Rodolfo Savica

Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

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.

Medical records documentation of constipation preceding Parkinson disease: A case-control study

Objective: Parkinson disease (PD) may affect the autonomic nervous system and may cause constipation; however, few studies have explored constipation preceding the motor onset of PD. We investigated constipation preceding PD using a case-control study design in a population-based sample. Methods: Using the medical records-linkage system of the Rochester Epidemiology Project, we identified 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to ascertain the occurrence of constipation preceding the onset of PD (or index year). Results: Constipation preceding PD or the index year was more common in cases than in controls (odds ratio [OR] 2.48; 95% confidence interval [CI] 1.49 to 4.11; p = 0.0005). This association remained significant after adjusting for smoking and coffee consumption (ever vs never), and after excluding constipation possibly induced by drugs. In addition, the association remained significant in analyses restricted to constipation documented 20 or more years before the onset of motor symptoms of PD. Although the association was stronger in women than in men and in patients with PD with rest tremor compared with patients with PD without rest tremor, these differences were not significant. Conclusions: Our findings suggest that constipation occurring as early as 20 or more years before the onset of motor symptoms is associated with an increased risk of Parkinson disease.

Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging

BACKGROUND The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals. METHODS The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions. RESULTS Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed. CONCLUSIONS Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.

Prescribing patterns of antiepileptic drugs in Italy : a nationwide population-based study in the years 2000-2005

To evaluate prevalence of use and prescribing patterns of antiepileptic drugs (AEDs) in Italian general practice. Primary care data were obtained from the Health Search Database, a longitudinal observational database implemented by the Italian College of General Practitioners (GPs). We selected 465 061 subjects registered by the end of 2005 in the lists of 320 GPs, homogeneously distributed throughout Italy. Prevalence of AED use was assessed in the entire sample and by drug type, age group, year and main geographic area (north, centre and south/islands). Overall, 24 383 subjects (5.2%) received at least one AED prescription in the study period. Prevalence of AED use (with 95% confidence interval) increased progressively from 7.1 (6.9–7.3) in 2000 to 11.8 (11.5–12.1) in 2005 for old AEDs and from 1.1 (1.0–1.2) to 12.2 (11.9–12.5) for new AEDs. Carbamazepine, phenobarbital and valproic acid were the most common AEDs until 2003, when gabapentin became first. There were no differences in prescribing patterns in the three main geographic areas. Newer AEDs were mostly used in patients aged 65 years and older. The more widespread use of newer AEDs was for mood disorders or pain. Older AED currently remain first line drugs for epileptic disorders. An increasing use of AEDs has been recently observed over a 6‐year period in Italian general practice, mostly explained by newer compounds used for conditions other than epilepsy.

High School Football and Risk of Neurodegeneration: A Community-Based Study

OBJECTIVE To assess whether high school football played between 1946 and 1956, when headgear was less protective than today, was associated with development of neurodegenerative diseases later in life. METHODS All male students who played football from 1946 to 1956 in the high schools of Rochester, Minnesota, plus a non-football-playing referent group of male students in the band, glee club, or choir were identified. Using the records-linkage system of the Rochester Epidemiology Project, we reviewed (from October 31, 2010, to March 30, 2011) all available medical records to assess later development of dementia, Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS). We also compared the frequency of dementia, PD, or ALS with incidence data from the general population of Olmsted County, Minnesota. RESULTS We found no increased risk of dementia, PD, or ALS among the 438 football players compared with the 140 non-football-playing male classmates. Parkinson disease and ALS were slightly less frequent in the football group, whereas dementia was slightly more frequent, but not significantly so. When we compared these results with the expected incidence rates in the general population, only PD was significantly increased; however, this was true for both groups, with a larger risk ratio in the non-football group. CONCLUSION Our findings suggest that high school students who played American football from 1946 to 1956 did not have an increased risk of later developing dementia, PD, or ALS compared with non-football-playing high school males, despite poorer equipment and less regard for concussions compared with today and no rules prohibiting head-first tackling (spearing).

