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1.  Is sertraline treatment or depression remission in depressed Alzheimer’s patients associated with improved caregiver wellbeing? The Depression in Alzheimer’s Disease Study 2 (DIADS-2) 
To assess if sertraline treatment (vs. placebo) or remission of depression at 12 weeks (vs. non-remission) in Alzheimer’s patients is associated with improved caregiver wellbeing.
A randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of sertraline for the treatment of depression in individuals with Alzheimer’s disease.
Five clinical research sites across the United States.
Caregivers of patients enrolled in the Depression in Alzheimer’s Disease Study 2 (N=131).
All caregivers received standardized psychosocial support throughout the study.
Caregiver outcome measures included depression (Beck Depression Inventory), distress (Neuropsychiatric Inventory), burden (Zarit Burden Interview), and quality of life (Medical Outcomes Study Short Form Health Survey).
Fifty-nine percent of caregivers were spouses, 63.4% were female, and 64.1% were white. Caregivers of patients in both treatment groups had significant reductions in distress scores over the 24 week study period, but there was not a greater benefit for caregivers of patients taking sertraline. However, caregivers of patients whose depression was in remission at week 12 had greater declines in distress scores over the 24 weeks than caregivers of patients whose depression did not remit by week 12.
Patient treatment with sertraline was not associated with significantly greater reductions in caregiver distress than placebo treatment. Distress but not level of depression or burden lessened for all caregivers regardless of remission status and even more so for those who cared for patients whose depression remitted. Results imply an interrelationship between caregiver distress and patient psychiatric outcomes.
PMCID: PMC3910508  PMID: 24314887
sertraline; depression; Alzheimer’s; caregivers; DIADS-2
3.  Neuropsychological assessment in collaborative Parkinson’s disease research 
Cognitive impairment (CI) and behavioral disturbances can be the earliest symptoms of Parkinson’s disease (PD), ultimately afflict the vast majority of PD patients, and increase caregiver burden. Our two Morris K. Udall Centers of Excellence for Parkinson’s Disease Research were supported by the National Institute of Neurological Disorders and Stroke (NINDS) to recommend a comprehensive yet practical approach to cognitive and behavioral assessment to fuel collaborative research. We recommend a step-wise approach with two levels of standardized evaluation to establish a common battery, as well as an alternative testing recommendation for severely impaired subjects, and review supplemental tests that may be useful in specific research settings. Our flexible approach may be applied to studies with varying emphasis on cognition and behavior, does not place undue burden on participants or resources, and has a high degree of compatibility with existing test batteries to promote collaboration.
PMCID: PMC3612566  PMID: 23164549
4.  Cognitive impairment and PD patients' capacity to consent to research 
Neurology  2013;81(9):801-807.
To examine how cognitive impairment affects Parkinson disease (PD) patients' research consent capacity.
A cross-sectional study of 90 patients with PD, divided using Mattis Dementia Rating Scale–2 scores into 3 groups of 30 (normal, borderline, and impaired), and 30 neurologically normal older adults completed 2 capacity interviews (an early-phase randomized and controlled drug trial and a sham-controlled surgical implantation of genetic tissue) using the MacArthur Competence Assessment Tool for Clinical Research. Expert clinicians used the interviews to classify the patients as either capable or not capable of providing their own informed consent. These judgments were compared with performance on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE).
Cognitively normal PD patients typically scored well on the capacity measures. In contrast, patients with impaired cognition were not capable of providing their own informed consent: 17% (5/30) on the drug trial and 3% (1/30) on the surgery trial were judged capable. Patients with borderline impairment showed adequate performance on measures of appreciation and reasoning, but impaired performance on understanding the drug trial compared with normal controls and normal PD patients, and on understanding the surgery trial compared with normal controls. Sixty-seven percent (20/30) on the drug trial and 57% (17/30) on the surgery trial were judged capable of consent. Receiver operating characteristic analyses showed that the MMSE and MoCA could detect the likelihood of impaired capacity, with the MoCA demonstrating greater sensitivity.
PD patients with borderline cognitive impairment have impairments in their decisional capacity. The MoCA may be useful to identify the patients at risk of impaired capacity.
PMCID: PMC3908465  PMID: 23892706
5.  Effect of Citalopram on Agitation in Alzheimer's Disease – The CitAD Randomized Controlled Trial 
Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer's disease (AD). Pharmacological treatment options, including antipsychotics are not satisfactory.
