Therese A. Treves

Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease

Summary.Objectives. To study the relationships between clinical features of Parkinsons disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. Background. The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. Method. 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 ± 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 ± 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). Results. The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage ≤2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4–5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (≥59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (<59 years n = 83). Dementia was significantly associated with older age of PD onset (β = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (β = −0.04, p = 0.02). The presence of dementia was also significantly associated with depression (β = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. Conclusion. Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset.

ACE, MTHFR, Factor V Leiden, and APOE Polymorphisms in Patients With Vascular and Alzheimer’s Dementia

BACKGROUND AND PURPOSE There is a growing interest in the use of genetic markers in the differential diagnosis of dementia. In the current study we examined the usefulness of genetic risk factors for vascular disease as markers for vascular dementia (VD). METHODS The groups included 41 patients with VD, 49 patients with dementia of the Alzheimers type, and 40 age-matched control subjects without dementia. These patients were genotyped for vascular disease-associated polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), factor V Leiden (FVL), and a common genetic risk factor for AD, apolipoprotein E epsilon4 (APOE epsilon4). RESULTS There was no significant association between ACE, MTHFR, and FVL genotypes with VD whether compared with subjects with AD or with control subjects. There was a higher frequency of APOE epsilon4 alleles in patients with AD (30%, P=0.016) and VD (26%, P=0.07) compared with control subjects (15%). CONCLUSIONS VD is not associated with the genetic risk factors for vascular disease examined in this study, indicating that the pathogenesis of VD may differ from other vascular diseases.

The Tel Aviv Stroke Registry: 3600 Consecutive Patients

BACKGROUND AND PURPOSE We undertook to estimate the frequency of various risk factors and the type and severity of stroke in different ethnic groups documented in a large hospital-based stroke registry. Tel Aviv is a metropolis with about 400000 inhabitants and about 600000 daily visitors and workers. The Tel Aviv Medical Center (TAMC) is the only tertiary medical care facility to which all patients with acute stroke are referred. Israel is a country with a heterogeneous population, of which a significant proportion was born abroad. The people differ in their genetic background, as well as in their early environmental conditions, lifelong diet, and other habits. This variety has proved to be a fertile ground for the study of different neurological diseases, including stroke. METHODS A prospective hospital-based registry using systematic computer coding of data of all consecutive stroke patients admitted to the TAMC has been conducted since May 1988. Different aspects of the amassed data were analyzed statistically. RESULTS From May 1988 until April 1994, 3600 stroke patients were admitted to the TAMC. The mean age was 73.2 years, and 58.2% were males. Cerebral infarctions were diagnosed in 80.9%, primary intracerebral hemorrhages in 8.0%, and transient ischemic attacks in 11.1%. There were 861 patients (24%) who were admitted with recurrent strokes. Past medical history of hypertension was the major risk factor (occurring in 52.2% of the patients), followed by ischemic heart disease (29.7%), diabetes mellitus (25.2%), smoking (17.0%), atrial fibrillation (14.3%), and hyperlipidemia (8.4%). Ischemic heart disease and atrial fibrillation were more frequent in patients from Europe and America (Ashkenazi group), whereas diabetes mellitus and smoking were more prominent in the other groups. The in-hospital mortality rate was 13.8% and was similar in both ethnic groups. CONCLUSIONS This registry allows the study of the risk factors, natural history, and clinical manifestations of stroke in different ethnic groups.

Failure of aspirin treatment after stroke.