Incidence of Dementia With Lewy Bodies and Parkinson Disease Dementia

IMPORTANCE Epidemiologic data on dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) remain limited in the United States and worldwide. These data are essential to guide research and clinical or public health interventions. OBJECTIVE To investigate the incidence of DLB among residents of Olmsted County, Minnesota, and compare it with the incidence of PDD. DESIGN The medical records linkage system of the Rochester Epidemiology Project was used to identify all persons who developed parkinsonism and, in particular, DLB or PDD from 1991 through 2005 (15 years). A movement disorders specialist reviewed the complete medical records of each suspected patient to confirm the diagnosis. SETTING Olmsted County, Minnesota, from 1991 through 2005 (15 years). PARTICIPANTS All the residents of Olmsted County, Minnesota, who gave authorization for medical record research. MAIN OUTCOMES AND MEASURES Incidence of DLB and PDD. RESULTS Among 542 incident cases of parkinsonism, 64 had DLB and 46 had PDD. The incidence rate of DLB was 3.5 per 100,000 person-years overall, and it increased steeply with age. The incidence of PDD was 2.5 overall and also increased steeply with age. The incidence rate of DLB and PDD combined was 5.9. Patients with DLB were younger at onset of symptoms than patients with PDD and had more hallucinations and cognitive fluctuations. Men had a higher incidence of DLB than women across the age spectrum. The pathology was consistent with the clinical diagnosis in 24 of 31 patients (77.4%) who underwent autopsy. CONCLUSIONS AND RELEVANCE The overall incidence rate of DLB is lower than the rate of Parkinson disease. The incidence of DLB increases steeply with age and is markedly higher in men. This men to women difference may suggest different etiologic mechanisms. Our findings may guide health care planning and prompt new studies.

Plasma Ceramide and Glucosylceramide Metabolism Is Altered in Sporadic Parkinson's Disease and Associated with Cognitive Impairment: A Pilot Study

Background Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinsons disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition. Methods Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS. Results Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment. Conclusion These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.

Salivary Phosphate-Binding Chewing Gum Reduces Hyperphosphatemia in Dialysis Patients

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders, only half of hemodialysis (HD) patients achieve recommended serum phosphate levels. A hyperphosphoric salivary content, which correlates linearly with serum phosphate, has been reported in HD patients. We hypothesized that binding salivary phosphate during periods of fasting in addition to using phosphate binders with meals could improve the treatment of hyperphosphatemia. We assessed the phosphate-binding capacity of the natural polymer chitosan by (31)P nuclear magnetic resonance and established that 10 and 20% (wt/vol) middle viscosity chitosan solutions bind 30 and 50% of the phosphate contained in PBS, respectively. Thirteen HD patients with serum phosphate levels >6.0 mg/dl despite treatment with sevelamer hydrochloride chewed 20 mg of chitosan-loaded chewing gum twice daily for 2 wk at fast in addition to their prescribed phosphate-binding regimen. Salivary phosphate and serum phosphate significantly decreased during the first week of chewing; by the end of 2 wk, salivary phosphate decreased 55% from baseline (73.21 +/- 19.19 to 33.19 +/- 6.53; P < 0.00001), and serum phosphate decreased 31% from baseline (7.60 +/- 0.91 to 5.25 +/- 0.89 mg/dl; P < 0.00001). Salivary phosphate returned to baseline by day 15 after discontinuing the chewing gum, whereas serum phosphate levels took 30 d to return to baseline. Parathyroid hormone and serum calcium concentrations were not affected by the gum. In conclusion, adding salivary phosphate binding to traditional phosphate binders could be a useful approach for improving treatment of hyperphosphatemia in HD patients.

Incidence and pathology of synucleinopathies and tauopathies related to parkinsonism.

IMPORTANCE The frequency and distribution of synucleinopathies and tauopathies manifesting with parkinsonism in the general population are poorly understood, thus affecting health care planning and research. OBJECTIVE To investigate the incidence and distribution of specific types of parkinsonism and related proteinopathies. DESIGN We used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects who received a screening diagnostic code related to parkinsonism in Olmsted County, Minnesota, from January 1, 1991, through December 31, 2005 (15 years). A movement disorders specialist reviewed the complete medical records of each subject who screened positive to determine the type of parkinsonism and the presumed proteinopathy using specified criteria. SETTING Geographically defined population. PARTICIPANTS All residents of Olmsted County who provided authorization to use their data for medical records research (population-based sample). MAIN OUTCOME AND MEASURES Incidence of parkinsonism and specific proteinopathies. RESULTS Among 542 incident cases of parkinsonism, 409 (75.5%) were classified as proteinopathies. Of the 389 patients with presumed synucleinopathies (71.8%), 264 had Parkinson disease (48.7% of all cases). The incidence rate of synucleinopathies was 21.0 per 100 000 person-years overall and increased steeply with age. The incidence rate of tauopathies was 1.1 overall (20 cases), and the most common tauopathy was progressive supranuclear palsy (16 cases). Thirty-six subjects had drug-induced parkinsonism (6.6%), 11 had vascular parkinsonism (2.0%), 1 had amyotrophic lateral sclerosis in parkinsonism (0.2%), 1 had parkinsonism secondary to surgery (0.2%), and 84 remained unspecified (15.5%). Men had a higher incidence than women for most types of parkinsonism. Findings at brain autopsy confirmed the clinical diagnosis in 53 of 65 patients who underwent autopsy (81.5%). CONCLUSIONS AND RELEVANCE The incidence of proteinopathies related to parkinsonism increases steeply with age and is consistently higher in men than women. Clinically diagnosed synucleinopathies are much more common than tauopathies. Findings at autopsy confirm the clinical diagnosis of presumed proteinopathy. Our findings may guide health care planning and prompt new research directions.