The primary objective was to evaluate the efficacy of citalopram for agitation in patients with AD. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
Design, Setting and Participants
The Citalopram for Agitation in Alzheimer's Disease Study (CitAD) was a multicenter, randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable AD and clinically significant agitation from eight academic centers in the US and Canada from August 2009 to January 2013.
Participants (n=186) were randomized to receive a psychosocial intervention plus either citalopram (n=94) or placebo (n=92) for 9 weeks. Dose began at 10 mg/d with planned titration to 30 mg/d over 3 weeks based on response and tolerability.
Main Outcomes and Measures
Primary outcome measures were the Neurobehavioral Rating Scale, agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) Other outcomes were the Cohen-Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory (NPI), activities of daily living (ADLs), caregiver distress, cognitive safety (MMSE), and adverse events.
Participants on citalopram showed significant improvement compared to placebo on both primary outcome measures. NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 [95% CI: −1.80 to −0.06], p = 0.036. mADCS-CGIC results showed 40% of citalopram participants having moderate or marked improvement from baseline compared to 26% on placebo, with estimated treatment effect (odds ratio of being at or better than a given CGIC category) of 2.13 [95% CI 1.23 to 3.69], p = 0.007. Participants on citalopram showed significant improvement on the CMAI, total NPI and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points [95% CI: −1.97 to −0.13], p = 0.026) and QT interval prolongation (18.1 ms [95% CI: 6.1, 30.1], p = 0.004) were seen in the citalopram group.
Conclusions and Relevance
Among patients with probable Alzheimer's disease and agitation receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress, but cognitive and cardiac adverse effects of citalopram may limit its practical application at the 30 mg/d dose studied in this trial.
PMCID: PMC4086818  PMID: 24549548
6.  Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial 
PLoS ONE  2014;9(6):e98426.
A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group.
CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1∶1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began.
Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death.
Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.
Trial Registration NCT00898807
PMCID: PMC4051660  PMID: 24914549
7.  The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the Non-Motor Symptoms of Parkinson's Disease 
The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treatments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full articles in English between January 2002 and December 2010 were reviewed. Criteria for inclusion and ranking followed the original program outline and adhered to EBM methodology. For efficacy conclusions, treatments were designated: efficacious, likely efficacious, unlikely efficacious, non-efficacious, or insufficient evidence. Safety data were catalogued and reviewed. Based on the combined efficacy and safety assessment, Implications for clinical practice were determined using the following designations: clinically useful, possibly useful, investigational, unlikely useful, and not useful. Fifty-four new studies qualified for efficacy review while several other studies covered safety issues. Updated and new efficacy conclusions were made for all indications. The treatments that are efficacious for the management of the different non-motor symptoms are as follows: pramipexole for the treatment of depressive symptoms, clozapine for the treatment of psychosis, rivastigmine for the treatment of dementia, and botulinum toxin A (BTX-A) and BTX-B as well as glycopyrrolate for the treatment of sialorrhea. The practical implications for these treatments, except for glycopyrrolate, are that they are clinically useful. Since there is insufficient evidence of glycopyrrolate for the treatment of sialorrhea exceeding 1 week, the practice implication is that it is possibly useful. The treatments that are likely efficacious for the management of the different non-motor symptoms are as follows: the tricyclic antidepressants nortriptyline and desipramine for the treatment of depression or depressive symptoms and macrogol for the treatment of constipation. The practice implications for these treatments are possibly useful. For most of the other interventions there is insufficient evidence to make adequate conclusions on their efficacy. This includes the tricyclic antidepressant amitriptyline, all selective serotonin reuptake inhibitors (SSRIs) reviewed (paroxetine, citalopram, sertraline, and fluoxetine), the newer antidepressants atomoxetine and nefazodone, pergolide, Ω-3 fatty acids as well as repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression or depressive symptoms; methylphenidate and modafinil for the treatment of fatigue; amantadine for the treatment of pathological gambling; donepezil, galantamine, and memantine for the treatment of dementia; quetiapine for the treatment of psychosis; fludrocortisone and domperidone for the treatment of orthostatic hypotension; sildenafil for the treatment of erectile dysfunction, ipratropium bromide spray for the treatment of sialorrhea; levodopa/carbidopa controlled release (CR), pergolide, eszopiclone, melatonin 3 to 5 mg and melatonin 50 mg for the treatment of insomnia and modafinil for the treatment of excessive daytime sleepiness. Due to safety issues the practice implication is that pergolide and nefazodone are not useful for the above-mentioned indications. Due to safety issues, olanzapine remains not useful for the treatment of psychosis. As none of the studies exceeded a duration of 6 months, the recommendations given are for the short-term management of the different non-motor symptoms. There were no RCTs that met inclusion criteria for the treatment of anxiety disorders, apathy, medication-related impulse control disorders and related behaviors other than pathological gambling, rapid eye movement (REM) sleep behavior disorder (RBD), sweating, or urinary dysfunction. Therefore, there is insufficient evidence for the treatment of these indications. This EBM review of interventions for the non-motor symptoms of PD updates the field, but, because several RCTs are ongoing, a continual updating process is needed. Several interventions and indications still lack good quality evidence, and these gaps offer an opportunity for ongoing research.
PMCID: PMC4020145  PMID: 22021174
Parkinson's disease; evidence-based medicine; dopamine agonists; tricyclic antidepressants; selective serotonin reuptake inhibitors (SSRIs); omega-3 fatty-acids; transcranial magnetic stimulation
8.  Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease (QUIP) and the QUIP-rating scale in a German speaking sample 
Journal of Neurology  2014;261(5):936-942.
Impulsive-compulsive disorders are frequent in patients with Parkinson’s disease (PD). Recently, a screening questionnaire and rating scale were developed for these disorders: the questionnaire for impulsive-compulsive disorders (QUIP) and QUIP-rating scale (QUIP-RS). We assessed the validity of these instruments in the German language in order to reevaluate the benefit and to obtain German screening tools in clinical practice. A convenience sample of 156 patients was assessed in Kiel and Vienna. The patients filled out the QUIP-current, the QUIP-anytime and the QUIP-RS. We validated the questionnaires against a gold standard diagnosis via receiver operating characteristic curves and determined optimal cut-off scores for the instruments. Excluding walkabout, which was not shown to be valid, sensitivities ranged from 60–92 % for the QUIP-current, 68–91 % for the QUIP-anytime, and 73–100 % for the QUIP-RS. Specificities were >71 % for QUIP-current, >69 % for QUIP-anytime and >62 % for QUIP-RS. With its very good sensitivities, the QUIP-RS is a valid instrument to assess impulsive-compulsive disorders and makes an early detection of behavioral disorders in PD possible. The QUIP-anytime was also shown to be a valid screening instrument. Both are expected to prove useful in scientific and clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-014-7299-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4148320  PMID: 24609972
ICD; Addiction; PD; QUIP; QUIP-RS
9.  APOE ε4 Increases Risk for Dementia in Pure Synucleinopathies 
JAMA neurology  2013;70(2):223-228.
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Genetic case-control association study.
Academic research.
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
PMCID: PMC3580799  PMID: 23407718
10.  Screening for impulse control symptoms in patients with de novo Parkinson disease 
Neurology  2013;80(2):176-180.
To determine the frequency and correlates of impulse control and related behavior symptoms in patients with de novo, untreated Parkinson disease (PD) and healthy controls (HCs).
The Parkinson's Progression Markers Initiative is an international, multisite, case-control clinical study conducted at 21 academic movement disorders centers. Participants were recently diagnosed, untreated PD patients (n = 168) and HCs (n = 143). The outcome measures were presence of current impulse control and related behavior symptoms based on recommended cutoff points for the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP)-Short Form.
There were 311 participants with complete QUIP data. Frequencies of impulse control and related behavior symptoms for patients with PD vs HCs were as follows: gambling (1.2% vs 0.7%), buying (3.0% vs 2.1%), sexual behavior (4.2% vs 3.5%), eating (7.1% vs 10.5%), punding (4.8% vs 2.1%), hobbyism (5.4% vs 11.9%), walkabout (0.6% vs 0.7%), and any impulse control or related behavior (18.5% vs 20.3%). In multivariable models, a diagnosis of PD was not associated with symptoms of any impulse control or related behavior (p ≥ 0.10 in all cases).
PD itself does not seem to confer an increased risk for development of impulse control or related behavior symptoms, which further reinforces the reported association between PD medications and impulse control disorders in PD. Given that approximately 20% of patients with newly diagnosed PD report some impulse control or related behavior symptoms, long-term follow-up is needed to determine whether such patients are at increased risk for impulse control disorder development once PD medications are initiated.
PMCID: PMC3589192  PMID: 23296128
11.  Cognitive Outcomes after Sertaline Treatment in Patients with Depression of Alzheimer’s Disease 
While many depressed patients with Alzheimer’s disease are treated with antidepressants, the effect of such treatment on cognitive performance in these patients is not known. The authors report cognitive outcomes in patients with depression of Alzheimer’s disease (dAD) after a 24-week trial of sertraline or placebo.
Placebo-controlled, randomized, double-blind trial.
Outpatient memory clinics at 5 academic medical centers in the United States.
131 patients with dAD (60 men) and Mini Mental State Exam (MMSE) scores of 10–26.
Sertraline (n=67), target dose of 100mg daily, or matching placebo (n=64). Caregivers received standardized psychosocial intervention throughout the trial.
MMSE, ADAS-Cog, letter fluency, backwards Digit Span, Symbol Digit Modalities Test, and Finger Tapping Test, administered at baseline, and 8, 16, and 24 weeks following baseline.
A series of linear models indicated no effect of treatment or of depression remission on cognitive test performance at 24 weeks. Regardless of treatment condition, very little change in cognitive test performance was noted in general.
Treatment with sertraline in patients with dAD is not associated with greater improvement in cognition at week 24 as compared to treatment with placebo.
PMCID: PMC3508666  PMID: 23032478
12.  Psychosis in Parkinson’s Disease Without Dementia: Common and Comorbid With Other Non-Motor Symptoms 
Psychosis in Parkinson’s disease (PD) is common and associated with a range of negative outcomes. Dementia and psychosis are highly correlated in PD, but the frequency and correlates of psychosis in patients without cognitive impairment are not well understood. One hundred and ninety-one non-demented PD patients at two movement disorders centers participated in a study of neuropsychiatric complications in PD and completed a detailed neurological and neuropsychiatric assessment, including the rater-administered Parkinson Psychosis Rating Scale for hallucinations, delusions, and minor symptoms of psychosis (illusions and misidentification of persons). Psychotic symptoms were present in 21.5% of the sample. Visual hallucinations were most common (13.6%), followed by auditory hallucinations (6.8%), illusions or misidentification of people (7.3%), and paranoid ideation (4.7%). Visual hallucinations and illusions or misidentification of people were the most common comorbid symptoms (3.1%). Depression (P = 0.01) and rapid eye movement behavior disorder symptoms (P = 0.03) were associated with psychosis in a multivariable model. The odds of experiencing psychotic symptoms were approximately five times higher in patients with comorbid disorders of depression and sleep-wakefulness. Even in patients without global cognitive impairment, psychosis in PD is common and most highly correlated with other non-motor symptoms. Screening for psychosis should occur at all stages of PD as part of a broad non-motor assessment. In addition, these findings suggest a common neural substrate for disturbances of perception, mood, sleep-wakefulness, and incipient cognitive decline in PD.
PMCID: PMC3511789  PMID: 22674352
Parkinson’s disease; psychosis; non-demented; cognitively intact
13.  Citalopram for agitation in Alzheimer’s disease (CitAD): design and methods 
Agitation is one of the most common neuropsychiatric symptoms of Alzheimer’s disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimer’s disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.
CitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study has eight recruiting clinical centers, a chair’s office and a coordinating center located in university settings in the United States and Canada. 200 people having probable Alzheimer’s disease with clinically significant agitation and without major depression are being recruited. Patients are randomized to receive citalopram (target dose of 30 mg/day) or matching placebo. Caregivers of patients in both treatment groups receive a structured psychosocial therapy. Agitation will be compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change which are the primary outcomes. Functional performance, cognition, caregiver distress and rates of adverse and serious adverse events will also be measured.
The authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in Alzheimer’s disease.
PMCID: PMC3333484  PMID: 22301195
Alzheimer dementia; citalopram; agitation; randomized trial
14.  Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale 
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson’s disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time.
PMCID: PMC3537263  PMID: 22134954
dopamine agonists; impulse control disorder; Parkinson’s disease
15.  Sertraline for the Treatment of Depression in Alzheimer Disease: Genetic Influences 
To assess the potential for genetic influences on sertraline treatment efficacy for depression of Alzheimer disease (dAD). Four functional genetic variants were studied: 2 serotonin receptors (HTR2A-T102C and HTR2C-Cys23Ser), the serotonin transporter (5HTT-LPR), and brain-derived neurotrophic factor (BDNF-Val66Met). Treatment response by genotype was measured by (1) the modified Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change, (2) the Cornell scale for Depression in Dementia, and (3) remission of depression.
