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Background and Objectives: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use., Results: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use., Discussion: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia., Classification of Evidence: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background and Objectives: Estrogen has the potential to influence brain physiology implicated in dementia pathogenesis. Hormone replacement therapy (HRT) might be expected to influence the risk of dementia. Observational data indicated that HRT was associated with reductions in dementia risk, but experimental evidence demonstrates that HRT increases the incidence of dementia. To determine the effect of HRT on the risk of dementia, a retrospective cohort study was performed using a nationwide claims dataset in Taiwan., Methods: A population-based longitudinal study was performed using data from the Longitudinal Health Insurance Database in Taiwan. A total of 35,024 women with HRT were enrolled as the exposed cohort and 70,048 women without HRT were selected on the basis of propensity matching as the comparison cohort. All participants were followed up until the diagnosis of dementia, death, or at the end of December 31, 2013, whichever occurred first. Overall, the average duration of follow-up (±SD) in the HRT and comparison cohorts was 12.3 (±2.3) and 12.2 (±2.4), respectively. The Cox proportional hazards regression models were conducted to produce hazard ratios (HRs) with 95% CIs to evaluate the association of HRT with the risk of dementia., Results: In the follow-up period, the cumulative incidence of dementia for the HRT cohort (20.04 per 1,000) was significantly higher than the corresponding cumulative incidence for the comparison cohort (15.79 per 1,000), resulting in an adjusted HR of 1.35 (95% CI 1.13-2.62). There was an increased risk of dementia with a higher cumulative dose of HRT prescription ( p for trend <0.0001)., Discussion: This cohort study documented that HRT was associated with an increased risk of dementia. The clinical implications of this study merit further investigations., (© 2022 American Academy of Neurology.)

Objective: To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas., Methods: This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia., Results: We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61-0.73) and 0.78 (95% CI 0.72-0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79-0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87-1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63-0.91), had good renal function (HR 0.86; 95% CI 0.76-0.97), and were white (HR 0.87; 95% CI 0.77-0.99)., Conclusions: After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia., (© 2017 American Academy of Neurology.)

Objectives: To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions., Methods: Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables., Results: Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm(3)) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90)., Conclusions: Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.

Objective: To study cycad-derived products as possible risk factors for dementia, mild cognitive impairment (MCI), and parkinsonism-dementia complex (PDC) on Guam., Methods: Complete risk factor data from in-person interviews of 166 cases of Guam dementia, 50 cases of amnestic MCI, and 21 cases of PDC were compared with 1,581 controls in the base population regarding exposure to cycad-derived products from a traditional food (fadang), consumption of fruit bats, and use of cycad-derived topical medicine., Results: Adjusted odds ratios (ORs) and 95% CIs for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05 to 1.91) to 2.87 (1.48 to 5.56) and were consistently elevated and significant across all three diagnostic outcomes. Associations independent of exposure in young adulthood were for picking (OR 0.78, 95% CI 0.64 to 0.96) and processing (OR 0.77, 95% CI 0.63 to 0.94) fadang in childhood with Guam dementia. Men showed stronger and more consistent relations across exposure groups in young adulthood compared with women. No associations were found for consumption of fruit bats or exposure to cycad used as a topical medicine for any of the outcomes. Estimated adjusted population attributable risks suggest that exposure to eating fadang in young adulthood incurred the highest attributable risk percent., Conclusions: Environmental lifestyle and diet may contribute to the etiology of neurodegenerative diseases in the native population of Guam.

The authors studied a 72-year-old man with polymyalgia rheumatica who, after taking 100 mg of prednisone for 3 months, developed a psychosis followed by dementia. It was initially considered that the dementia was a separate neurodegenerative condition, probably of Alzheimer type, but when steroids were discontinued, he rapidly returned to his previous level of functioning. Reviewing the literature regarding the effects of steroids on cerebral function, the authors found that such cases of "reversible dementia" are not uncommon, although rarely given the emphasis they deserve. The authors believe, given the extensive use of steroids in medical practice, that physicians should be more aware of this important cause of reversible dementia.

Background: Treatment-related leukoencephalopathy is the leading toxicity after successful treatment of primary CNS lymphoma (PCNSL). Its mechanism is poorly understood and there are no autopsy data available on such patients., Methods: From a database of immunocompetent patients with PCNSL diagnosed between 1985 and 2001, the authors identified five autopsied patients who died of leukoencephalopathy. The authors reviewed their clinical records, MRI, and autopsy findings., Results: The median age was 74 years (range 41 to 79) at PCNSL diagnosis. Symptoms of neurotoxicity developed a median of 1 month after treatment completion, and median survival was 30 months (range 22 to 68 months) after neurotoxicity onset. All had white matter hyperintensity on T2-weighted MRI, and two developed enhancing lesions 5 and 14 months following completion of treatment. At autopsy no PCNSL was identified. Myelin and axonal loss, gliosis, pallor, spongiosis, and rarefaction of the white matter were found in all; two patients had tissue necrosis that correlated with the enhancement on MRI, and one had fibrinoid necrosis of vessels. Four of the five patients had atherosclerosis of large cerebral vessels in the circle of Willis and all had small vessel disease; two had recent strokes at autopsy., Conclusions: Treatment-induced leukoencephalopathy is not a late delayed consequence of neurotoxic treatment but can be seen very early in some patients. Vascular disease may be a component of this white matter injury.

