Inferior Frontal Sulcal Hyperintensities on Brain MRI Are Associated with Amyloid Positivity beyond Age-Results from the Multicentre Observational DELCODE Study.

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aß42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05-3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57-2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00-1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26-0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid ß beyond age.

Conflict adaptation and related neuronal processing in Parkinson's disease.

Non-motor symptoms like cognitive impairment are a huge burden for patients with Parkinson's disease. We examined conflict adaptation by using the congruency sequence effect as an index of adaptation in 17 patients with Parkinson's disease and 18 healthy controls with an Eriksen flanker task using functional magnet resonance imaging to reveal possible differences in executive function performance. We observed overall increased response times in patients with Parkinson's disease compared to healthy controls. A flanker interference effect and congruency sequence effect occurred in both groups. A significant interaction of current and previous trial type was revealed, but no effect of response sequence concerning left or right motor responses. Therefore, top-down conflict monitoring processes are likely the main contributors leading to the congruency sequence effect in our paradigm. In both groups incongruent flanker events elicited activation in the middle temporal gyrus, inferior parietal cortex, dorsolateral prefrontal cortex and the insula in contrast to congruent flanker events. A psychophysiological interactions analysis revealed increased functional connectivity of inferior parietal cortex as a seed to the left prefrontal thalamus during incongruent vs. congruent and neutral stimuli in patients with Parkinson's disease that may reflect compensatory facilitating action selection processes. We conclude that patients with Parkinson's disease exhibit conflict adaptation comparable to healthy controls when investigated while receiving their usual medication.

Longitudinal Neurocognitive and Pulmonological Profile of Long COVID-19: Protocol for the COVIMMUNE-Clin Study.

BACKGROUND: There is a dearth of information about "brain fog," characterized by concentration, word-finding, or memory problems, which has been listed in the new World Health Organization provisional classification "U09.9 Post-COVID-19 Condition." Moreover, the extent to which these symptoms may be associated with neurological, pulmonary, or psychiatric difficulties is unclear. OBJECTIVE: This ongoing cohort study aims to carefully assess neurocognitive function in the context of the neurological, psychiatric, and pulmonary sequelae of SARS-CoV-2 infection among patients with asymptomatic/mild and severe cases of COVID-19 after remission, including actively recruited healthy controls. METHODS: A total of 150 participants will be included in this pilot study. The cohort will comprise patients who tested positive for SARS-CoV-2 infection with either an asymptomatic course or a mild course defined as no symptoms except for olfactory and taste dysfunction (n=50), patients who tested positive for SARS-CoV-2 infection with a severe disease course (n=50), and a healthy control group (n=50) with similar age and sex distribution based on frequency matching. A comprehensive neuropsychological assessment will be performed comprising nuanced aspects of complex attention, including language, executive function, verbal and visual learning, and memory. Psychiatric, personality, social and lifestyle factors, sleep, and fatigue will be evaluated. Brain magnetic resonance imaging, neurological and physical assessment, and pulmonological and lung function examinations (including body plethysmography, diffusion capacity, clinical assessments, and questionnaires) will also be performed. Three visits are planned with comprehensive testing at the baseline and 12-month visits, along with brief neurological and neuropsychological examinations at the 6-month assessment. Blood-based biomarkers of neurodegeneration will be quantified at baseline and 12-month follow-up. RESULTS: At the time of submission, the study had begun recruitment through telephone and in-person screenings. The first patient was enrolled in the study at the beginning of April 2021. Interim data analysis of baseline information is expected to be complete by December 2021 and study completion is expected at the end of December 2022. Preliminary group comparisons indicate worse word list learning, short- and long-delayed verbal recall, and verbal recognition in both patient cohorts compared with those of the healthy control group, adjusted for age and sex. Initial volumetric comparisons show smaller grey matter, frontal, and temporal brain volumes in both patient groups compared with those of healthy controls. These results are quite robust but are neither final nor placed in the needed context intended at study completion. CONCLUSIONS: To the best of our knowledge, this is the first study to include objective and comprehensive longitudinal analyses of neurocognitive sequelae of COVID-19 in an extreme group comparison stratified by disease severity with healthy controls actively recruited during the pandemic. Results from this study will contribute to the nascent literature on the prolonged effects of COVID-19 on neurocognitive performance via our coassessment of neuroradiological, neurological, pulmonary, psychiatric, and lifestyle factors. TRIAL REGISTRATION: International Clinical Trials Registry Platform DRKS00023806; https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00023806. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30259.

