The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.
The rarity of young-onset dementia (YOD), the broad differential diagnosis and unusual clinical presentations present unique challenges to correctly recognize the condition and establish an accurate diagnosis. Limited data exist regarding clinical features associated with dementia prior to the age of 45.
We retrospectively assessed cognitive and noncognitive neurological characteristics of 235 patients who presented for evaluation of YOD to investigate the clinical characteristics of YOD compared to later-onset dementias and to identify clinical features associated with specific etiologies that may aid in the evaluation of YOD.
Multiple cognitive domains were affected in most patients, and no significant differences in affected domains existed between groups. Early psychiatric and behavioral features occurred at very high frequencies. Nearly 80% of this YOD cohort had additional noncognitive symptoms or signs as a feature of their disease. Chorea was strongly associated with Huntington disease. Parkinsonism was not seen in patients having an autoimmune/inflammatory etiology.
The rarity of YOD and the high frequency of early psychiatric features led to frequent misdiagnosis early in the clinical course. The high frequency of noncognitive symptoms and signs may aid clinicians in distinguishing patients requiring a more extensive evaluation for YOD.
Young-onset dementia; Cognitive decline, age of onset; Presenile dementia, clinical features
In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors.
Cross-sectional analysis of 7,199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score.
Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values<0.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p<0.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p<0.001).
The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.
screening; cerebrovascular disorders; epidemiology; memory; semantic fluency; depression
The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually.
Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants.
Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.
Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.
Multispecialty group academic medical center.
Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.
Main Outcome Measure
Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.
We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.
MRI; progranulin; frontotemporal dementia; PGRN
Seizures have been recognized to occur in multiple sclerosis since early descriptions of the disease. Various studies have attempted to determine the incidence and prevalence of seizures in multiple sclerosis; although they differ in the reported prevalence, seizures do appear to be more common in multiple sclerosis cohorts than in the general population.
The pathological underpinning of seizures in multiple sclerosis remains indeterminate. Cortical and subcortical demyelination and inflammation may explain the increased frequency of seizures in multiple sclerosis, although this hypothetical correlation remains to be proven.
Management of seizures in multiple sclerosis is similar to the management of seizures in other patients. Consideration of the underlying neurological deficits related to multiple sclerosis may be necessary, and dosages should be adjusted if increased sensitivity to antiepileptic side effects or interaction with other centrally-acting medications is suspected. The prognosis of epilepsy in patients with MS remains uncertain, with some studies suggesting a more favorable prognosis than others.
Multiple sclerosis; seizure; epilepsy
To characterize a cohort of individuals who have experienced rapidly progressive dementia with onset prior to age 45.
Very little data regarding the clinical features or clinical spectrum of rapidly progressive young-onset dementia (RP-YOD) is available, primarily consisting of case reports or small series.
A search of the Mayo Clinic medical record was employed to identify patients who had onset prior to age 45 of rapidly progressive dementia. All available medical records, laboratory data, neuroimaging studies, and pathological data were reviewed.
Twenty-two patients met the pre-defined inclusion and exclusion criteria. Behavioral and affective disorders, cerebellar dysfunction and visual and/or oculomotor dysfunction were common early clinical features within the cohort, as were clinical features often associated with Creutzfeldt-Jakob disease (CJD). Diagnostic testing identified an etiology in most patients.
Presentations of RP-YOD result from a variety of etiologies and significant overlap in clinical features is observed. Clinical features often associated with CJD appear to be common within the entire cohort of RP-YOD patients. Diagnostic studies aided in establishing a diagnosis in most patients, however five had uncertain diagnoses despite exhaustive evaluation.
rapidly progressive dementia; young-onset dementia; presenile dementia; Creutzfeldt-Jakob disease; young-onset
Alternative medicine has an extensive worldwide history and is commonly used by older patients. A number of different alternative medicines are used by patients having Alzheimer's disease. It is both desirable and expected for clinicians to be acquainted with these medications.
This paper discusses the available clinical trial evidence regarding eight agents commonly used by people having Alzheimer's disease. We provide an overview of the history and basic scientific evidence available for each agent, followed by a critical analysis of the evidence available from clinical trials, including the number of participants, trial duration and specific outcomes evaluated.
While many of these compounds have been associated with interesting basic science, none has shown clear clinical benefit to date. Data available for some, such as ginkgo biloba, curcumin and huperzine A, suggest that further evaluation is warranted. Familiarity with this literature will allow clinicians to provide meaningful recommendations to patients who wish to use these agents.
Alzheimer's disease; alternative medicine; ginkgo biloba; huperzine A; piracetam
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.
To perform a pilot study to examine a range of cognitive flexibility tasks early in cocaine withdrawal.
Previous neuropsychological investigations of cocaine withdrawal have conflicted regarding whether impaired cognitive flexibility occurs. However, most studies have examined patients later in withdrawal. Anxiety and yohimbine-induced panic are greatest early in withdrawal, and both anxiety and increased noradrenergic tone can impair cognitive flexibility.
Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence–matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention.
As predicted, impairments were found on the cognitive flexibility tasks. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention.
We propose that the cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic networks. Further research will explore the effects of pharmacologic manipulation of the noradrenergic system on cognition in acute withdrawal. Recently, propranolol has been shown to benefit patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response.
cocaine; withdrawal; cognitive flexibility; memory; language; norepinephrine; neuropsychology