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ObjectiveTo describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.MethodsIn a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.ResultsFive of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.ConclusionA subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.

Background Gait and balance abnormalities are a significant source of morbidity and mortality in progressive supranuclear palsy (PSP). Gait impairment in PSP is primarily assessed clinically on exam or with the use of rating scales. Three dimensional video based gait and balance analysis performed in a laboratory setting is a highly accurate method of motion analysis (Wren et al., 2020), however limited data is available in patients with PSP. Research question In this study we assess the objective features of postural control, kinematics, kinetic and temporal-spatial gait metrics in PSP, using three-dimensional video motion analysis in a laboratory setting compared to normal controls. Methods Three-dimensional motion was captured using a 10-camera motion capture system, 41 body markers and ground embedded force plates in 16 patients with PSP patients and compared to motorically normal controls. Results Spatiotemporal, kinematic, and kinetic gait measures effectively differentiated patients with PSP from controls. Patients had slower gait velocity, lower cadence, increased double support time and abnormal antero-posterior sway. Joint kinematics and kinetics were reduced and showed less variation among patients with PSP compared to controls which is suggestive of bradykinesia. Objective gait measures of abnormality correlated with clinical disease severity. Postural sway metrics distinguished PSP from controls and captured gait imbalance. Significance Objective measures of gait and balance abnormalities in patients with PSP provide an outcome measure that can be potentially used for early disease detection, in clinical trials and to validate portable motion capture devices in the future.

Objective:To describe the phenotypes, treatment response, and outcome of IgLON5 autoimmunity.Methods:Archived serum and CSF specimens from 367 patients known to harbor unclassified antibodies which stained neural synapses diffusely (mimicking amphiphysin-IgG) were reevaluated by indirect immunofluorescence assay (IFA) using a composite of mouse tissues and recombinant IgLON5-transfected cell-based assay (CBA, Euroimmun).Results:Available specimens (serum, 25; CSF, 9) from 26/367 patients (7%) had identical IFA appearance and robust IgLON5 CBA positivity. Clinical information was available for 20/26 patients; 13 were women. Median disease-onset age was 62 years (range, 46–75 years). Most patients had insidious onset and progression of neurological symptoms affecting movement and sleep predominantly. Sleep disorders were sleep-disordered breathing (11) and parasomnias (3). Brainstem disorders were gait instability (14), dysphagia (10), abnormal eye movements (7), respiratory dysfunction (6), ataxia (5), craniocervical dystonia (3), and dysarthria (3). Findings compatible with hyperexcitability included myoclonus (3), cramps (3), fasciculations (2), and exaggerated startle (2). Neuropsychiatric disorders included cognitive dysfunction (6), psychiatric symptoms (5), and seizures (1). Dysautonomia, in 9, affected bladder function (7), gastrointestinal motility (3), thermoregulation (3), and orthostatic tolerance (1). Just 2 patients had coexisting autoimmune disease. Brain MRI findings were nonspecific and CSF was noninflammatory in all tested. Seven of 9 immunotherapy-treated patients improved: 6 of those 7 were stable at last follow-up. Three untreated patients died. Each IgLON5-IgG subclass (1–4) was readily detectable in ≥80% of specimens using CBA.Conclusions:IgLON5-IgG is diagnostic of a potentially treatable neurological disorder, where autoimmune clues are otherwise lacking.

The 4-repeat (4R)-tauopathies can be clinically heterogeneous and difficult to diagnose. An FDG-PET pattern of hypometabolism has been previously reported in clinically suspected 4R-tauopathies. Considering that pathological confirmation has not been used as inclusion criteria in these studies, however, the possibility exists that atypical cases were excluded. We studied pathologically confirmed cases of 4R-tauopathies to determine if FDG-PET patterns of hypometabolism different than those previously described exist. We identified all autopsy confirmed 4R-tauopathies with FDG-PET imaging performed between 2010 and 2013 within the Mayo Clinic database. Clinical features and FDG-PET imaging were compared to a group of normal controls. Ten patients, seven of which had autopsy-confirmed progressive supranuclear palsy (PSP), were identified. We also identified two cases with globular glial tauopathy (GGT) and one case of corticobasal degeneration (CBD). The overall predominant imaging findings included bilateral caudate hypometabolism in nine cases, mild asymmetric thalamic hypometabolism in eight, midbrain hypometabolism in seven, and bilateral hypometabolism in the supplementary motor area in seven. No differences were observed between PSP and GGT. The one CBD case had asymmetric parietal hypometabolism that was not seen in the PSP and GGT cases. As previously described, 4R-tauopathies are associated with frontal, caudate, midbrain and thalamic hypometabolism on FDG-PET. This is the first report of FDG-PET in GGT, and although our series was limited, no features distinguish GGT from PSP. There was some evidence that parietal hypometabolism may be suggestive of CBD.

Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubule-associated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN = 6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p = 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure. Neurology (R) 2011; 77: 393-398

Background: Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. Methods: This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. Results: All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. Conclusions: Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.

Neurodegenerative dementias are characterized by the deposition of soluble aberrant protein(s). β-Amyloid, the microtubule-associated protein tau, and α-synuclein are the most well-recognized proteins associated with neurodegenerative dementias. Recently, another protein, the transactive response DNA binding protein of 43 kDa (TDP-43), was discovered to play a major role in frontotemporal lobar degeneration (FTLD), a group of diseases associated with young-onset dementia. TDP-43 has now been linked to more than 10 diseases, including amyotrophic lateral sclerosis (ALS). Clinical Pharmacology & Therapeutics (2010) 88 4, 555–558. doi:10.1038/clpt.2010.112

Objective: To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA). Methods: This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest. Results: In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus. Conclusions: The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.

Background: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. Methods: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). Results: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. Conclusions: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

Background: Leukoencephalopathy with neuroaxonal spheroids is a rare cause of severe, subacute dementia that usually presents in childhood and is inherited in an autosomal dominant pattern. The authors present clinical, radiologic, and pathologic features of adult-onset, sporadic cases mimicking cerebral-type progressive MS. Methods: Five patients referred to an MS subspecialty clinic from 1999 to 2006 suspected of having primary cerebral MS. All patients were reviewed clinically, radiologically, and pathologically at Mayo Clinic Rochester. Diagnostic brain biopsies were examined by two neuropathologists. Results: All patients had severe, progressive cognitive and motor impairment, often with prominently asymmetrical features and diffuse nonenhancing subcortical white matter lesions on brain MRI. Cerebrovascular and spinal cord imaging were normal. CSF showed elevated neuron-specific enolase without elevated oligoclonal bands or IgG index. Extensive evaluations for alternative diagnoses were unrevealing. Pathologic examination confirmed leukodystrophy with neuroaxonal spheroids and pigmented glia on all patients. Therapies initiated did not alter the severe progressive disease course. Conclusions: Leukoencephalopathy with neuroaxonal spheroids occurs sporadically, in adults, and mimics cerebral-type MS or other leukodystrophies. Brain biopsy may be diagnostic in life; however, no treatment is known to be effective. Pathologic diagnosis is important to avoid potentially toxic therapies aimed at CNS inflammatory diseases such as MS. GLOSSARY: FLAIR = fluid attenuation inversion recovery; NSE = neuron-specific enolase.

Background: Chronic liver failure may be associated with pallidal MRI T1 hyperintensity and heterogeneous neurologic syndromes, including parkinsonism, cognitive impairment, and others. Manganese accumulation may be responsible for the imaging and clinical findings. Objective: To measure manganese plus other metal concentrations in pallidum and additional brain regions and to examine the corresponding neuropathology in cases of chronic liver failure. Methods: Regional brain metal concentrations were measured in seven chronic liver failure cases, four with pallidal T1 hyperintensity and three with normal MRI, plus five controls. Neuropathologic examination employed α-synuclein and tau immunohistochemistry. Results: In patients with pallidal T1 hyperintensity, pallidal manganese concentrations were increased sevenfold over controls and over fourfold vs liver patients with normal MRI; manganese concentrations were also significantly elevated in all other brain regions. Copper was additionally increased in all brain regions, whereas other metal concentrations were similar to control values. Neuropathology revealed mild to moderate Alzheimer type II gliosis in the liver failure groups and negative α-synuclein and tau immunostaining except for one case (intermediate Alzheimer disease pathology). Conclusion: In chronic liver failure, manganese accumulation is responsible for the pallidal MRI T1 hyperintensity. Pallidal copper was also elevated in affected cases, but copper does not have the paramagnetic properties to generate isolated T1 hyperintensity. Basal ganglia manganese or copper accumulation may be responsible for the parkinsonism sometimes seen in chronic liver failure. Pallidal MRI T1 hyperintensity is a biomarker of manganese overload.