Teaching an old dog new tricks: serum troponin T as a biomarker in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Diagnosis, management and therapeutic trials are hampered by a lack of informative biomarkers. Troponins are components of skeletal and cardiac muscles. Acute elevation of cardiac isoforms of troponin I and T in serum indicates myocardial injury. Case reports suggested that serum levels of cardiac troponin T, but not cardiac troponin I are chronically elevated in myotrophic lateral sclerosis and other neuromuscular disorders. Using standard clinical laboratory methodologies, we studied serum troponin levels in a multicentric cross-sectional cohort of 75 amyotrophic lateral sclerosis patients and 30 Alzheimer's disease controls and 29 healthy controls (DESCRIBE-ALS cohort) and in a real-world cohort of 179 consecutive patients from our amyotrophic lateral sclerosis clinic at the University Hospital Bonn. We found that serum cardiac troponin T is elevated in >60% of amyotrophic lateral sclerosis patients, while cardiac troponin I is always normal. Serum cardiac troponin T levels increase over time and correlate with disease severity as measured with the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score. There was no correlation with the phosphorylated neurofilament heavy chain levels in the cerebrospinal fluid. We propose that cardiac troponin T elevations in amyotrophic lateral sclerosis are of non-cardiac origin and may serve as a proxy of lower motor neuron or skeletal muscle involvement. They potentially help to stratify patients according to lower motoneuron involvement. Further research will determine the biological origin of the cardiac troponin T elevation and its validity as a diagnostic and/or prognostic marker. Our finding also serves as a reminder to interpret cardiac troponin T elevations in patients with neuromuscular diseases with caution.

Interrelations of Alzheimer´s disease candidate biomarkers neurogranin, fatty acid-binding protein 3 and ferritin to neurodegeneration and neuroinflammation.

There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP-3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non-pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker-defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP-3 and neurogranin were elevated in subjects with pathological levels of t-tau independent of beta-amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM-1), and C1q. These interrelations existed in subjects with pathological and sub-pathological tau levels, in particular for FABP-3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non-pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP-3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD.

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study.

INTRODUCTION: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. METHODS: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. RESULTS: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. DISCUSSION: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

Botulinum neurotoxin serotype D - A potential treatment alternative for BoNT/A and B non-responding patients.

OBJECTIVES: Botulinum neurotoxin serotypes A and B (BoNT/A & B) are highly effective medicines to treat hyperactive cholinergic neurons. Due to neutralizing antibody formation, some patients may become non-responders. In these cases, the serotypes BoNT/C-G might become treatment alternatives. BoNT/D is genetically least related to BoNT/A & B and thereby circumventing neutralisation in A/B non-responders. We produced BoNT/D and compared its pharmacology with BoNT/A ex vivo in mice tissue and in vivo in human volunteers. METHODS: BoNT/D was expressed recombinantly in E. coli, isolated by chromatography and its ex vivo potency was determined at mouse phrenic nerve hemidiaphragm preparations. Different doses of BoNT/D or incobotulinumtoxinA were injected into the extensor digitorum brevis (EDB) muscles (n = 30) of human volunteers. Their compound muscle action potentials were measured 11 times by electroneurography within 220 days. RESULTS: Despite a 3.7-fold lower ex vivo potency in mice, a 110-fold higher dosage of BoNT/D achieved the same clinical effect as incobotulinumtoxinA while showing a 50% shortened duration of action. CONCLUSIONS: BoNT/D blocks dose-dependently acetylcholine release in human motoneurons upon intramuscular administration, but its potency and duration of action is inferior to approved BoNT/A based drugs. SIGNIFICANCE: BoNT/D constitutes a potential treatment alternative for BoNT/A & B non-responders.

Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1.

Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT. Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT.

Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease.

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease. ABBREVIATIONS: BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease.

BACKGROUND: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD. METHODS: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time. RESULTS: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories. CONCLUSIONS: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.

Occurrence of Crohn's disease with Parkinson's disease.

We retrospectively investigated the co-occurrence of Crohn's disease in a cohort of 876 patients with Parkinson's disease, based on the observation that LRRK2 is a shared genetic risk factor. We identified 2 patients with Crohn's disease; this number was consistent with the number of cases expected in the general population.

FTDP-17 with Pick body-like inclusions associated with a novel tau mutation, p.E372G.

Mutations in microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Here, we describe a patient with FTDP-17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40-year-old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP-17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP-17 due to p.E372G were similar to those of p.G389R, including tau-immunoreactive Pick body-like neuronal inclusions and swollen, tapering thread-like processes in white matter immunoreactive for 3-repeat and 4-repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP-17 similar to p.G389R.

Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers. METHODS: To estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls. RESULTS: LRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP. CONCLUSIONS: Our study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society.

Cancer in Parkinson's disease.

INTRODUCTION: We examined the prevalence of cancer in patients with Parkinson's disease (PD) and controls evaluated at the Mayo Clinic in Jacksonville, Florida, between 2003 and 2014. METHODS: We retrospectively collected information regarding cancer diagnoses and diagnosis of PD from 971 unrelated PD patients and 478 controls, and all were white. For PD patients, we examined cancers diagnosed before and after PD diagnosis separately in addition to considering all cancer diagnoses. RESULTS: Twenty different cancers were identified. In PD patients, the most common types of cancer were skin cancer (17.3% overall; 10.6% before PD), followed by nonmelanoma skin cancer (16.0% overall; 9.7% before PD), prostate cancer in men (12.8% overall; 9.2% before PD), breast cancer in women (10.6% overall; 6.3% before PD), and melanoma (2.4% overall; 1.1% before PD). Compared to controls, a significantly lower frequency of nonmelanoma skin cancer (odds ratio [OR]: 0.62, P = 0.0024) and any skin cancer (OR: 0.57, P = 0.0002) was observed in PD patients. These differences were greater when considering only cases with cancers that occurred before PD diagnosis (OR: 0.49, P < 0.0001; OR: 0.45, P < 0.0001, respectively), and there was a lower frequency of melanoma and any cancer preceding PD diagnosis compared to controls (OR: 0.31, P = 0.003; OR: 0.36, P < 0.0001). There was no evidence of a frequency difference for any other cancer. CONCLUSIONS: PD patients had a lower frequency of skin cancers or any cancer prior to PD diagnosis compared to controls, suggesting that cancer may have a protective effect on PD risk.