Background and Purpose Despite its low efficacy, aspirin is the most widely used drug for secondary stroke prevention. The reasons why stroke recurs while patients are on aspirin are unknown. We have analyzed a series of patients who had recurrent strokes while on aspirin. Methods Out of 2231 consecutive patients who were admitted to the Tel Aviv Medical Center from May 1988 through December 1992 with the diagnosis of ischemic stroke, 129 admissions were due to recurrent ischemic strokes while the patients were already on aspirin, and these were defined as aspirin failures. The clinical characteristics of those patients in whom aspirin treatment failed were compared with three control groups, each comprising 129 patients who had had only a single ischemic stroke and were then taking aspirin. One control group was matched for aspirin dose and date of first stroke; another control group was matched for age, sex, and date of first stroke; and a third control group was matched for age, sex, date of first stroke, and aspirin dose. Statistical analysis was carried out by two-tailed Students t test and x2 test. Results The average period until stroke was longer for patients on higher aspirin doses.Patients matched for aspirin dose and date of first stroke did not differ significantly in age (72.4 years in aspirin failures versus 74.2 years in the first control group) and sex (89 versus 94 men, respectively). Matching for age, sex, and date of first stroke but not for aspirin dose demonstrated a trend toward high frequency of aspirin failure in patients taking lower doses of aspirin (x2 test for trend=3.5; P=.06). Comparison of aspirin-failure patients with a control group matched for age, sex, date of first ischemic stroke, and aspirin dose demonstrated that these patients more commonly had statistically significant hyperlipidemia (odds ratio, 2.6; 95% confidence interval, 1.0 to 6.8; P=.04) and ischemic heart disease (odds ratio, 2.3; 95% confidence interval, 1.3 to 3.9; P=.002). Conclusions We conclude that age and sex do not influence the efficacy of aspirin. Lower aspirin dose in patients with stroke recurrence suggests that aspirin doses of 500 mg daily or more should be used in secondary stroke prevention. Hyperlipidemia and ischemic heart disease are risk factors for stroke recurrence despite aspirin treatment, which requires further clinical and laboratory evaluation. (Stroke. 1994;25:275-277.)

Dementia and Antiphospholipid Antibodies

Antiphospholipid antibodies (aPLAb) may cause both focal ischemic and diffuse brain damage and may be associated with dementia. We have examined the relationship of aPLAb to dementia in the elderly. Blood samples were obtained from 87 consecutive patients with dementia (74 ± 11 years old) and 69 controls (78 ± 9 years old), residents of an old age home who were not overtly demented. Levels of aPLAb were measured by a standardized ELISA, utilizing cardiolipin as antigen, and we considered levels above 20 IgG antiphospholipid units (GPLU) as significantly elevated. We found that 5 of the 87 demented patients (6%), but none of the 69 controls, had significantly elevated aPLAb levels (p = 0.03, one-tailed Fisher’s exact test). All the patients with high aPLAb levels were diagnosed clinically as having dementia of the Alzheimer type, except for 1 who had mixed dementia, and none had features of an immune-mediated disease. Thus, a small but significant number of patients with dementia have high levels of aPLAb. The role of the aPLAb in these patients, with apparently diffuse brain disease, is currently unknown.

Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study.

ObjectiveThe use of cannabis as a therapeutic agent for various medical conditions has been well documented. However, clinical trials in patients with Parkinson disease (PD) have yielded conflicting results. The aim of the present open-label observational study was to assess the clinical effect of cannabis on motor and non–motor symptoms of PD. MethodsTwenty-two patients with PD attending the motor disorder clinic of a tertiary medical center in 2011 to 2012 were evaluated at baseline and 30 minutes after smoking cannabis using the following battery: Unified Parkinson Disease Rating Scale, visual analog scale, present pain intensity scale, Short-Form McGill Pain Questionnaire, as well as Medical Cannabis Survey National Drug and Alcohol Research Center Questionnaire. ResultsMean (SD) total score on the motor Unified Parkinson Disease Rating Scale score improved significantly from 33.1 (13.8) at baseline to 23.2 (10.5) after cannabis consumption (t = 5.9; P < 0.001). Analysis of specific motor symptoms revealed significant improvement after treatment in tremor (P < 0.001), rigidity (P = 0.004), and bradykinesia (P < 0.001). ConclusionsThere was also significant improvement of sleep and pain scores. No significant adverse effects of the drug were observed. The study suggests that cannabis might have a place in the therapeutic armamentarium of PD. Larger, controlled studies are needed to verify the results.