We utilized data from the Depression in Alzheimer’s Disease Study 2 (DIADS-2), a 24-week, randomized, multicenter trial showing no significant treatment effect of sertraline on dAD. Proportional odds logistic regression and mixed effects models were used to examine the above mentioned outcome measures.
No significant interactions were seen between any of the genetic polymorphisms and the selected outcomes above at 12 or 24 weeks.
Treatment outcomes in the DIADS-2 trial were not significantly influenced by genetic variation at the loci that were assessed. Future studies should continue to examine the interaction of depression-related genetic variants with antidepressant treatment in Alzheimer disease patients with depression.
PMCID: PMC3535452  PMID: 22228829
Alzheimer disease; sertraline; depression; randomized trial; dementia; antidepressant
16.  Alzheimer's disease pattern of brain atrophy predicts cognitive decline in Parkinson's disease 
Brain  2011;135(1):170-180.
Research suggests overlap in brain regions undergoing neurodegeneration in Parkinson's and Alzheimer's disease. To assess the clinical significance of this, we applied a validated Alzheimer's disease-spatial pattern of brain atrophy to patients with Parkinson's disease with a range of cognitive abilities to determine its association with cognitive performance and decline. At baseline, 84 subjects received structural magnetic resonance imaging brain scans and completed the Dementia Rating Scale-2, and new robust and expanded Dementia Rating Scale-2 norms were applied to cognitively classify participants. Fifty-nine non-demented subjects were assessed annually with the Dementia Rating Scale-2 for two additional years. Magnetic resonance imaging scans were quantified using both a region of interest approach and voxel-based morphometry analysis, and a method for quantifying the presence of an Alzheimer's disease spatial pattern of brain atrophy was applied to each scan. In multivariate models, higher Alzheimer's disease pattern of atrophy score was associated with worse global cognitive performance (β = −0.31, P = 0.007), including in non-demented patients (β = −0.28, P = 0.05). In linear mixed model analyses, higher baseline Alzheimer's disease pattern of atrophy score predicted long-term global cognitive decline in non-demented patients [F(1, 110) = 9.72, P = 0.002], remarkably even in those with normal cognition at baseline [F(1, 80) = 4.71, P = 0.03]. In contrast, in cross-sectional and longitudinal analyses there was no association between region of interest brain volumes and cognitive performance in patients with Parkinson's disease with normal cognition. These findings support involvement of the hippocampus and parietal–temporal cortex with cognitive impairment and long-term decline in Parkinson's disease. In addition, an Alzheimer's disease pattern of brain atrophy may be a preclinical biomarker of cognitive decline in Parkinson's disease.
PMCID: PMC3316476  PMID: 22108576
Alzheimer's disease; dementia; mild cognitive impairment; Parkinson's disease; neurodegeneration
17.  Dopamine and Impulse Control Disorders in Parkinson’s Disease 
Annals of neurology  2008;64(Suppl 2):S93-100.
There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs.
PMCID: PMC3530139  PMID: 19127573
18.  Pattern of Depressive Symptoms in Parkinson’s Disease 
Psychosomatics  2009;50(5):448-454.
Depressive symptoms are common in Parkinson’s disease (PD); however, it is unclear whether there are specific depressive symptom patterns in patients with PD and co-morbid depression (dPD).
The goal of this study is to examine the frequency and correlates of specific depressive symptoms in PD.
A sample of 158 individuals with PD completed the self-rated Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS). By multiple-regression analysis, the authors examined the association between HANDS total and subscale scores and various demographic variables.
The frequency of depression was 37% (N=58). Patients with a history of depression before PD had significantly more serious depression than those who had no such history. Of those who were more depressed, the most common symptoms of depression endorsed were low energy, difficulty with concentration/making decisions, feeling blue, feeling hopeless, and having poor sleep.
There is a relatively high prevalence of dPD. Items on the HANDS that discriminated best between depressed and nondepressed subjects with PD included feeling blue, feeling hopeless, feeling worthless, lack of interest, and self-blame. It remains to be defined whether dPD should be understood primarily as a psychological reaction to a physical disability or perceived impending one, or as a direct expression of the neuropathology of PD.
