The effect of schooling on reported age of onset of cognitive decline: A collaborative study.

Higher education has been reported to be a protective factor against dementia. We suggest that the strength of a risk factor may be measured by the length of time by which it delays disease onset; therefore, we examined whether people with lower education develop cognitive decline at an earlier age than people with more schooling. The study population was based on patients referred to our Memory Clinics from 1994 to 2004. Analysis of covariance was used to evaluate the effect of schooling on the reported age of memory decline, in patients with mild cognitive impairment (MCI) and in patients diagnosed with Alzheimer's disease (AD). The mean reported age of onset of cognitive decline was unexpectedly lower in patients with higher education than in patients with fewer schooling years, with a relatively small effect size (beta=-0.6), and the effect was more marked in the MCI group. Every year of schooling advanced the reported age of onset by 6months among patients with MCI (t=-6.18, p<.001) and by 3months among patients with AD (t=-2.4, p=0.017). Education may affect the reported age of onset of cognitive decline, but its magnitude is small. It is possible that increased awareness in more educated people leads them to consult earlier; this could explain the paradoxical finding of earlier reported age of onset of cognitive decline in patients with higher education.

Modeling the dementia epidemic.

The incidence of dementia increases steeply with age in older people, although from the tenth decade the slope may be smoother, perhaps reflecting different pathological processes in the oldest old. The prevalence depends upon interaction of age with other factors (e.g., comorbidities, genetic or environmental factors) that in turn are subject to change. If onset of dementia could be postponed by modulating its risk factors, this could significantly affect its incidence. Analysis of risk and protection factors should take into account the critical period during which these factors play a role. For example, the impact of education and diabetes mellitus occurs in early- and midlife, respectively, while maintaining optimal physical and mental activity and controlling vascular factors later in life may slow the rate of cognitive decline. Modifying factors need to be evaluated for different clinical groups, taking into account genetic background, age, and duration at exposure. The aim of the present article is to try to take stock of epidemiological data concerning factors affecting the prevalence of dementia and predict future developments, as well as to look for possible interventions that could affect outcome.

Clinical characteristics of Parkinson's disease among Jewish Ethnic groups in Israel.

Yemenite Jews in Israel are a distinctive ethnic division of the Jewish diaspora. Clinical findings, disease course and genetic tests for the LRRK2 6055G > A (G2019S) mutation were compared between Ashkenazi and Yemenite Israeli patients with Parkinson's disease (PD). Age of onset was significantly younger in the Yemenites (P < 0.001). There were no differences in the distribution of initial symptoms, environmental risk factors or rate of motor/non-motor phenomena. The Yemenite group had a more severe disease (P < 0.001), and a more rapid disease course (P = 0.006). The frequency of Lrrk2 substitution was 12.7% in the Ashkenazi group and was not observed in the Yemenites. These results show that there are differences between Israeli Jewish ethnic groups in the severity and progression of PD, but not in clinical symptoms. The high frequency of Lrrk2 G2019S in the Ashkenazi and its absence in the Yemenite Jews suggests a specific ancestral pattern of inheritance in Ashkenazi Jews.

[(123)I]-FP-CIT SPECT and olfaction test in patients with combined postural and rest tremor.

Mixed-type tremors pose a clinical diagnostic challenge. The aim of the study was to better characterize patients with combined postural and rest tremor. Patients were categorized into four groups: essential tremor (ET) (n = 7), combined rest + postural tremor (n = 17), PD (n = 17), and control subjects (n = 9). All underwent the University of Pennsylvania Smell Identification Test (UPSIT). The mixed-tremor group was also evaluated with SPECT imaging using the dopamine transporter (DaT) ligand (123)I-labeled FP-CIT. There was no significant difference in olfaction scores between the mixed tremor and essential tremor groups (23.2 +/- 6.6 vs 21.7 +/- 4.9) or between these groups and controls (27.2 +/- 5.0). The patients with PD had significantly lower scores than all the other groups (13.7 +/- 5.4, p < 0.001). Of the 12 patients with mixed tremor evaluated by SPECT, 9 had normal findings. This study suggests that rest tremor is part of the spectrum of ET, even in patients with long-standing disease. However, in a minority of patients, there might be transformation of ET-PD.

Long-term tetrahydroaminoacridine treatment and quantitative EEG in Alzheimer's disease.

The development of therapies for Alzheimer's disease (AD) has focused on drugs designed to correct the loss of cholinergic function within the central nervous system. Quantitative EEG (qEEG) changes associated with AD consist of background slowing. One way to study the effects of cholinergic drugs may be through assessment of their qEEG effects. The aim of the current work was to evaluate the effect of long-term treatment with tetrahydroaminoacridine (THA) on qEEG in AD patients.

Skin biopsy for assessment of autonomic denervation in Parkinson's disease.

Autonomic dysfunction in Parkinson's disease (PD) is considered a late complication of the disease or an adverse effect of anti-parkinsonian medications. Morphological changes are demonstrated only by postmortem examination. The study objective was to evaluate peripheral autonomic neural involvement in PD using punch skin biopsy. The study sample included 22 patients (mean age 50 +/- 7.7 years, mean disease duration 5.3 +/- 3.8 years) and 19 controls. Four-millimeter skin biopsies were immunohistochemically stained with anti-PGP 9.5 antibody. Autonomic innervation of the blood vessels, sweat glands, and erector pili muscles was assessed and rated from 0 (normal) to 2 (severe). Cutaneous autonomic innervation was decreased in patients compared to controls. Semi quantitative analysis demonstrated reduced autonomic innervation of the blood vessels (1.0 +/- 0.8 vs. 0.42 +/- 0.8 in controls; p < 0.02), of sweat glands (0.95 +/- 0.67 vs. 0.47 +/- 0.61; p < 0.02) and of the erector pili muscles (1.06 +/- 0.55 vs 0.21 +/- 0.42; p < 0.001). This method demonstrates that the peripheral autonomic system is affected in PD at early stage of the disease and that autonomic involvement in PD may be more prevalent than previously thought.

Incidence of dementia in patients with subjective memory complaints.

BACKGROUND: The risk of developing dementia by elderly patients with only subjective memory complaints (SMC) is unclear. Our objective was to assess the prognosis of such patients regarding subsequent development of dementia. METHODS: From 1992 to 1996, 211 consecutive patients (age 67.4 +/- 9.4 years, mean +/- SD) were diagnosed as having SMC. These patients were followed for 3 years or to the time they were diagnosed with dementia, whichever came first. A survival analysis was performed for occurrence of dementia within 3 years. RESULTS: The duration of memory decline was shorter among patients who developed dementia than among those who did not (32.6 vs. 49.9 months, F = 3.3, p = 0.07). Patients who developed dementia tended to be older at the reported onset of memory decline (71 vs. 66.2 years, F = 3.2, p = 0.07). Lower risk of dementia was associated with higher cognitive performance at entry [odds ratio (OR) = 0.74 (0.59-0.92)] and longer time from onset of memory decline to referral [OR = 0.91 (0.85-0.98)]. CONCLUSION: Subjects with SMC have an increased risk of developing dementia, particularly those with lower cognitive status at entry and with older age at onset of memory complaints, and shorter duration of their memory complaints.

The effects of acute loading with levodopa and levodopa with selegiline on blood pressure and plasma norepinephrine levels in chronic Parkinson's disease patients.

OBJECTIVES: Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. MATERIALS AND METHODS: Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). RESULTS: Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. CONCLUSION: PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.

Postictal mixed transcortical aphasia.

Postictal aphasia has been described in left temporal lobe seizures. It may be of fluent, non-fluent or global type. We present here a patient who displayed signs of mixed transcortical aphasia (MTCA). The patient was a 67 year old man who underwent excision of a left frontal parasagittal meningioma in 1987. Since then he has been treated with phenytoin for generalized tonic-clonic seizures (GTCS). He was admitted in status epilepticus. On awakening, the patient was non-fluent with palilalia and echolalia. His repetition was relatively preserved but all the other language functions were impaired. This picture faded away within a few hours. Brain CT, performed during this postictal state, was normal except for signs related to frontal craniotomy. SPECT, which was performed after language functions returned to normal, displayed left frontal, cingular and insular hypoperfusion. The postictal language dysfunction of the patient corresponded to MTCA. Although our case has frontal, he had no other structural lesion that could explain either diffuse ischemia of the left hemisphere or watershed areas secondary to the generalized seizures. The uniqueness of this case is the combination of postictal MTCA with good prognosis.

EEG changes during long-term treatment with donepezil in Alzheimer's disease patients.

In this pilot study, we examined the long-term treatment effect of donepezil on the quantitative EEG (qEEG) in 12 Alzheimer's disease patients. The qEEGs of the mean absolute and relative amplitudes of betal, alpha, theta and delta activities were obtained at baseline and during donepezil treatment. Comparisons of awake qEEG prior to and during treatment were performed using a 2-way analysis of variance (ANOVA) with repeated measures. In patients with mild dementia (n = 5), the qEEG analysis showed a significant reduction of the mean absolute theta activity (p = 0.05) by donepezil, particularly in frontal and temporo-parietal areas. In patients with moderate/severe dementia (n = 7), a significant decrease in the mean absolute beta 1 activity (p = 0.02), particularly in the frontal and occipital areas may be attributed to disease progression which was not counteracted by the long-term treatment. The differences in qEEG in patients with different stages of dementia under donepezil treatment may be related to different compensatory capacities due to structural and functional brain disturbances.