Hypertrophic olivary degeneration: A clinico-radiologic study.

INTRODUCTION: The frequency and causes of hypertrophic olivary degeneration (HOD) are unknown. We compared the clinical and radiological characteristics of unilateral HOD and bilateral HOD. METHODS: We performed a search of a radiologic report database for patients who were radiologically diagnosed as having HOD. This database includes the patients examined at the Mayo Clinic in Florida and Arizona. We used the search terms "hypertrophic olivary degeneration", "HOD", and "olivary" in the reports recorded from 1995 to 2015. Pertinent medical records and magnetic resonance imaging (MRI) scans of the brain for those with HOD were reviewed retrospectively. RESULTS: We identified 142 MRI studies on 95 cases who had radiologically proven HOD, 39 cases had unilateral HOD and 56 with bilateral HOD. In symptomatic cases, the most common symptom was ataxia. Palatal tremor was observed in almost half of all HOD cases. While cerebrovascular diseases were the most frequent etiology in both types of HOD (n = 24, 62% in unilateral; n = 17, 30% in bilateral), more than half of bilateral HOD cases had an unknown etiology (52%, n = 29), whereas only 13% (n = 5) of the unilateral cases had an unknown etiology (χ(2) test, P < 0.001). The lesions of unilateral HOD had a tendency to improve radiologically over time, whereas those associated with bilateral HOD were likely to worsen (χ(2) test, P < 0.05). CONCLUSIONS: Our study showed that bilateral HOD is more common than unilateral HOD. Half of bilateral HOD cases had no obvious cause and some worsened over time. This may implicate a possible primary neurodegenerative process.

Tremor in progressive supranuclear palsy.

INTRODUCTION: Tremor is thought to be a rare feature of progressive supranuclear palsy (PSP). METHODS: We retrospectively reviewed the database of the CurePSP brain bank at Mayo Clinic Florida to retrieve all available clinical information for PSP patients. All patients underwent a standard neuropathological assessment and an immunohistochemical evaluation for tau and α-synuclein. DNA was genotyped for the MAPT H1/H2 haplotype. RESULTS: Of the 375 PSP patients identified, 344 had a documented presence or absence of tremor, which included 146 (42%) with tremor, including 29 (20%) with postural/action tremors, 16 (11%) with resting tremor, 7 (5%) with intention tremor, 20 (14%) with a combination of different types of tremor, and 74 (51%) patients who had tremor at some point during their illness, but details were unavailable. The tremor severity of 96% of the patients (54/55) who had this data was minimal to mild. The probability of observing a tremor during a neurological examination during the patient's illness was estimated to be ∼22%. PSP patients with postural/action tremors and PSP patients with resting tremor responded to carbidopa-levodopa therapy more frequently than PSP patients without tremor, although the therapy response was always transient. There were no significant differences in pathological findings between the tremor groups. CONCLUSIONS: Tremor is an inconspicuous feature of PSP; however, 42% (146/344) of the PSP patients in our study presented some form of tremor. Because there is no curative therapy for PSP, carbidopa/levodopa therapy should be tried for patients with postural, action, and resting tremor.

Genetic Disorders with Tau Pathology: A Review of the Literature and Report of Two Patients with Tauopathy and Positive Family Histories.

BACKGROUND: Tauopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau protein within neurons and glia. Although most cases are sporadic, hereditary tauopathies have also been reported. SUMMARY: In this article, we review genetic disorders in which tau pathology has been reported and present two novel families with primary tauopathies. Mutations in the microtubule-associated protein tau gene (MAPT) cause a small subset of primary tauopathies. Mutations in 21 other genes and an 18q deletion syndrome have also been reported to be associated with tau pathology reminiscent of Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease or Pick's disease. In 8 of the 21 genes, tau pathology was only seen in cases with some 'specific' mutations. In the remaining genes, tau pathology, often in the form of Alzheimer-type neurofibrillary lesions, was a common finding but was 'not mutation specific'. The probands of the two families were diagnosed with progressive supranuclear palsy based on clinicopathological evaluation. Their family histories were relevant for parkinsonism in 3 siblings of family 1 and 1 brother and the father from family 2, but these were not autopsy-confirmed. DNA from the brains of the probands from these families was screened for MAPT and leucine-rich repeat kinase 2 gene mutations, but no mutations were identified. KEY MESSAGES: MAPT mutations are a cause of familial tauopathies, but other genes have also been associated with tau pathology. Novel genes still await discovery.

A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease.

Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner.