Mark J. Sedler

Loss of Dopamine Transporters in Methamphetamine Abusers Recovers with Protracted Abstinence

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [11C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12–17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.

Schizophrenia in the Internalizing-Externalizing Framework: A Third Dimension?

BACKGROUND Prior studies of common disorders in community-dwelling adults identified internalizing and externalizing spectra of mental illness. We investigated the placement of schizophrenia and schizotypal personality disorder in this framework and tested the validity of the resulting organization in a clinical population. METHODS The data came from the Suffolk County Mental Health Project cohort (N = 628), which consists of first-admission patients with psychosis recruited from inpatient units throughout Suffolk County, NY (72% response rate). The sample was reassessed multiple times over the following 10 years. Complete diagnostic data were available for 469 participants. Mental health professionals diagnosed 11 target conditions based on semistructured clinical interviews, review of medical records, and reports of significant others. Two validators were included: family history of schizophrenia and 10-year illness course. RESULTS Confirmatory factor analysis revealed that the The Diagnostic and Statistical Manual of Mental Disorders-IV grouping of conditions fit the data poorly. The best alternative classification consisted of three clusters: internalizing, externalizing, and schizophrenic. Both validators supported the coherence and distinctiveness of the schizophrenic cluster. CONCLUSIONS We replicated internalizing and externalizing spectra in a clinical population, identified a schizophrenic spectrum, and provided initial evidence of its validity. These findings suggest that schizotypal personality disorder may be better placed with schizophrenia, antisocial conditions with substance use disorders, and major depression with anxiety disorders.

Ziprasidone for agitation or psychosis in dementia: four cases.

Objective: These case reports examine the potential efficacy and safety of ziprasidone for the treatment of agitation or psychosis in dementia. Method: The authors performed a retrospective chart review of three patients with DSM-IV diagnoses of dementia, treated with ziprasidone for agitation/psychosis on an academic psychiatric inpatient unit in 2002–2003. In addition, these three case reports are supplemented by a clinical report of the first outpatient with DSM-IV diagnosis of dementia completing a prospective open-label six-week study in 2004 evaluating the use of oral ziprasidone for agitation/psychosis in dementia. Qualitative descriptions of clinical improvement provide outcome data for these case reports. Results: Four patients with dementia with agitation/psychosis experienced marked behavioral improvement after receiving oral doses of ziprasidone (20–160 mg/day), without any evidence of problematic cardiac or other side-effects. Two of the four patients had final EKGs and both of these patients demonstrated no change of QTc interval after administration of ziprasidone. Conclusions: These case reports suggest that oral ziprasidone may be an effective and safe medication for the treatment of agitation or psychosis in patients with dementia.

Neuroimaging signatures of frailty: A population-based study in community-dwelling older adults (the Atahualpa Project).

Frailty is a geriatric state of physical vulnerability that might be associated with cognitive decline in the absence of a concurrent neurodegenerative disorder. This assumes that neuroimaging studies are normal, but such examinations have rarely been considered for a frailty work‐up. The present study identifies neuroimaging signatures in older adults interviewed with the Edmonton Frail Scale (EFS).

The bicaudate index inversely associates with performance in the Montreal Cognitive Assessment (MoCA) in older adults living in rural Ecuador. The Atahualpa project

Assessment of cognitive impairment in rural areas of developing countries is complicated by illiteracy and cross‐cultural factors. A better way to estimate the usefulness of cognitive screening instruments is to evaluate their correlation with imaging biomarkers. The bicaudate index (a marker of central atrophy) correlates with cognitive performance. We assessed the relationship of the bicaudate index with the MoCA to estimate the usefulness of this test to detect individuals with cognitive decline in these regions.

The association of ankle-brachial index with silent cerebral small vessel disease: results of the Atahualpa Project

Background An abnormal ankle-brachial index has been associated with overt stroke and coronary heart disease, but little is known about its relationship with silent cerebral small vessel disease. Aim To assess the value of ankle-brachial index as a predictor of silent small vessel disease in an Ecuadorian geriatric population. Methods Stroke-free Atahualpa residents aged ≥60 years were identified during a door-to-door survey. Ankle-brachial index determinations and brain magnetic resonance imaging were performed in consented persons. Ankle-brachial index ≤0·9 and ≥1·4 were proxies of peripheral artery disease and noncompressible arteries, respectively. Using logistic regression models adjusted for age, gender, and cardiovascular health status, we evaluated the association between abnormal ankle-brachial index with silent lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. Results Mean age of the 224 participants was 70 ± 8 years, 60% were women, and 80% had poor cardiovascular health status. Ankle-brachial index was ≤0·90 in 37 persons and ≥1·4 in 17. Magnetic resonance imaging showed lacunar infarcts in 27 cases, moderate-to-severe white matter hyperintensities in 47, and cerebral microbleeds in 26. Adjusted models showed association of lacunar infarcts with ankle-brachial index ≤ 0·90 (OR: 3·72, 95% CI: 1·35–10·27, P = 0·01) and with ankle-brachial index ≥ 1·4 (OR: 3·85, 95% CI: 1·06–14·03, P = 0·04). White matter hyperintensities were associated with ankle-brachial index ≤ 0·90 (P= 0·03) and ankle-brachial index ≥ 1·4 (P = 0·02) in univariate analyses. There was no association between ankle-brachial index groups and cerebral microbleeds. Conclusions In this population-based study conducted in rural Ecuador, apparently healthy individuals aged ≥60 years with ankle-brachial index values ≤0·90 and ≥1·4 are almost four times more likely to have a silent lacunar infarct. Ankle-brachial index screening might allow recognition of asymptomatic people who need further investigation and preventive therapy.