Clinical characteristics of neuroleptic-induced parkinsonism

Summary. In order to characterize the clinical spectrum of neuroleptic-induced parkinsonism (NIP), we studied a population of consecutive psychiatric in-patients treated with neuroleptics for at least two weeks, who were diagnosed by their psychiatrist as having parkinsonism. Parkinsonism was confirmed by a movement disorders specialist who performed neurological assessment including the motor examination and the activities of daily living (ADL) sections of the Unified Parkinsons Disease Rating Scale (UPDRS), and the Hoehn and Yahr (H&Y) staging.Seventy-five patients (54 males), aged 46 ± 13 years (range 21 to 73 years) were included in the analysis. The mean duration of neuroleptic therapy was 15 ± 12 years, while 61% were treated for more than 10 years. Most of the patients (n = 66, 88%) were scored as H&Y stage 2.5 or less. Rest tremor was present in 44% of the patients, and usually persisted in action. Forty-one patients (61%) had symmetrical involvement. Parkinsonian signs were significantly more common and pronounced in the upper in comparison with the lower limbs (p = 0.0001). Gait disturbances were mild and freezing of gait was very rare (n = 2). Neither age nor duration of therapy or their interaction affected the total motor score or any of the motor sub-scores. In conclusion, NIP differs from PD for more bilateral involvement with relative symmetry, and by affecting upper limbs more often than the lower ones. NIP tends to be associated with the triad of bradykinesia, tremor and rigidity while PD tends to involve gait and posture more often. NIP develops unrelated to duration of neuroleptic treatment or age of the patient, suggesting an individual predisposition to blockage of the dopaminergic receptors.

Prevalence and clinical features of dementia associated with the antiphospholipid syndrome and circulating anticoagulants.

The increasing prevalence with age of antiphospholipid antibodies (aPL), of dementia and of stroke complicates the study of a causal relationship between antiphospholipid syndrome (APS) and dementia. Prolonged aPTT due to circulating anticoagulants (CAC) may serve as a more specific laboratory marker of APS. In a hospital-based study, we examined all patients with CAC and included 23 who fulfilled standard criteria for primary APS. These patients were assessed for dementia, vascular brain disease, autoimmune disease activity and dementia risk factors. Among CAC-positive APS patients, 13 of the 23 (56%) were demented and these were significantly older (mean age+/-S.E., 68+/-3 years) than the nondemented APS group (n=10, 51+/-4 years; p<0.01, Students t-test). The demented patients had significantly more pathology on computerized brain tomography (CT) and electroencephalography (EEG) studies but six of them had no clinical or CT evidence of vascular brain disease. Erythrocyte sedimentation rate was significantly lower in the dementia group, in which there was also a significant negative correlation between levels of aPL and age. CAC-positive APS patients seem to be at risk for developing dementia with age, suggesting a pathogenic role for prolonged exposure to elevated aPL.

Do Silent Brain Infarctions Predict the Development of Dementia After First Ischemic Stroke

BACKGROUND AND PURPOSE Silent brain infarctions (SBI) are common findings in advanced age, but their relationship to dementia is still uncertain. The present study was designed to evaluate whether SBI predict the development of dementia after first clinical ischemic stroke. METHODS We blindly studied admission CT scans of 175 consecutive nondemented patients presenting with ischemic stroke that clinically was their first stroke episode. SBI were defined as CT evidence of infarcts not compatible with the acute event. The patients were subsequently followed for their mental state for 5 years. Survival analysis, wherein onset of dementia was the end point, was performed on the total sample population and conducted separately on those with and without SBI at admission. RESULTS Dementia developed in 56 patients (32%), including 22 of the 63 (35%) with SBI and 34 of the 112 (30%) without SBI. Thus, dementia was not related to SBI. CONCLUSIONS Our data indicate that SBI do not predict the development of dementia after stroke.

Periodic lateralized epileptiform discharges (PLEDs) following stroke are associated with metabolic abnormalities

PLEDs are an electroencephalographic phenomenon consisting of high voltage stereotyped periodic transients distributed over one hemisphere, associated with acute or subacute structural lesions as well as with metabolic abnormalities. We have evaluated the contribution of metabolic factors in patients with acute hemispheric stroke. Temperature, serum electrolytes, glucose, kidney and liver function tests were examined in two groups of 14 patients each following acute hemispheric stroke differing in regard to the appearance of PLEDs in the EEG. CT features of the infarcts were also compared. Patients with PLEDs had more metabolic derangements as compared to patients with no PLEDs (Mann-Whitney ranking test P = 0.01). Hyperglycemia and fever were significantly associated with PLEDs (logistic regression model, P < 0.05). There was no significant difference regarding radiological findings between the two groups. We conclude that acute stroke as a structural lesion predisposes to PLEDs but the latter may be triggered by metabolic disturbances, mainly hyperglycemia and fever.