Apraxia of speech (AOS) is a motor speech disorder characterized by slow speaking rate, abnormal prosody and distorted sound substitutions, additions, repetitions and prolongations, sometimes accompanied by groping, and trial and error articulatory movements. Although AOS is frequently subsumed under the heading of aphasia, and indeed most often co-occurs with aphasia, it can be the predominant or even the sole manifestation of a degenerative neurological disease. In this study we determine whether the clinical classifications of aphasia and AOS correlated with pathological diagnoses and specific biochemical and anatomical structural abnormalities. Seventeen cases with initial diagnoses of a degenerative aphasia or AOS were re-classified independently by two speech-language pathologists--blinded to pathological and biochemical findings--into one of five operationally defined categories of aphasia and AOS. Pathological diagnoses in the 17 cases were progressive supranuclear palsy in 6, corticobasal degeneration in 5, frontotemporal lobar degeneration with ubiquitin-only-immunoreactive changes in 5 and Pick's disease in 1. Magnetic resonance imaging analysis using voxel-based morphometry (VBM), and single photon emission tomography were completed, blinded to the clinical diagnoses, and clinicoimaging and clinicopathological associations were then sought. Interjudge clinical classification reliability was 87% (kappa = 0.8) for all evaluations. Eleven cases had evidence of AOS, of which all (100%) had a pathological diagnosis characterized by underlying tau biochemistry, while five of the other six cases without AOS did not have tau biochemistry (P = 0.001). A majority of the 17 cases had more than one yearly evaluation, demonstrating the evolution of the speech and language syndromes, as well as motor signs. VBM revealed the premotor and supplemental motor cortices to be the main cortical regions associated with AOS, while the anterior peri-sylvian region was associated with non-fluent aphasia. Refining the classification of the degenerative aphasias and AOS may be necessary to improve our understanding of the relationships among behavioural, pathological and imaging correlations.

Background: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested.Method: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated.Results and conclusion: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Pathologic changes in the superior cerebellar peduncles (SCP) are common in progressive supranuclear palsy (PSP), but atrophy of the SCP has never been systematically studied.To investigate the SCP width in PSP cases and controls with morphometric methods.The mean width of the SCP in transverse sections of the pons at the level of trigeminal nerve was determined in 48 PSP cases (29 men, 19 women; mean age 72.5 +/- 8.2 years) and 29 age-matched control subjects, many with neurodegenerative disorders that can be clinically mistaken for PSP. As the origin of the SCP is the cerebellar dentate nucleus, correlations were sought between SCP atrophy and severity of grumose degeneration in the dentate nucleus.The average width of the SCP was less in PSP (range 0.09 to 0.24 cm) than in controls (range 0.21 to 0.43 cm; Mann-Whitney U test, p0.001), including control cases that had been clinically misdiagnosed as PSP (range 0.26 to 0.41 cm). Severity of SCP atrophy normalized by brain weight correlated with disease duration (Spearman rank order correlation, r = 0.367, p = 0.028), suggesting that SCP atrophy is a relatively early feature of PSP. No correlation was found between grumose degeneration and SCP width.SCP atrophy is common in PSP and correlates with disease duration. Given that measurements of the SCP are within the resolution of MRI, it remains to be determined if SCP atrophy can be used as a diagnostic marker of PSP.

The authors assessed the frequency of spinal cord α-synuclein pathology in neurologically asymptomatic individuals older than 60 years of age (N = 106). Using α-synuclein immunohistochemistry, nine cases (8%) had incidental Lewy neurites in the intermediolateral column and at least some α-synuclein pathology in the dorsal motor nucleus of the vagus, locus ceruleus, and central raphe nucleus. Sparse α-synuclein pathology was also detected in the substantia nigra, basal forebrain, amygdala, or cortex in all but two cases.

Single case reports have described movement disorders including parkinsonism, dystonia and chorea, but not corticobasal syndrome as a consequence of central pontine and extrapontine myelinolysis. We report a case of a 61-year-old woman who developed progressive asymmetric parkinsonism with ideomotor apraxia and cortical sensory deficits following central pontine myelinolysis.

