Institute for Neurodegenerative Disorders

New Haven, CT, United States

Institute for Neurodegenerative Disorders

New Haven, CT, United States
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Hannestad J.O.,Yale University | Hannestad J.O.,UCB Pharma | Cosgrove K.P.,Yale University | Dellagioia N.F.,Yale University | And 8 more authors.
Biological Psychiatry | Year: 2013

Background The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of β2-subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in subjects with bipolar disorder. Methods Twenty-five subjects with bipolar disorder (15 depressed, 10 euthymic) and 25 sex- and age-matched control subjects had a [123I]5IA-85380 single photon emission computed tomography scan to quantify β2*-nAChR VT/fP (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average VT/fP was compared between groups and correlated with clinical characteristics. Postmortem analysis of β2*-nAChRs was conducted using equilibrium binding with [125I]5IA in subjects with bipolar disorder and matched control subjects. Results We showed significantly lower β 2*-nAChR availability (20%-38%) in subjects with bipolar depression compared with euthymic and control subjects across all brain regions assessed (frontal, parietal, temporal, and anterior cingulate cortex, hippocampus, amygdala, thalamus, striatum). The postmortem binding study in which endogenous acetylcholine was washed out did not show a statistically significant difference in β2*-nAChR number in temporal cortex of the bipolar depressed and control groups (15% difference; p =.2). Conclusions We show that the alteration in the cholinergic system observed during a depressive episode appears to resolve during euthymia. We suggest that lower VT/fP observed in vivo may be due to a combination of higher endogenous acetylcholine levels during depression, which could compete with radiotracer binding to the receptor in vivo, and lower receptor number in bipolar depression. Identification of differences in cholinergic signaling in subjects with bipolar depression may improve our understanding of its etiology and reveal new treatment targets. © 2013 Society of Biological Psychiatry.

Berg D.,German Center for Neurodegenerative Diseases | Marek K.,Institute for Neurodegenerative Disorders | Ross G.W.,VA Pacific Islands Health Care System | Ross G.W.,Kuakini Medical Center | Poewe W.,University of Innsbruck
Movement Disorders | Year: 2012

It is currently widely acknowledged that the natural history of PD includes a preclinical phase, and there are increasing efforts to identify markers that would allow the identification of individuals at risk for PD. Here, we discuss the issues related to defining at-risk populations for PD and review findings of current population-based cohorts that have reported potential biomarkers for PD, such as the Honolulu-Asia Aging Study (HAAS) and the PRIPS (Prospective Validation of Risk factors for the development of Parkinson Syndromes) study. We also discuss enriched risk cohorts designed to evaluate specificity and predictive value of markers exemplified by the PARS (Parkinson Associated Risk Study) and the TREND (Tübinger evaluation of Risk factors for the Early detection of NeuroDegeneration) study. Although there is still a long way to go, studies designed according to these concepts might eventually provide sufficient data to form the basis for future screening programs for PD risk to be applied at a population level. © 2012 Movement Disorder Society.