The Effect of Age in the Association between Frailty and Poor Sleep Quality: A Population-Based Study in Community-Dwellers (The Atahualpa Project).

PURPOSE To assess the effect of age in the association between poor sleep quality and frailty status. DESIGN AND SETTING Population-based, cross-sectional study conducted in Atahualpa, a rural village located in coastal Ecuador. METHODS Out of 351 Atahualpa residents aged ≥ 60 years, 311 (89%) were interviewed with the Pittsburgh Sleep Quality Index (PSQI) and the Edmonton Frail Scale (EFS). The independent association between PSQI and EFS scores was evaluated by the use of a generalized linear model adjusted for relevant confounders. A contour plot with Shepard interpolation was constructed to assess the effect of age in this association. RESULTS Mean score in the PSQI was 5 ± 2 points, with 34% individuals classified as poor sleepers. Mean score in the EFS was 5 ± 3 points, with 46% individuals classified as robust, 23% as prefrail, and 31% as frail. In the fully adjusted model, higher scores in the PSQI were significantly associated with higher scores in the EFS (β 0.23; 95% CI 0.11-0.35; P < .0001). Several clusters depicted the strong effect of age in the association between PSQI and EFS scores. Older individuals were more likely to have high scores in the EFS and the PSQI, and younger individuals had low EFS scores and were good sleepers. Clusters of younger individuals who were poor sleepers and had high EFS scores accounted for the independent association between PSQI and EFS scores. CONCLUSIONS This study shows the strong effect of age in the association between poor sleep quality and frailty status.

Prevalence, correlates, and prognosis of peripheral artery disease in rural ecuador-rationale, protocol, and phase I results of a population-based survey: an atahualpa project-ancillary study

Background. Little is known on the prevalence of peripheral artery disease (PAD) in developing countries. Study design. Population-based study in Atahualpa. In Phase I, the Edinburgh claudication questionnaire (ECQ) was used for detection of suspected symptomatic PAD; persons with a negative ECQ but a pulse pressure ≥65 mmHg were suspected of asymptomatic PAD. In Phase II, the ankle-brachial index will be used to test reliability of screening instruments and to determine PAD prevalence. In Phase III, participants will be followed up to estimate the relevance of PAD as a predictor of vascular outcomes. Results. During Phase I, 665 Atahualpa residents aged ≥40 years were enrolled (mean age: 59.5 ± 12.6 years, 58% women). A poor cardiovascular health status was noticed in 464 (70%) persons of which 27 (4%) had a stroke and 14 (2%) had ischemic heart disease. Forty-four subjects (7%) had suspected symptomatic PAD and 170 (26%) had suspected asymptomatic PAD. Individuals with suspected PAD were older, more often women, and had a worse cardiovascular profile than those with nonsuspected PAD. Conclusions. Prevalence of suspected PAD in this underserved population is high. Subsequent phases of this study will determine whether prompt detection of PAD is useful to reduce the incidence of catastrophic vascular diseases in the region.

The Association between Earlobe Crease (Frank’s Sign) and Abnormal Ankle-Brachial Index Determination Is Related to Age: A Population-Based Study

Background Information on the association between earlobe crease (ELC) and peripheral artery disease is limited. We assessed this association in community-dwelling older adults. Study Design A total of 294 Atahualpa residents aged ≥60 years were enrolled. ELC were visually identified by two raters. The ankle-brachial index (ABI), used as a surrogate of peripheral artery disease, was categorized using American Heart Association criteria. Using logistic regression and probability models, adjusted for demographics and cardiovascular risk factors, we assessed the relationship between ELC and abnormal ABI determinations, as well as the influence of age on this association. Results ELC was identified in 141 (48%) individuals, and abnormal ABI determination was carried out in 56 (19%). The association between ELC and abnormal ABI was nonsignificant in logistic regression and probability models with individuals stratified according to their median age. Conclusions The association between ELC and abnormal ABI determinations is probably attenuated by the high prevalence of both conditions in older persons. ELC might not be useful for identifying candidates for ABI determination.

Inverse relationship between the Evans index and cognitive performance in non-disabled, stroke-free, community-dwelling older adults. A population-based study

OBJECTIVE The Evans Index (EI) is used for recognition of individuals with normal pressure hydrocephalus. However, recent studies suggest that the EI is not a reliable marker of this condition. Rather, the EI may be inversely correlated with cognitive performance, but information on this correlation is lacking. We aimed to assess the relationship between the EI and cognitive performance in community-dwelling older adults. PATIENTS AND METHODS The study included 314 non-disabled, stroke-free, individuals aged ≥60 years enrolled in the Atahualpa Project undergoing brain MRI and MoCA testing. Using generalized linear models, adjusted for demographics, cardiovascular risk factors edentulism, depression, global cortical atrophy and white matter hyperintensities of vascular origin, we assessed the relationship between the EI and cognitive performance. Predictive margins of the MoCA score according to percentiles of the EI were also evaluated, after adjusting for variables reaching significance in univariate models. RESULTS The mean EI was 0.248 ± 0.022 and the mean MoCA score was 19.7 ± 4.8 points. A fully-adjusted generalized linear model showed a significant inverse relationship between the EI and the MoCA score. Predictive models showed a decrease in the MoCA score according to increased levels of the EI (β: -3.28; 95% C.I.: -6.09 to -0.47; p = 0.022). CONCLUSION The independent effect of the EI on the MoCA score provides evidence of the utility of the EI to evaluate cognitive performance.