PMCID: PMC3529169  PMID: 19855029
19.  Involuntary emotional expression disorder (IEED) in Parkinson’s disease 
Parkinsonism & related disorders  2009;15(7):511-515.
To estimate the frequency and correlates of involuntary emotional expression disorder (IEED) in Parkinson’s disease (PD) using the Center for Neurologic Study-Lability Scale (CNS-LS) and recently-proposed diagnostic criteria for IEED.
IEED is characterized by uncontrollable emotional episodes, typically unrelated to or in excess of the underlying mood, and occurring with minimal or no stimulus. IEED has been reported to occur in many neurological disorders and neurodegenerative diseases, but its prevalence and correlates in PD have not been well studied. Additionally, there is no published research using recently-proposed IEED diagnostic criteria in any population.
193 patients with idiopathic PD were assessed with a neuropsychiatric battery, including the CNS-LS and the 15-item Geriatric Depression Scale (GDS-15). A subset (N =100) was also administered a diagnostic interview by a blinded rater that applied criteria for both IEED and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) depressive disorders.
Applying formal diagnostic criteria, 7.0% of patients were diagnosed with IEED, and an additional 7.0% had subsyndromal IEED symptoms. Applying recommended CNS-LS cutoff scores from other populations, either 42.5% (cutoff ≥13) or 16.6% (cutoff ≥17) screened positive for IEED. Depressive symptoms were associated with higher CNS-LS scores (B[SE] =0.27[.08], P =.001) but not with a diagnosis of IEED (odds ratio =1.1, [95% CI =1.0–1.3], P =.16). The CNS-LS had poor discriminant validity for an IEED diagnosis (AUC =.79, no cutoff value with sensitivity and specificity both >60%).
IEED and depression are overlapping but distinct disorders in PD. IEED symptoms may occur in up to 15% of PD patients, but a disorder occurs in only half of those, suggesting that often IEED symptoms are not clinically significant in this population. The CNS-LS does not appear to be a good screening instrument for IEED in PD, in part due to its high correlation with depressive symptoms.
PMCID: PMC3524499  PMID: 19181560
Involuntary emotional expression disorder; Pseudobulbar affect; Emotional lability; Depression; Parkinson’s disease
20.  Parkinson's Disease: The Quintessential Neuropsychiatric Disorder 
Although diagnosed by characteristic motor features, Parkinson's disease may be preceded, and is frequently accompanied by, a wide range of cognitive and neuropsychiatric features. In addition to the most commonly studied disorders of dementia, depression, and psychosis, other relatively common and clinically significant psychiatric complications include impulse control disorders, anxiety symptoms, disorders of sleep and wakefulness, and apathy. These problems may be underrecognized and are frequently undertreated. The emergent focus on nonmotor aspects of Parkinson's disease over the past quarter of a century is highlighted by a nonlinear increase in the number of articles published devoted to this topic. Although the development of newer antidepressants, atypical antipsychotics, and cholinesterase inhibitors in recent years has had a positive benefit on the management of these troublesome and distressing symptoms, responses are frequently suboptimal, and this remains an area of major unmet therapeutic need.
PMCID: PMC3513835  PMID: 21626547
Parkinson's; dementia; neuropsychiatric; depression; psychosis
21.  Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease 
Archives of Neurology  2011;68(12):1562-1568.
To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD).
Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD.
The Parkinson’s Disease and Movement Disorders Center at the University of Pennsylvania.
Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain.
The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β=−0.37; P=.001), and PDD patients demonstrated hippocampal (β=−0.32; P=.004) and additional medial temporal lobe atrophy (β=−0.36; P=.003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P=.04) and a similar pattern to that of PDD patients (P=.81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume.
Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.
PMCID: PMC3290902  PMID: 22159053
22.  Olfactory dysfunction is associated with neuropsychiatric manifestations in Parkinson’s disease 
Hyposmia, psychiatric disorders and cognitive problems are common non-motor manifestations in Parkinson's Disease but how they are related remains unclear.
To investigate the relationship between olfactory dysfunction and neuropsychiatric manifestations we performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London-Drexel and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification test.
There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%, p<0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean(standard deviation) 6.2(3.2) vs. 8.4(2.8), p<0.001) and executive performance (Tower of London total moves, 52(38) vs. 34(21), p<0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex and disease characteristics in logistic regression models.
The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common non-motor symptoms.