News Article | October 26, 2016

The wild animals attacked almost every night while Mark slept. He would wake up panicked and sweating, having acted out some terrifying scenes. Mark (not his real name) went to a psychotherapist, who led him through talk therapy and psychoanalysis to try to uncover the cause of these terrible dreams. For years, nothing seemed to help. Then he consulted neurologist Brit Mollenhauer, who diagnosed him with Parkinson's disease. Sleep problems were part of Mark's condition. With her help, he finally got the right therapy. “Everyone thinks Parkinson's disease starts with a tremor,” says Mollenhauer, head of clinical research at the Paracelsus Elena Klinik in Kassel, Germany. But before there are any movement problems, she says, “it's already in the body”. About half of people who have these sleep issues, known as rapid eye movement (REM) sleep behaviour disorder, will develop Parkinson's within about 15 years. REM sleep behaviour disorder causes vivid dreams and often makes people act them out, because the nervous system's mechanism for keeping the body still during sleep has deteriorated. When asked to look back on the years leading up to their diagnosis, people with Parkinson's commonly say that they experienced sleep problems, depression and a diminishing sense of smell long before they were diagnosed. Yet, until recently, general practitioners and psychotherapists did not recognize these symptoms as early signs of Parkinson's disease. And even if Mark had been flagged as being at risk, there would have been nothing to offer him to slow the disease. Those who study the non-motor symptoms of Parkinson's hope to change that. Clinicians are getting better at addressing these issues, and researchers hope to find broader therapies that will do more than treat the individual symptoms. Large studies are also using non-motor symptoms as signals to illuminate the origins and progression of the disease. Finding people who are still in the early stages of the disease, and tracking its development, will be central to measuring the success of new therapies. Non-motor symptoms might also help researchers to untangle the underlying pathology of Parkinson's — and show it to be more complex than previously thought. It is not yet possible to diagnose Parkinson's until there are movement problems such as a tremor, rigidity or trouble walking. But by the time such symptoms appear, the disease has already progressed significantly. Neurologists have known about the non-movement symptoms of Parkinson's for a long time, but it took years to formally acknowledge them. “Until recently it was considered a pure motor disorder,” says Jaime Kulisevsky, a neurologist at Sant Pau Hospital in Barcelona, Spain. But this is because doctors had not regularly asked patients about other issues. In 2015, the International Parkinson and Movement Disorder Society added olfactory problems and the death of neurons that serve the heart as supportive diagnostic criteria for the disease (see page S2). These made the cut because they can be quantified by using a 'scratch-and-sniff' test and imaging. Most Parkinson's therapies, including deep brain stimulation and a precursor to the neurotransmitter dopamine called levodopa, ease tremors and rigidity. These symptoms are caused by the death of neurons that produce dopamine in part of the brain called the substantia nigra (see page S10). It was only after motor problems were controlled that it became clear that Parkinson's is about much more than just movement and dopamine. Dopamine therapy does not help to relieve the non-motor symptoms of Parkinson's, which seem to be caused by the death of, or damage to, other kinds of neuron all over the body. The cognitive and psychiatric symptoms have been underestimated partly because patients think they are not relevant to what some people believe is purely a motor disorder. Hallucinations, for example, were thought to be part of the later stages of the disease, so doctors did not routinely ask people newly diagnosed with the disease about them. “If you don't ask, patients typically don't complain about them,” says Kulisevsky. Kulisevsky is particularly interested in cognitive symptoms. As part of a larger, five-year, multicentre study in Spain called COPPADIS, he and his colleagues asked 50 patients whether they experienced hallucinations and, if so, their nature and severity. The results suggested that hallucinations occur much earlier in Parkinson's than previously thought ( et al. Mov. Disord. 31, 45–52; 2015). At diagnosis, 30% of patients in the COPPADIS group reported “a sense of presence”: a visual, tactile or auditory hallucination that someone or something is standing or moving nearby. Mild cognitive impairment can also occur early. Kulisevsky often asks family members whether the patient has trouble making a meal or doing two things at once. Identifying these problems is easier now that there is a questionnaire for rating cognitive impairment that is specific to Parkinson's. The latest estimates suggest that up to 20% of people have cognitive issues at diagnosis, and these are not just older patients, says Giselle Petzinger, a neurologist at the University of Southern California in Los Angeles. After five or six years, the proportion has risen to more than 40%. Furthermore, half of people with Parkinson's have clinically significant anxiety or depression, says Irene Richard, a neurologist at the University of Rochester Medical Center in New York. This is more than just being down about the movement issues: there is no correlation between physical disability in Parkinson's and severity of depression. “Some people don't view this as a symptom of their Parkinson's, but as a failure of will,” Richard says. “I tell them: 'You wouldn't say that about your tremor'.” Clinicians can often treat these non-motor symptoms, such as depression and REM sleep behaviour disorder, with therapies that were designed for other diseases (see 'A whole-body disease'). But treating them individually is not ideal, says Todd Sherer, chief executive of the Michael J. Fox Foundation for Parkinson's Research. “The field is in whack-a-mole mode,” Sherer says. The only thing that seems to help multiple symptoms, he says, is exercise. Petzinger agrees with Sherer on the limits of a symptom-by-symptom understanding of Parkinson's — not only for therapeutic practice, but also for neurologists' understanding of the disease. “We silo them up, but all these non-motor symptoms in Parkinson's disease are interrelated,” she says. Even motor symptoms have cognitive aspects: people must constantly make mental adjustments as they make their way through a changing environment. Petzinger is testing the value of exercises that engage both motor and cognitive circuits in an ongoing clinical trial. People with Parkinson's still retain brain plasticity and can relearn some skills, she says. The exercises in the trial are not “just jumping jacks” or other simple aerobic activities, says Petzinger — they are Parkinson's-specific and are designed to encourage learning and multitasking. Once someone can walk with good posture at normal speed and with a good stride length, the researchers add a second challenge that requires more cognition, such as bouncing a ball while they walk. The trial will evaluate whether symptoms improve after the exercises. These activities will be compared with aerobic exercise alone and, as a control, social interaction. The pattern and progression of non-motor symptoms provide a window into the underlying mechanisms of Parkinson's disease. Progression