alzheimers disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal, clinical, and cognitive assessments. These data, when combined with genetic, neuroimaging, and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Furthermore, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI, with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow‐up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.

The Association Between Lower Extremity Continuous Peripheral Nerve Blocks and Patient Falls After Knee and Hip Arthroplasty

BACKGROUND: Continuous peripheral nerve blocks (CPNB) may induce muscle weakness, and multiple recently published series emphasize patient falls after postarthroplasty CPNB. However, none have included an adequate control group, and therefore the relationship between CPNB and falls remains speculative. METHODS: We pooled data from 3 previously published, randomized, triple-masked, placebo-controlled studies of CPNB involving the femoral nerve after knee and hip arthroplasty. RESULTS: No patients receiving perineural saline (n = 86) fell (0%; 95% confidence interval [CI] = 0%–5%), but there were 7 falls in 6 patients receiving perineural ropivacaine (n = 85; 7%; 95% CI = 3%–15%; Fishers exact test P = 0.013). CONCLUSIONS: Our analysis suggests that there is a causal relationship between CPNB and the risk of falling after knee and hip arthroplasty.

Pirfenidone for Diabetic Nephropathy

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

rTMS for Suppressing Neuropathic Pain: A Meta-Analysis

UNLABELLED This pooled individual data (PID)-based meta-analysis collectively assessed the analgesic effect of repetitive transcranial magnetic stimulation (rTMS) on various neuropathic pain states based on their neuroanatomical hierarchy. Available randomized controlled trials (RCTs) were screened. PID was coded for age, gender, pain neuroanatomical origins, pain duration, and treatment parameters analyses. Coded pain neuroanatomical origins consist of peripheral nerve (PN); nerve root (NR); spinal cord (SC); trigeminal nerve or ganglion (TGN); and post-stroke supraspinal related pain (PSP). Raw data of 149 patients were extracted from 5 (1 parallel, 4 cross-over) selected (from 235 articles) RCTs. A significant (P < .001) overall analgesic effect (mean percent difference in pain visual analog scale (VAS) score reduction with 95% confidence interval) was detected with greater reduction in VAS with rTMS in comparison to sham. Including the parallel study (Khedr et al), the TGN subgroup was found to have the greatest analgesic effect (28.8%), followed by PSP (16.7%), SC (14.7%), NR (10.0%), and PN (1.5%). The results were similar when we excluded the parallel study with the greatest analgesic effect observed in TGN (33.0%), followed by SC (14.7%), PSP (10.5%), NR (10.0%), and PN (1.5%). In addition, multiple (vs single, P = .003) sessions and lower (>1 and < or =10 Hz) treatment frequency range (vs >10 Hz) appears to generate better analgesic outcome. In short, rTMS appears to be more effective in suppressing centrally than peripherally originated neuropathic pain states. PERSPECTIVE This is the first PID-based meta-analysis to assess the differential analgesic effect of rTMS on neuropathic pain based on the neuroanatomical origins of the pain pathophysiology and treatment parameters. The derived information serves as a useful resource in regards to treatment parameters and patient population selection for future rTMS-pain studies.

Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD)

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD. METHODS In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression. RESULTS The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39-0.84, p=0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66 95% CI 0.48-0.92) than lifetime non-drinkers. CONCLUSIONS In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD.

Predictors of response to an attention modification program in generalized social phobia.

OBJECTIVE At least 3 randomized, placebo-controlled, double-blind studies have supported the efficacy of computerized attention modification programs (AMPs) in reducing symptoms of anxiety in patients diagnosed with an anxiety disorder. In this study we examined patient characteristics that predicted response to AMP in a large sample of individuals diagnosed with generalized social phobia. METHOD The sample comprised 112 individuals seeking treatment for generalized social phobia who completed a randomized clinical trial comparing AMP (n = 55) with a placebo condition (i.e., attention control condition; n = 57). We examined the following domains of baseline predictors of treatment response: (a) demographic characteristics (gender, age, ethnicity, years of education); (b) clinical characteristics (Axis I comorbidity, trait anxiety, depression); and (c) cognitive disturbance factors (attentional bias for social threat, social interpretation bias). RESULTS Results revealed that ethnicity predicted treatment response across both conditions: Participants who self-identified as non-Caucasian displayed better overall response than did Caucasians. The only prescriptive variable to emerge was attentional bias for social threat at preassessment. Participants in the AMP group who exhibited larger attentional bias scores displayed significantly greater reductions in clinician-rated social anxiety symptoms than did their counterparts in the attention control condition. CONCLUSIONS These results suggest that AMP may be targeted to individuals most likely to benefit from these programs.