Objective: To monitor the evolution of hallucinations over 4 years in a stratified sample of patients with PD., Methods: Using a modified version of the Unified PD Rating Scale (UPDRS) Thought Disorder question, the authors stratified patients into five baseline behavioral groups. They recruited up to 20 patients for each group to participate in sequential interviews (Rush Hallucination Inventory) at baseline and 6, 18, and 48 months. UPDRS motor examinations and Mini Mental State Examinations (MMSE) were obtained at baseline and 48 months. Data were analyzed with Wilcoxon rank sum tests, Mantel-Haenszel tests, and Spearman correlations. To determine features that influenced the new development of hallucinations, a cumulative logit regression model of hallucination severity over time was fit using generalized estimating equations., Results: Based on the design stratification, 60 patients had no hallucinations at baseline (20 with no behavioral problems, 20 with sleep fragmentation, 20 with altered dream phenomena). Twenty-nine patients had hallucinations (20 with retained insight and 9 with loss of insight). At 48 months, the authors could account for all but two subjects (98% retrieval). In 4 years, the presence of hallucinations increased (33% at baseline, 44% at 18 months, and 63% at 48 months, p < 0.0001). The presence of frequent hallucinations (at least three times weekly) also increased (p = 0.0002). Having hallucinations at baseline or at any given assessment was a strong predictor at all follow-up evaluations of continued hallucinations (p < 0.0001). Hallucinations were not associated with increased mortality (chi(2) = 0.59, df (1), p = 0.47). Among the 60 subjects without hallucinations at baseline, time was the only significant factor influencing the development of hallucination over 48 months. Baseline age, PD duration, sex, medications, and UPDRS or MMSE scores did not influence the incidence of hallucinations., Conclusions: This prospective, longitudinal study documents the persistent and progressive nature of hallucinations in PD patients on chronic dopaminergic therapy. The consistent association of hallucinations with combined levodopa/agonist therapy suggests that these drugs may play a role in the pathophysiology of hallucinations.

We reviewed the histories of patients seen in a large Parkinson's disease clinic from 1983 to 1989 to determine if there is a relationship between the timing of initiation of levodopa therapy and the development of motor response fluctuations, dyskinesias, and dementia. There were no factors predisposing to the development of response fluctuations or dementia. Younger age at disease onset predisposed to the development of dyskinesia. Dyskinesias occurred in a greater proportion of patients in whom the initiation of levodopa therapy was delayed by more than 2 years from disease diagnosis than among those in whom treatment was started earlier. We thus failed to identify any adverse consequences of early levodopa treatment in our patient population.

We studied 14 chronic toluene abusers with a comprehensive neuropsychological evaluation and cerebral magnetic resonance imaging (MRI). There were 10 men and 4 women, and the mean age was 29 years. Using a blinded global assessment of neuropsychological functioning, we found 3 patients to be normal, 3 in a borderline range, and 8 impaired. Independent analyses of white matter changes on MRI disclosed that the degree of white matter abnormality was strongly correlated (p less than 0.01) with neuropsychological impairment. Dementia in toluene abuse appears to be related to severity of cerebral white matter involvement.

Mental symptoms increased in frequency among 100 patients with parkinsonism treated with levodopa. Dementia was found in about one-third of patients throughout the 6-year treatment period. Thirteen patients became demented during the study, and dementia worsened severely in seven others. Agitated confusion became increasingly frequent and was observed in 60 percent of patients taking levodopa for 6 years. Withdrawal from levodopa decreased agitation, but not dementia. Ten patients received L-tryptophan along with levodopa, but no change in mentation was observed. In view of previous studies of mentation in Parkinson's disease and reports of widespread neuronal changes in the brain of autopsied patients with parkinsonism, our results suggest that the high incidence of dementia in patients with Parkinson's disease who take levodopa reflects prolongation of the course of the illness rather than a direct effect of the medication.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.

We analyzed multiple trace elements in tap water, dialysis fluids, and CSF of patients on dialysis and with chronic renal insufficiency. Before placement of a deionizer in the dialysis unit, we found elevated levels of aluminum, barium, copper, silicon, and zinc in tap water and dialysis fluids. These were corrected by the deionizer. CSF silicon content was increased in patients with chronic renal insufficiency and on dialysis; CSF aluminum, barium, copper, and zinc were normal.

Acute encephalopathy caused by gasoline sniffing is well recognized, but has been thought to be completely reversible. We report a patient who developed a progressive encephalopathy characterized by ataxia, tremor and dementia following repeated, deliberate gasoline inhalation. Blood and urine lead levels were consistently elevated and at autopsy, the formalin-fixed brain lead content was between 5200 and 6500 micrograms/100 gm of tissue. This case shows that repeated gasoline sniffing can result in irreversible encephalopathy and that both the acute and chronic encephalopathy probably result from organic lead intoxication and not from the gasoline itself.