seems to tally with where protein aggregates are found in the nervous system (see page S13). The protein α-synuclein forms clumps called Lewy bodies, which have been found in neurons in the parts of the brain that control movement, but also throughout the cortex and the peripheral nervous system. There are hints that Lewy bodies are associated with non-motor symptoms and with damage to parts of the nervous system that depend on neurotransmitters other than dopamine. The presence of α-synuclein in different places in the nervous system may explain the heterogeneity of Parkinson's symptoms, says John Trojanowski, who studies protein aggregations in neurodegenerative diseases at the University of Pennsylvania in Philadelphia. He compares this diversity of symptoms to the variety of effects from a stroke. “A stroke in the cerebellum might not cause any memory problems, but the tiniest stroke in the hippocampus will,” he says. People with Parkinson's develop a core of motor problems, plus a hotch-potch of non-motor symptoms that reflect where the other damage has occurred. Heiko Braak, an anatomist at Goethe University in Frankfurt, Germany, has proposed that Parkinson's disease proceeds in a series of stages, progressing from non-motor to motor symptoms, which correlate with the distribution of Lewy bodies in the nervous system. The first stage is in the olfactory system, accounting for early degradation of the sense of smell, closely followed by the lower brainstem, which can induce sleep disorders. Braak proposes that motor problems emerge only in the third and fourth stages. In the final stages, when Lewy bodies have reached the cortex, cognitive problems culminate in dementia. Unfortunately, hypotheses such as Braak staging are difficult to study in living people because there are no imaging agents for α-synuclein, says Trojanowski. The only way to connect α-synuclein distribution with symptoms is to observe the symptoms while patients are alive, and then look for Lewy bodies during an autopsy, which provides only a snapshot. Scientists can also look for the protein in the cerebrospinal fluid of living patients, but the test cannot pinpoint its origins. The best researchers can do at the moment is image the neurons that are richest in dopamine. In the 1990s, David Goldstein, a neurocardiologist at the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, developed a radiotracer called fluorodopamine to visualize sympathetic neurons with a positron emission tomography scan, which led to an unexpected discovery. About half of people with Parkinson's have orthostatic hypotension: when they stand up, their blood pressure drops. Goldstein showed that this effect is correlated with the death of sympathetic neurons in the heart (D. S. Goldstein et al. Neurology 58, 1247–1255; 2002). “This was the first clear evidence for a mechanism of a non-motor aspect of Parkinson's disease,” he says. Goldstein is now using his imaging tracer to find signs of Parkinson's earlier in the course of the disease. Current trials are hindered by the fact that it is only possible to enrol patients in the later stages of disease. This is because a Parkinson's diagnosis can be made only once motor symptoms appear, by which time about half of a patient's dopamine neurons have already died, says Sherer. To do better clinical trials, researchers must find participants earlier and track the progression of the disease. They must also identify the right mix of risk signals, including non-motor symptoms. The difficulty here is that the symptoms are so diverse, and each seems to correlate only weakly with the risk of developing Parkinson's disease. About 95% of people with Parkinson's gradually lose their sense of smell, but so do many people with Alzheimer's and schizophrenia. Several groups are trying to eliminate these uncertainties by combining non-motor risk signals with biomarkers and imaging. Kenneth Marek, president of the Institute for Neurodegenerative Disorders in New Haven, Connecticut, is involved in the Parkinson's Associated Risk Study (PARS), which is exploring whether the loss of smell can be combined with imaging to help detect the disease earlier. PARS leaders sent standardized scratch-and-sniff tests to thousands of people who had been pre-screened online, and received 5,000 tests back. The researchers selected the respondents with the worst sense of smell in their gender and age groups for further study. Of these, 203 were given extensive clinical tests and dopamine-imaging studies; 23 were found to have both a poor sense of smell and abnormally low dopamine levels, so were considered to be at high risk of developing Parkinson's. Of these, 14 (61%) went on to develop the disease over four years of study (data from a poster by D. Jennings et al. at the 18th International Congress of Parkinson's Disease and Movement Disorders, 2014). Meanwhile, Goldstein is leading a US National Institutes of Health (NIH) study called PD Risk that looks at the correlation between nerve loss in the heart and neurotransmitter levels, measured in both the spinal fluid and in imaging scans. Goldstein presented preliminary results at the World Parkinson's Congress in Portland, Oregon, in September. In the trial, NIH researchers started with 3,176 individuals, from whom they identified 22 who had three or more risk factors, such as diminished sense of smell and REM sleep behavioural disorder. They imaged this group using three different tracers for dopamine and related metabolites. After 3 years, 4 of the 22 had developed Parkinson's, and 2 were diagnosed with a related disease called Lewy body dementia. All those who developed Parkinson's had low levels of dopamine on imaging tests, which Goldstein said suggests that the test can identify high-risk patients. “If you have lost these neurons, it's not a matter of risk — you have the disease. It's a matter of time,” says Goldstein. To measure progress in a clinical trial, not only do researchers need to identify people in the earlier stages of disease, but they also need to find reliable, quantitative biomarkers that can track disease progression (see page S4). “We treat heart disease by bringing blood pressure down, we treat viral load to prevent AIDS, because these things are strongly correlated,” says Marek. When these numbers change, pharmaceutical companies and doctors know a drug is working. Marek hopes to find the Parkinson's equivalents. Marek and Mollenhauer hope the criteria for the early identification of people at high risk of the disease will be sharpened by a large, international study called the Parkinson's Progression Marker Initiative (PPMI). The PPMI, which has recruited 100 people at high risk of disease, 400 recently diagnosed patients and 200 healthy controls, is designed to find correlations between clinical signs such as a diminishing sense of smell and biomarkers such as levels of neurotransmitters in the spinal fluid, and imaging and blood biomarkers. Because of its size and scope, the PPMI could identify the right mix of signals that warn of early onset, as well as mark progression. Neurologists know that the severity of non-motor symptoms determines the quality of life for people with Parkinson's. Now they hope that these symptoms will help them to diagnose the disease before movement problems begin. “People who are at risk, but don't have it yet, are the ideal group to try to slow the degenerative process,” says Goldstein. Non-motor symptoms may be the best guides in the search for treatments that can slow Parkinson's disease or even stop it in its tracks.