Prevalence of Alzheimer's type dementia in an elderly Arab population.

The aim of this study was to estimate the prevalence of dementia of the Alzheimer type (DAT) in an Arab Israeli community. Epidemiological studies of dementia have rarely been reported in Arab populations. The target population, aged 60 years or older, comprised 821 persons (362 males) who, on 1 October 1995, were residents of the rural area of Wadi Ara. These persons were examined for symptoms of dementia (DSM-IV criteria), using a semistructured questionnaire for collection of demographic and medical data. Age, gender, and education-specific prevalence rates were calculated for this population and compared to those obtained in other studies. DAT was diagnosed in 20.5% of this population. Its prevalence increased steeply with age, from 8% among those younger than 70 years to 33% among those aged 70-79 and 51% among those 80 years or older. Illiteracy was very common in this population, and strongly associated with higher prevalence of DAT (27% vs. 4%, P < 0.001). DAT was more prevalent among females than males (25% vs. 15%, P < 0.001). However, illiteracy was also significantly more frequent among women (96% vs. 42%, P < 0.001). After correction for illiteracy, the gender difference lost statistical significance. Few women smoked, but among men, the prevalence of DAT in those who smoked was lower as compared to non-smokers (14% vs. 23%, a non-significant difference). These results were confirmed by logistic regression wherein DAT was included as the dependent variable and age, illiteracy, gender and smoking as independent variables (OR=2.8, 2.8, 1.2 and 0.7, respectively; P < 0.005 for each, except for smoking). Our findings suggest that this population is unique because of extremely high rates of dementia. While the results support a protective effect of schooling against the development of dementia, other factors (e.g. genetic) must be sought to explain this high frequency.

Freezing of gait in patients with advanced Parkinson's disease.

BACKGROUND: Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in advanced stage of Parkinson's disease (PD). The contribution of the underlying pathological process and the antiparkinsonian treatment to the development of FOG are controversial. OBJECTIVE: To study the relationships between clinical features of PD and therapeutic modalities in patients with advanced PD and FOG. METHODS: Consecutive patients with 5 years or more of PD symptoms (n = 172) (99 men) with mean age at symptoms onset of 58.3 +/- 13.2 years and mean symptoms 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 patients' charts, and other documents. A patient was considered as "freezer" if he/she reported recent experience that the legs got stuck to the ground while trying to walk. The presence of dyskinesia, early morning dystonia or significant postural reflex abnormalities were assessed through history and neurological examination. Duration of treatment with antiparkinsonian drugs was calculated from history charts. Chi square and t test were used to compare the patients with and without FOG. Logistic regression was used for the comparison of association between the presence of FOG (dependent variable) disease duration and disease stage (explanatory variables) and duration of treatment with anti-parkinsonian drugs. RESULTS: The study population consisted of 45 patients at Hoehn and Yahr (H&Y) stage 2.5 (26%), 104 patients at stage 3 (60.5%), and 23 patients at H&Y stages 4-5 (13.5%). Ninety one patients (53%) reported FOG at the time of the study. Severity of the disease expressed by H&Y stage at "off" was a significant contributing factor for FOG with a significant trend (z = 4.38, p < 0.0001), as was longer duration of levodopa treatment, and confirmed by FOG using the multivariate logistic regression (p = 0.01 and p = 0.004, respectively). Using a univariate model, longer duration of treatment with dopamine agonists contribute to the appearance of FOG (p = 0.07) while longer duration of amantadine treatment decreased the appearance of FOG (p = 0.09). There was a significant association between FOG and the presence of dyskinesia (p < 0.002), early morning foot dystonia (p < 0.003) and significant postural instability (p < 0.0005). CONCLUSION: FOG is a common symptom in advanced PD. It is mainly related to disease progression and levodopa treatment.

Clinical characteristics of neuroleptic-induced parkinsonism.

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 Parkinson's 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.

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

OBJECTIVES: To study the relationships between clinical features of Parkinson's 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 < or = 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 (> or = 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 (beta = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (beta = -0.04, p = 0.02). The presence of dementia was also significantly associated with depression (beta = 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.

Demented patients' participation in a clinical trial: factors affecting the caregivers' decision.