PMCID: PMC3168697  PMID: 21611985
Parkinson's Disease; olfaction; non-motor symptoms; psychiatric symptoms; cognitive symptoms
23.  Do treatment effects vary among differing baseline depression criteria in Depression in Alzheimer’s Disease Study – 2 (DIADS-2)? 
To determine if the effect of sertraline in the Depression in Alzheimer’s Disease Study – 2 (DIADS-2) differed in subgroups of patients defined by baseline depression criteria.
DIADS-2 was a randomized, parallel, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of sertraline (target dose of 100mg/day) for the treatment of depression in patients with Alzheimer’s disease. DIADS-2 enrolled 131 patients who met criteria for depression of Alzheimer’s disease (dAD). Analyses reported here examined if the effect of sertraline differed in various subgroups, including those meeting criteria for major depressive episode (MaD), minor depressive episode (MiD) and Alzheimer’s-associated affective disorder (AAAD) at baseline.
At baseline, 52 of 131 participants (39.7%) met criteria for MaD, 54 (41.2%) for MiD and 90 (68.7%) for AAAD. For the primary outcome of modified Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (mADCS-CGIC) scores at 12 weeks of follow-up, the odds of being at or better than a given mADCS-CGIC category did not significantly differ between the two treatment groups for those patients with MaD at baseline (ORsertraline = 0.66 [95% CI: 0.24, 1.82], p = 0.42); tests for interactions between treatment group and baseline depression diagnostic subgroup were not significant for MaD vs. MiD vs. neither (χ2 = 1.05 (2df), p = 0.59) or AAAD vs. no AAAD (χ2 = 0.06 (1df), p = 0.81).
There was no evidence that sertraline treatment was more efficacious in those patients meeting baseline criteria for MaD compared to MiD or to neither.
Trial registration, NCT00086138
PMCID: PMC3414254  PMID: 20672243
Alzheimer’s dementia; sertraline; depression; randomized trial
24.  Patterns and Trends in Antipsychotic Prescribing for Parkinson Disease Psychosis 
Archives of neurology  2011;68(7):899-904.
Antipsychotic (AP) use is common in Parkinson disease (PD), but APs can worsen parkinsonism, evidence for efficacy is limited, and use in patients with dementia increases mortality.
To examine the frequency and characteristics, including changes over time, of AP use in a large cohort of patients with PD.
Using Veterans Affairs data from fiscal year (FY) 2008, rates and predictors of AP prescribing were determined for patients with PD and psychosis stratified by dementia status (N=2597) and a comparison group of patients with dementia and psychosis without PD (N=6907). Fiscal year 2008 and FY2002 data were compared to examine changes in AP prescribing over time.
Department of Veterans Affairs outpatient facilities.
Outpatients with PD and psychosis and outpatients without PD with dementia and psychosis, all receiving care at Veterans Affairs facilities in FY2002 and FY2008.
Main Outcome Measure
Antipsychotic prescribing, including overall, class, and specific medications.
In FY2008, 50% of patients with PD having a diagnosis of psychosis were prescribed an AP. Among treated patients, the atypical AP quetiapine was most frequently prescribed (66%), but approximately 30% received high-potency APs. Clozapine was rarely prescribed (<2%). In multivariate models, diagnoses of PD and dementia were associated with AP use. Comparing FY2008 with FY2002, AP use in PD was unchanged, with decreases in risperidone and olanzapine use offset by an increase in quetiapine prescribing and the introduction of aripiprazole.
Half of the patients with PD and psychosis receive APs, not uncommonly high-potency agents associated with worsening parkinsonism, and frequency of use has been unchanged since the “black box” warning for AP use in patients with dementia was issued. Recent trends are a shift to quetiapine use and the common use of aripiprazole. As psychosis and dementia are frequently comorbid in PD, safety risks associated with AP use in this population need to be assessed.
PMCID: PMC3141727  PMID: 21747029
25.  Plasma EGF levels predict cognitive decline in Parkinson's Disease 
Annals of neurology  2010;69(4):655-663.
Most people with Parkinson's disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD.
A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, i.e. proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients.
Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p<0.001); many of the other 10 analytes co-varied with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an eightfold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients.
Our data suggest that plasma EGF may be a biomarker for progression to CI in PD.
PMCID: PMC3155276  PMID: 21520231
Epidermal growth factor; EGF; Parkinson's Disease; Parkinson's Disease with Dementia; Biomarker; Plasma

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