Schapira A.H.V.,University College London | McDermott M.P.,University of Rochester | Barone P.,University of Salerno | Comella C.L.,Rush University Medical Center | And 7 more authors.
The Lancet Neurology | Year: 2013

Background: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). Methods: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with, number NCT00321854. Findings: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug. Interpretation: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects. © 2013 Elsevier Ltd.

Jennings D.,Institute for Neurodegenerative Disorders | Siderowf A.,Avid Radiopharmaceuticals | Stern M.,University of Pennsylvania | Seibyl J.,Institute for Neurodegenerative Disorders | And 3 more authors.
Neurology | Year: 2014

Objectives: The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD). Methods: In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires). Tier 2 assessments (neurologic examination, DAT imaging, and other biomarker assessments) were completed by 303 subjects. The main outcome of the study is to compare age-expected [123I]b-CIT striatal binding ratio in hyposmic and normosmic subjects. Results: Tier 1 assessments were mailed to 9,398 eligible subjects and returned by 4,999; 669 were hyposmic. Three hundred three subjects (203 hyposmic, 100 normosmic) completed baseline evaluations. DAT deficit was present in 11%of hyposmic subjects compared with 1% of normosmic subjects. Multiple logistic regression demonstrates hyposmia (odds ratio [OR] 12.4; 95% confidence interval [CI] 1.6, 96.1), male sex (OR 5.5; 95% CI 1.7, 17.2), and constipation (OR 4.3; 95% CI 1.6, 11.6) as factors predictive of DAT deficit. Combining multiple factors (hyposmia, male sex, and constipation) increased the percentage of subjects with a DAT deficit to .40%. Conclusion: Subjects with DAT deficit who do not meet criteria for a diagnosis of PD can be identified by olfactory testing. Sequential biomarker assessment may identify those at risk of PD. Selecting hyposmic individuals enriches the population for DAT deficit, and combining hyposmia with other potential risk factors (male sex, constipation) increases the percentage of subjects with a DAT deficit compatible with prodromal PD. © 2014 American Academy of Neurology.

Marek K.,Institute for Neurodegenerative Disorders | Seibyl J.,Institute for Neurodegenerative Disorders | Eberly S.,University of Rochester | Oakes D.,University of Rochester | And 4 more authors.
Neurology | Year: 2014

Objective: To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up. Methods: Baseline (n = 799) and 22-month follow-up (n = 701) [ 123I] β-CIT SPECT scans were acquired. The percent change in [123I] β-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators' diagnosis at study termination were compared between SWEDD and DAT deficit subjects. Results: SWEDD subjects (n = 91) compared with DAT deficit subjects (n = 708) showed reduced UPDRS score at baseline (18.7 [SD 8.5] vs 25.5 [SD 10.5], p < 0.05) and minimal change in both [123I] β-CIT striatal binding ratio (20.2% [SD 12.2] vs 28.5% [SD 11.9], p < 0.0001) and UPDRS score (0.5 [SD 6.9] vs 10.5 [SD 8.9], p < 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects. Conclusion: These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD. © 2014 American Academy of Neurology.