Cisplatin was incorporated into an in-situ forming biodegradable implant delivery system (ATRIGELO) consisting of a biodegradable polymer dissolved in a pharmaceutically acceptable solvent. The polymer solution with the suspended cisplatin was injected subcutaneously into the flank or shoulder of six healthy beagle dogs where the water-insoluble polymer precipitated upon contact with body fluids and formed a solid implant for the controlled release of the drug. Each dog received four injections, spaced thirty days apart, of a formulation containing either poly(DL-lactide-co-caprolactone) (PLC) or pely(DL-lactide-co-glycolide) (PLGA) dissolved in dimethyl sulfoxide (DM8O) and loaded with 8% by weight cisplatin. Dosage levels of 70, 105, and 157.5 mg/m2 were used to determine dosage escalation effects. Injections of the same formulations without the drug served as controls. Samples of blood were taken at appropriate times over the four months of treatment and analyzed for platinum concentration by atomic absorption spectroscopy. Local tissue and systemic toxicities were also determined. Both formulations exhibited sustained release of cisplatin with peak serum concentrations of platinum being attained in about two days followed by gradually decreasing platinum levels to day thirty. Consistent drug release profiles were observed for each of the four thirty-day treatment periods. The dosage escalation results exhibited an approximate 50% increase in peak platinum levels and area-under-the-curve (AUC) values for each 50% increase in drug dose. Local tissue toxicity to the cisplatin-containing implants was variable and appeared to be unrelated to dose level or direction number. Tissue reaction to the implants without drug was minimal indicating a role of cisplatin in the tissue reactions. Systemic toxicity, as judged by clinical parameters and clinicopathologic evaluation, was not noted at any dose level or injection time.

Obsessions and compulsive (OC) behaviors are a frequent feature of behavioral variant frontotemporal dementia (bvFTD), but their structural correlates have not been definitively established.Patients with bvFTD presenting to the Mayo Clinic Alzheimer's Disease Research Center were recruited. Each patient's caregiver was given the Yale-Brown Obsessive-Compulsive scale (YBOCS) to document the type and presence of OC behaviors and to rate their severity. All subjects underwent standardized magnetic resonance imaging (MRI) that was evaluated using voxel-based morphometry (VBM). Seventeen patients with bvFTD were recruited, and 11 were included in the study and compared with 11 age- and gender-matched controls. Six were excluded for lack of MRI at the time of survey or a pre-existing neurodegenerative condition.Nine of the 11 reported OC behaviors, with the most frequent compulsions being checking, hoarding, ordering/arranging, repeating rituals, and cleaning. In the VBM analysis, total YBOCS score correlated with gray matter loss in the bilateral globus pallidus, left putamen, and in the lateral temporal lobe, particularly the left middle and inferior temporal gyri (P 0.001 uncorrected for multiple comparisons).Obsessive-compulsive behaviors were frequent among these patients. The correlation with basal ganglia atrophy may point to involvement of frontal subcortical neuronal networks. Left lateral temporal lobe volume loss probably reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.

Objective: To determine whether clinical and demographic features are associated with prognosis in patients with frontotemporal dementia and motor neuron disease (FTD-MND). Methods: This was a case series of FTD-MND categorized according to behavioral- or language-dominant symptoms at presentation and throughout the disease course. Demographic, clinical, imaging, and survival data were analyzed with respect to dominant FTD-MND type. Voxel-based morphometry was used to assess and compare regional patterns of atrophy in behavioral- and language-dominant FTD-MND types. Results: Of the 56 patients with FTD-MND who were identified, 31 had dominant behavioral symptoms and 25 had dominant language symptoms; 53 patients had died. A survival difference was present between types, with patients with behavioral-dominant symptoms surviving 506 days longer than patients with language-dominant symptoms (mean 1,397 vs 891 days; p = 0.002). There was also a difference in time from diagnosis to death ( p = 0.02) between groups. Patients with language-dominant disease were more likely to have bulbar-onset than limb-onset motor neuron disease (MND) ( p = 0.01). There was a similar pattern of frontal and temporal lobe atrophy in both types, although there was some evidence for the behavioral type to have more frontal atrophy and the language type to have more left temporal atrophy. Conclusions: In our series of patients with FTD-MND, language-dominant FTD-MND was associated with bulbar-onset MND and a shorter survival. There was also evidence that the dominant FTD-MND type is related to differences in brain atrophy patterns.

Our objective was to document the clinical and imaging features of Othello's syndrome (delusional jealousy).The study design was a retrospective case series of 105 patients with Othello's syndrome that were identified using the Electronic Medical Record system of Mayo Clinic.The average age at onset of Othello's syndrome was 68 (25-94) years with 61.9% of patients being male. Othello's syndrome was most commonly associated with a neurological disorder (73/105) compared with psychiatric disorders (32/105). Of the patients with a neurological disorder, 76.7% had a neurodegenerative disorder. Seven of eight patients with a structural lesion associated with Othello's syndrome had right frontal lobe pathology. Voxel-based morphometry showed greater gray matter loss predominantly in the dorsolateral frontal lobes in the neurodegenerative patients with Othello's compared to matched patients with neurodegenerative disorders without Othello's syndrome. Treatment success was notable for patients with dopamine agonist induced Othello's syndrome in which all six patients had improvement in symptoms following decrease in medication.This study demonstrates that Othello's syndrome occurs most frequently with neurological disorders. This delusion appears to be associated with dysfunction of the frontal lobes, especially the right frontal lobe.

Objective: To determine whether TDP-43 type is associated with distinct patterns of brain atrophy on MRI in subjects with pathologically confirmed frontotemporal lobar degeneration (FTLD). Methods: In this case-control study, we identified all subjects with a pathologic diagnosis of FTLD with TDP-43 immunoreactive inclusions (FTLD-TDP) and at least one volumetric head MRI scan (n = 42). In each case we applied published criteria for subclassification of FTLD-TDP into FTLD-TDP types 1-3. Voxel-based morphometry was used to compare subjects with each of the different FTLD-TDP types to age-and gender-matched normal controls (n = 30). We also assessed different pathologic and genetic variants within, and across, the different types. Results: Twenty-two subjects were classified as FTLD-TDP type 1, 9 as type 2, and 11 as type 3. We identified different patterns of atrophy across the types with type 1 showing frontotemporal and parietal atrophy, type 2 predominantly anterior temporal lobe atrophy, and type 3 predominantly posterior frontal atrophy. Within the FTLD-TDP type 1 group, those with a progranulin mutation had significantly more lateral temporal lobe atrophy than those without. All type 2 subjects were diagnosed with semantic dementia. Subjects with a pathologic diagnosis of FTLD with motor neuron degeneration had a similar pattern of atrophy, regardless of whether they were type 1 or type 3. Conclusions: Although there are different patterns of atrophy across the different FTLD-TDP types, it appears that genetic and pathologic factors may also affect the patterns of atrophy. Neurology (R) 2010;75:2212-2220

Background: Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). Methods: We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome. Results: Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients. Conclusions: These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.

Frontotemporal lobar degeneration (FTLD) can be subdivided into those in which the abnormal protein is tau (FTLD-TAU), the TAR DNA binding protein 43 (FTLD-TDP) and the fused in sarcoma protein (FTLD-FUS). We have observed severe caudate atrophy at autopsy in FTLD-FUS, and hence, we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD-FUS from FTLD-TDP and FTLD-TAU.From a cohort of 207 cases of FTLD, we identified all cases of FTLD-FUS that had a volumetric antemortem head MRI (n = 3). Caudate and frontal lobe volumes were measured in all three cases using atlas-based parcellation and SPM5 and were compared to 10 randomly selected cases of FTLD-TDP and 10 randomly selected cases of FTLD-TAU. Total grey matter volumes were also calculated for all cases.The FTLD-FUS cases had significantly smaller caudate volumes (P = 0.02) yet similar frontal lobe grey matter volumes (P = 0.12) compared to FTLD-TDP and FTLD-TAU. Caudate volumes when corrected for total grey matter volume (P = 0.01) or frontal lobe grey matter volume (P = 0.01) were significantly smaller in FTLD-FUS than in FTLD-TDP and FTLD-TAU and showed no overlap with the other two groups.Caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU, suggesting that severe caudate atrophy may be a useful clinical feature to predict FTLD-FUS pathology.

Objective: To use a case-control study to assess and compare patterns of gray matter loss across groups of subjects with different mutations in the microtubule-associated protein tau (MAPT) gene. Methods: We identified all subjects from Mayo Clinic, Rochester, Minnesota, that screened positive for mutations in MAPT and had a head MRI (n = 22). Voxel-based morphometry was used to assess patterns of gray matter atrophy in groups of subjects with the IVS10 + 16, IVS10 + 3, N279K, S305N, P301L, and V337M mutations compared with age-and sex-matched controls. Results: All MAPT groups showed gray matter loss in the anterior temporal lobes, with varying degrees of involvement of the frontal and parietal lobes. Within the temporal lobe, the subjects with IVS10 + 16, IVS10 + 3, N279K, and S305N mutations (mutations that influence the alternative splicing of tau pre-messenger RNA) all showed gray matter loss focused on the medial temporal lobes. In contrast to these groups, the subjects with P301L or V337M mutations (mutations that affect the structure of the tau protein) both showed gray matter loss focused on the lateral temporal lobes, with a relative sparing of the medial temporal lobe. Conclusion: There seem to be differences in patterns of temporal lobe atrophy across the MAPT mutations, which may aid in the differentiation of the different mutation carriers. Furthermore, there seems to be a possible association between mutation function and pattern of temporal lobe atrophy. Neurology (R) 2009;73:1058-1065

Objective: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. Methods: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. Results: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. Conclusions: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis. Neurology (R) 2009; 72: 2024-2028

Objective: To compare patterns of gray matter loss in subjects with mutations in the progranulin ( PGRN ) gene to subjects with mutations in the microtubule-associated protein tau ( MAPT ) gene. Methods: We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group. Results: Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT . The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects. Conclusion: These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.

Frontotemporal dementia (FTD) often presents with behavioural changes warranting treatment with antipsychotic medications. It is known that patients with Lewy body dementia are sensitive to developing extrapyramidal symptoms (EPS) from these medications. This has not been emphasized in FTD. We report three patients with FTD that developed parkinsonism and prominent antecollis after treatment with newer antipsychotics, including olanzapine, risperidone and quetiapine. Patients with FTD might have increased sensitivity to antipsychotic medications as with Lewy body dementia. Although newer antipsychotics have favourable side effect profiles, there is increasing evidence that EPS develop more frequently than previously thought.

The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested.The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated.In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

We set out to determine the frequency of the different pathologies underlying frontotemporal degeneration (FTD) in our brain bank series, by reviewing all cases of pathologically diagnosed FTD over the last 12 years. We identified and reviewed 29 cases of FTD and classified them using the most recent consensus criteria with further histological analysis of 6 initially unclassifiable cases. Detailed histological analysis of these 6 cases revealed variable numbers of ubiquitin-positive (tau and alpha-synuclein-negative) inclusions in 5 cases, consistent with the diagnosis of frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). As a consequence of the current re-evaluation, 18 (62%) of the 29 cases with FTD have underlying pathology consistent with FTLD-U. Therefore in our brain bank series of frontotemporal degeneration, most cases were non-tauopathies with FTLD-U accounting for 62% of all the diagnoses.

Posterior cortical atrophy or the “visual variant” of Alzheimer’s disease is a clinical syndrome with visual agnosia, some or all the components of Balint’s syndrome, transcortical sensory aphasia, and Gerstmann’s syndrome.1 Although pathologically heterogeneous, several necropsy studies on patients with posterior cortical atrophy have shown Alzheimer’s disease pathology.1 We report a patient who presented with the features of posterior cortical atrophy who later developed mild parkinsonism, visual hallucinations, and delusions. Neuropathological evaluation revealed combined Alzheimer’s disease and Lewy body disease. A right handed retired diesel mechanic, with 12 years of formal education, was referred for evaluation of an “unusual dementia.” His difficulties started at the age of 58 with the insidious onset of visuospatial dysfunction. Initially he was not able to fill out bank deposit slips or write numbers correctly. He had been an avid reader but had to re-read material in order to comprehend it, and unsuccessfully used a card to keep his eyes focused when reading. He was not able to locate the refrigerator door handle until he groped over the surface to find it. His wife revealed that when he was 61 he was having difficulties working as a mechanic. Also, he could not see other cars and obstacles while driving, and he stopped driving at the age of 63 after being involved in two motor vehicle …