J. Eric Ahlskog

Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature

There is no clear consensus regarding the frequency (and hence, the risk), of dyskinesias or motor fluctuations during chronic levodopa therapy for Parkinsons disease (PD). Multiple clinical series have tabulated these frequencies since the advent of levodopa over 30 years ago. We were interested in determining: (1) the aggregate frequency figures in the existing literature; and (2) how clinical series from the early levodopa era, which included patients with longer durations of parkinsonism, compare to more recent (modern era) series.

Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study.

We studied the association between preceding psychiatric disorders and Parkinsons disease (PD) using a case‐control design. We used the medical records‐linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, Minnesota, during the years 1976–1995. Each case was matched by age (±1 yr) and sex to a general population control. We reviewed the complete medical records of cases and control subjects to detect preceding psychiatric disorders. The frequency of psychiatric disorders was higher in cases than in control subjects; the odds ratio was 2.2 for anxiety disorders (95% confidence interval [95% CI] = 1.4–3.4; p = 0.0003), 1.9 for depressive disorders (95% CI = 1.1–3.2; p = 0.02), and 2.4 for both anxiety disorders and depressive disorders occurring in the same individual (95% CI = 1.2–4.8; p = 0.02). When we restricted analyses to disorders present 5 years or more before the onset of motor symptoms of PD, the association with depressive disorders lost statistical significance. However, the association with anxiety disorders remained significant for disorders present 5, 10, or 20 years before onset of motor symptoms. Our results suggest that anxiety disorders and depressive disorders are associated with PD and that the causative process or the risk factors underlying PD are present many years before the appearance of motor symptoms.

Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging

A rapidly growing literature strongly suggests that exercise, specifically aerobic exercise, may attenuate cognitive impairment and reduce dementia risk. We used PubMed (keywords exercise and cognition) and manuscript bibliographies to examine the published evidence of a cognitive neuroprotective effect of exercise. Meta-analyses of prospective studies documented a significantly reduced risk of dementia associated with midlife exercise; similarly, midlife exercise significantly reduced later risks of mild cognitive impairment in several studies. Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls. Meta-analyses of RCTs of aerobic exercise in healthy adults were also associated with significantly improved cognitive scores. One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise. Animal studies indicate that exercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors by exercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans. Besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. Exercise should not be overlooked as an important therapeutic strategy.

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

Risk tables for parkinsonism and Parkinson's disease

We applied the incidence rates of parkinsonism and Parkinsons disease (PD) from Olmsted County, MN (1976-1990) to a hypothetical cohort undergoing the mortality rates observed in Minnesota, and computed the lifetime risk and the remaining lifetime risk of developing parkinsonism and PD. These risks were compared to cumulative incidences that do not take competing risks of death into account. The lifetime risk of developing parkinsonism from birth was 4.4% for men and 3.7% for women (ratio = 1.2). The corresponding risk of developing PD was 2.0% for men and 1.3% for women (ratio = 1.5). Because of the opposite effect of higher incidence and higher mortality rates in men, the lifetime risks were only slightly higher in men than in women. Lifetime cumulative incidences were consistently higher than lifetime risks; this difference was more pronounced in men and in older subjects. Lifetime risk estimates are useful in clinical practice, epidemiologic research, and public health.

Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration

Background: Copper deficiency in ruminants is known to cause an ataxic myelopathy. Copper deficiency as a cause of progressive myelopathy in adults is underrecognized. Objective: To describe the clinical, biochemical, electrophysiologic, and imaging characteristics in 13 patients with myelopathy associated with copper deficiency. Methods: The records of patients with a copper deficiency–associated myelopathy were reviewed. Clinical characteristics, laboratory investigations, and responses to therapeutic intervention were summarized. Results: Thirteen such patients were found, 11 of them in a 15-month period. All patients presented with prominent gait difficulty, reflecting a sensory ataxia due to dorsal column dysfunction and lower limb spasticity. All patients had polyneuropathy. A high or high-normal serum zinc level was seen in 7 of the 11 patients for whom this information was available. Somatosensory evoked potential studies done in eight patients showed impaired conduction in central proprioceptive pathways. Dorsal column signal change on spine MRI was present in three patients. An initial clue to the diagnosis was a very low ceruloplasmin level; further tests of copper metabolism excluded Wilson disease. The cause remained unexplained in most patients. Oral copper supplementation restored normal or near-normal copper levels in 7 of the 12 patients in whom adequate follow-up data were available; parenteral supplementation restored normal level in 3 further patients. Copper supplementation prevented further neurologic deterioration, but the degree of actual improvement was variable. Conclusions: Unrecognized copper deficiency appears to be a common cause of idiopathic myelopathy in adults. The clinical picture bears striking similarities to the syndrome of subacute combined degeneration associated with vitamin B12 deficiency. Early recognition and copper supplementation may prevent neurologic deterioration.

Does vigorous exercise have a neuroprotective effect in Parkinson disease

Parkinson disease (PD) is progressive, with dementia and medication-refractory motor problems common reasons for late-stage nursing-home placement. Increasing evidence suggests that ongoing vigorous exercise/physical fitness may favorably influence this progression. Parkinsonian animal models reveal exercise-related protection from dopaminergic neurotoxins, apparently mediated by brain neurotrophic factors and neuroplasticity (predicted from in vitro studies). Similarly, exercise consistently improves cognition in animals, also linked to enhanced neuroplasticity and increased neurotrophic factor expression. In these animal models, immobilization has the opposite effect. Brain-derived neurotrophic factor (BDNF) may mediate at least some of this exercise benefit. In humans, exercise increases serum BDNF, and this is known to cross the blood–brain barrier. PD risk in humans is significantly reduced by midlife exercise, documented in large prospective studies. No studies have addressed whether exercise influences dementia risk in PD, but exercised patients with PD improve cognitive scores. Among seniors in general, exercise or physical fitness has not only been associated with better cognitive scores, but midlife exercise significantly reduces the later risk of both dementia and mild cognitive impairment. Finally, numerous studies in seniors with and without dementia have reported increased cerebral gray matter volumes associated with physical fitness or exercise. These findings have several implications for PD clinicians. 1) Ongoing vigorous exercise and physical fitness should be highly encouraged. 2) PD physical therapy programs should include structured, graduated fitness instruction and guidance for deconditioned patients with PD. 3) Levodopa and other forms of dopamine replenishment therapy should be utilized to achieve the maximum capability and motivation for patients to maintain fitness.

When Does Parkinson Disease Start

There is convincing evidence that the Parkinson disease neurodegenerative process begins many years before the onset of motor manifestations. Initial estimates based on nigral neuropathological findings or striatal dopamine imaging suggested a 5- to 6-year preclinical period. However, more recent evidence of Lewy body pathology in other neuronal populations preceding nigral involvement suggests that the preclinical phase may be much longer. Epidemiologic studies of nonmotor manifestations, such as constipation, anxiety disorders, rapid eye movement sleep behavior disorder (RBD), and anemia, suggest that the preclinical period extends at least 20 years before the motor manifestations. Olfactory impairment and depression may also precede the onset of motor manifestations; however, the lag time may be shorter. Recognition of a nonmotor preclinical phase spanning 20 or more years should guide the search for predictive biomarkers and the identification of risk or protective factors for Parkinson disease.

Early-onset familial parkinsonism due to POLG mutations

To define the molecular etiology of early‐onset parkinsonism and peripheral neuropathy.

Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: An exploratory case‐control study

We studied the association of Parkinsons disease (PD) with type of menopause (natural or surgical), age at menopause, and postmenopausal estrogen replacement therapy using a case‐control design. We used the medical records‐linkage system of the Rochester Epidemiology Project to identify 72 women who developed PD in Olmsted County, MN, during the twenty years 1976–1995. Each incident case was matched by age (± 1 year) to a general population control subject. We collected exposure data through review of the complete medical records of cases and control subjects in the system. PD cases had undergone hysterectomy (with or without unilateral oophorectomy) significantly more often than control subjects (odds ratio [OR] = 3.36; 95% confidence interval [CI] = 1.05–10.77). In addition, PD cases had experienced early menopause (≤ 46 years) more commonly than control subjects (OR = 2.18; 95% CI = 0.88–5.39). Finally, PD cases had used estrogens orally or parenterally for at least 6 months after menopause less frequently (8%) than control subjects (14%; OR = 0.47; 95% CI = 0.12–1.85). However, the findings for early menopause and estrogen replacement therapy were not statistically significant. Despite the limited sample size of this exploratory study, we hypothesize that there is an increased risk of PD in conditions causing an early reduction in endogenous estrogen. This hypothesis needs to be confirmed in a larger study.