Di Iorio C.R.,Vanderbilt University | Watkins T.J.,Vanderbilt University | Dietrich M.S.,Vanderbilt University | Cao A.,Vanderbilt University | And 9 more authors.
Archives of General Psychiatry | Year: 2012

Context: MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial. Objective: To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin 2A receptor levels. Design: Cross-sectional case-control study comparing serotonin 2A receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin 2A receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin 2A receptor levels in the cerebral cortex were determined using serotonin 2A-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer. Setting: Academic medical center research laboratory. Participants: A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness. Main Outcome Measures: Cortical serotonin 2A receptor nondisplaceable binding potential (serotonin 2ABP ND). Results: MDMA users had increased serotonin 2ABP ND in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal- parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin 2ABP NDin frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin 2ABP ND. Conclusions: The recreational use of MDMA is associated with long-lasting increases in serotonin 2A receptor density. Serotonin 2A receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications. ©2012 American Medical Association. All rights reserved.

Cosgrove K.P.,Yale University | Cosgrove K.P.,Veterans Affairs Connecticut Healthcare System | Esterlis I.,Yale University | Esterlis I.,Veterans Affairs Connecticut Healthcare System | And 10 more authors.
Archives of General Psychiatry | Year: 2012

Context: Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and response to nicotine therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β 2 subunit (β 2*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men. Objectives: To examine β 2*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among β 2*-nAChR availability, tobacco smoking characteristics, and female sex steroid hormone levels. Design: Male (n = 26) and female (n = 28) tobacco smokers participated in an iodide 123-labeled 5-iodo-A-85380 ([ 123I]5-IA) single-photon emission computed tomography (SPECT) imaging session at 7 to 9 days of abstinence. Age-matched male (n = 26) and female (n = 30) nonsmokers participated in a [ 123I]5-IA SPECT imaging session. All participants completed a magnetic resonance imaging study. Setting: Academic imaging center. Participants: Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56). Main Outcome Measure: The [ 123I]5-IA SPECT images were converted to equilibrium distribution volumes and were analyzed using regions of interest. Results: The β 2*-nAChR availability was significantly higher in male smokers compared with male nonsmokers in striatum, cortex, and cerebellum, but female smokers did not have higher β 2*-nAChR availability than female nonsmokers in any region. In women, β 2*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the SPECT imaging day. In female smokers on imaging day, the progesterone level was positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal. Conclusions: The regulatory effects of nicotine in the brain (ie, tobacco smoking-induced upregulation of β 2*-nAChRs) seem to be distinctly different between men and women, and female sex steroid hormones likely have a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. To treat female smokers more effectively, it is critical that nonnicotinic-mediated medications should be explored. ©2012 American Medical Association. All rights reserved.

Barthel H.,University of Leipzig | Seibyl J.,Institute for Neurodegenerative Disorders | Sabri O.,University of Leipzig
Expert Review of Neurotherapeutics | Year: 2015

PET is a non-invasive imaging technique which allows the visualization and quantification of molecular processes, offering sensitive and early disease detection. Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to memory loss and other functional impairments. By employing different tracers targeting neurodegeneration, amyloid and tau aggregates, cholinergic neurotransmission, neuroinflammation and other processes, PET imaging enhances our understanding of the potential triggers of AD, the chronology of molecular events in AD, the detection of early AD, differentiation of AD dementia from other dementia disorders and the development of better drugs to treat AD. As such, PET imaging at different disease stages (asymptomatic, prodromal and dementia stages) is on its way to becoming a valuable routine clinical biomarker and a drug testing and research tool in AD. © 2015 Informa UK, Ltd.

Alagille D.,Institute for Neurodegenerative Disorders | Dacosta H.,Institute for Neurodegenerative Disorders | Baldwin R.M.,Institute for Neurodegenerative Disorders | Tamagnan G.D.,Institute for Neurodegenerative Disorders
Bioorganic and Medicinal Chemistry Letters | Year: 2011

We designed and synthesized a small series of 2-aryl-imidazo[2,1-b] benzothiazole, representing a combination of motifs from the two most potent amyloid imaging agents, PIB and IMPY. The binding affinity of the new compounds ranged from 6 to 133 nM. Among the best compounds, 3b (Ki = 6 nM) can be labeled with 11CH3 for PET imaging whereas 3j (K i = 10.9 nM) can be labeled with 123I for SPECT imaging. © 2011 Elsevier Ltd. All rights reserved.

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