Clinical trials for Alzheimer's disease take place in medical centers all over the world. Patients and caregivers have to decide whether or not to agree to participate in clinical trials. This study aimed to investigate the motivation that determines the caregivers' choice. Nineteen caregivers of demented patients who consented to participate in a clinical trial in our Memory Clinic and 10 caregivers who refused to participate were interviewed. The data were gathered by a self-report questionnaire covering various aspects of the caregivers' decision-making process. Among the reasons for agreeing to participate in the clinical trial were the respondents' belief that it would improve or help to maintain the patients' condition. Most of the respondents of both groups indicated that information regarding side effects and success probability was adequately provided in advance. The primary reason for refusal was the potential side effects of the drug. The implications of the findings are discussed.

Creutzfeldt-Jakob disease profile in patients homozygous for the PRNP E200K mutation.

We identified 70 Creutzfeldt-Jakob disease patients with the previously described E200K mutation in the prion protein gene. The purpose of this study was to define the clinical features of E200K homozygous patients (n = 5), compared with heterozygotes. We found a statistically significant younger age at disease onset for the homozygous patients, although the average age at onset in this group was still in midlife. Disease features were not statistically different in the two groups. Possible explanations are discussed.

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.

Recruitment rate to drug trials for dementia of the Alzheimer type.

Sample size calculations are important for planning drug trials and require anticipation of the proportion of potential patients finally recruited. Because most recent drug studies for dementia have similar requirements, it could be helpful to analyze the recruitment rate of recent studies. Records of demented patients candidates for drug trials for treatment of dementia of the Alzheimer type in 1994-1995 were analyzed for recruitment rate and reasons for nonrecruitment. From 279 patients with dementia of the Alzheimer type, only 13% were finally included in drug studies. The main reasons for non-enrollment included (1) cognitive test scores out of range for study inclusion criteria (Mini-Mental State Examination [MMSE] <12 [30%], MMSE >24 [5%]), (2) behavioral disturbances (25%), and (3) concomitant diseases (12%). Consent was refused in 8% of those to whom the experimental drug was offered. This low rate of enrollment, 13% of potential candidates, does not include postrecruitment drop-out cases, nor the availability of nonexperimental therapy for DAT. Further, the high selection may limit the generalizability of the results of such studies.

Denbufylline in dementia: a double-blind controlled study.

The xanthine derivative denbufylline has been evaluated in the treatment of cognitive dysfunction in 110 patients with vascular or mixed dementia (VD) and 226 patients with dementia of the Alzheimer type (DAT). After a run-in period of 4 weeks, during which all patients received placebo, the patients were randomly allocated to denbufylline 25, 50 or 100 mg or to placebo given twice daily for 16 weeks. By the end of the study (completed by 68% of the patients), but also at enrollment, the scores obtained on the Mini-Mental State Examination (MMSE) were higher among those who had received denbufylline than among those who had received placebo, but the differences were not statistically significant; a dose effect of denbufylline was not observed and there was no significant difference in the mean scores of the digit substitution subtest (DSST) of the Wechsler memory test. The responses of patients with VD were similar to those of patients with DAT. When patients were compared in terms of those who received denbufylline versus those who received placebo, improvement in the MMSE scores was observed in 46% of the patients who received placebo and 67% among those who received denbufylline (p < 0.05). An inverse relationship was found between the improvement that occurred during the run-in period and that observed by the end of the study, had the patients received denbufylline or placebo. No major adverse event was ascribed to denbufylline. In conclusion, denbufylline was not deemed efficacious in the treatment of DAT or VD, although patients who received denbufylline tended to improve in terms of cognitive scores, but the effects were not statistically significant. MMSE scores were found to be higher among patients who received denbufylline when these latter were combined as a single group, regardless of their diagnosis or dosage regimen. A placebo effect was observed in about half the patients who completed the study. Copyrightz1999S.KargerAG, Basel

Postmeningitis headache.

Acute meningitis is associated with headache, but the natural history of the headache following recovery is unknown. We addressed this issue in 141 patients admitted during 1990 to 1993 with laboratory-confirmed meningitis. We excluded patients younger than 5 years (n=44), elderly demented patients (n=6), and those with potential causes of headache other than meningitis (n=4). Seventeen candidates could not be traced. The remaining 70 patients were interviewed using a semistructured questionnaire that documented age, sex, type of meningitis, time of headache onset after infection, and headache description as well as any past and/or family history of headache. These patients were compared to age- and sex-matched controls (n=70). Prior to meningitis, 13 patients (19%) had had headaches (migrainous in 8) as did 18 controls (26%; migrainous in 8). Headache first appeared after meningitis in 19 patients (33%; migrainous in 6), increasing the total prevalence to 46%. We found no association between sex, type of meningitis, or family history and the development of postmeningitis headache. Patients who developed postmeningitis headache were significantly younger than those who did not. We conclude that there is an association between meningitis, either bacterial or aseptic, and subsequent persistent recurrent migrainous or nonmigrainous headache.