Peter Pressman

Diagnosis and Management of Behavioral Variant Frontotemporal Dementia

Frontotemporal dementia was documented over a century ago. The last decade, however, has seen substantial changes in our conceptions of this increasingly recognized disorder. Different clinical variants have been delineated, the most common of which is the behavioral variant (bvFTD). Updated diagnostic criteria have been established. New histopathological findings and genetic etiologies have been discovered. Research continues to uncover molecular mechanisms by which abnormal proteins accumulate in degenerating brain tissue. Novel neuroimaging techniques suggest that functional networks are diminished in bvFTD that might be relevant to empathy and social behavior. Despite rapid advances in our understanding of bvFTD, the disease is still under-recognized and commonly misdiagnosed. The result is inappropriate patient care. Recognizing the various presentations of bvFTD and its histological and genetic subtypes might further diagnosis, treatment, and research.

18F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study

18F‐flortaucipir (formerly 18F‐AV1451 or 18F‐T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18F‐flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).

18F‐flortaucipir tau PET distinguishes established progressive supranuclear palsy from controls and Parkinson's disease: A multicenter study

18F‐flortaucipir (formerly 18F‐AV1451 or 18F‐T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18F‐flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).

Rates of amyloid imaging positivity in patients with primary progressive aphasia

Importance The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11–labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Main Outcomes and Measures Clinical, cognitive, neuroimaging, and pathology results. Results Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET–positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Conclusions and Relevance Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11–labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.

Sensitive measures of executive dysfunction in non-demented Parkinson's disease *

BACKGROUND We examined the sensitivity of different executive function measures for detecting deficits in Parkinsons disease patients without dementia. METHODS Twenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales. RESULTS No significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores. CONCLUSIONS The NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non-demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD.

Associations Between Tau, β-Amyloid, and Cognition in Parkinson Disease

Importance Multiple disease processes are associated with cognitive impairment in Parkinson disease (PD), including Lewy bodies, cerebrovascular disease, and Alzheimer disease. It remains unknown whether tau pathology relates to cognition in patients with PD without dementia. Objective To compare tau aggregation in patients with PD who are cognitively normal (PD-CN), patients with PD with mild cognitive impairment (PD-MCI), and healthy control participants, and evaluate the relationships between &bgr;-amyloid (A&bgr;), tau, and cognition in patients with PD who did not have dementia. Design, Setting, and Participants This cross-sectional study recruited 30 patients with Parkinson disease (15 with PD-CN and 15 with PD-MCI) from a tertiary care medical center and research institutions from July 2015 through October 2016. One patient with PD-MCI did not receive a magnetic resonance imaging scan and thus was excluded from all analyses; 29 patients with PD were included in the present study. Participants underwent tau positron emission tomographic (PET) scanning with fluorine 18–labeled AV-1451, A&bgr; PET scanning with carbon 11–labeled Pittsburgh compound B, magnetic resonance imaging, cognitive testing, and neurologic evaluation. Imaging measures were compared with 49 healthy control participants. Main Outcomes and Measures Outcomes were tau PET measurements of groups of patients with PD-CN and PD-MCI. We hypothesized that tau aggregation across groups would be related to age and A&bgr; status. Results Of the 78 participants, 47 (60%) were female, and the mean (SD) age was 71.1 (6.6) years. Six patients with PD (21%) were A&bgr;-positive, of whom 1 was mildly cognitively impaired; 23 were A&bgr;-negative (79%). (Of the 49 healthy controls, 25 were A&bgr;-negative and 24 A&bgr;-positive.) Voxelwise contrasts of whole-brain tau PET uptake between patients with PD-CN and patients with PD-MCI, and additionally between all patients with PD and A&bgr;-negative controls, did not reveal significant differences. Tau PET binding did not differ between patients with PD-MCI and PD-CN in brain regions reflecting Alzheimer disease Braak stages 1/2, 3/4, or 5/6, and did not differ from A&bgr;-negative healthy older adults. Mean (SD) tau PET binding was significantly elevated in A&bgr;-positive patients with PD relative to A&bgr;-negative patients with PD within brain regions reflecting Alzheimer disease Braak stage 3/4 (1.22 [0.07] vs 1.14 [0.07]; P = .03) and Braak stage 5/6 (1.20 [0.07] vs 1.11 [0.08]; P = .02). Conclusions and Relevance These findings suggest that patterns of cortical A&bgr; and tau do not differ in people with PD-CN, people with PD-MCI, and healthy older adults. Age, A&bgr;, and tau do not differentiate patients with PD-CN and PD-MCI. Tau deposition is related to A&bgr; status and age in both people with PD and healthy older adults. Cognitive deficits in people with PD without dementia do not appear to reflect measureable Alzheimer disease.

Comparing Volume Loss in Neuroanatomical Regions of Emotion versus Regions of Cognition in Healthy Aging

Many emotional functions are relatively preserved in aging despite declines in several cognitive domains and physical health. High levels of happiness exist even among centenarians. To address the hypothesis of whether preservation of emotional function in healthy aging may relate to different rates of age-related volume loss across brain structures, we performed two volumetric analyses on structural magnetic resonance neuroimaging of a group of healthy aging research participants using Freesurfer version 5.1. Volumes selected as supporting cognition included bilateral midfrontal and lateral frontal gyri, lateral parietal and temporal cortex, and medial temporal lobes. Volumes supporting emotion included bilateral amygdala, rostral anterior cingulate, insula, orbitofrontal cortex, and nucleus accumbens. A cross-sectional analysis was performed using structural MRI scans from 258 subjects. We found no difference in proportional change between groups. A longitudinal mixed effects model was used to compare regional changes over time in a subset of 84 subjects. Again, there was no difference in proportional change over time. While our results suggest that aging does not collectively target cognitive brain regions more than emotional regions, subgroup analysis suggests relative preservation of the anterior cingulate cortex, with greater volume loss in the nucleus accumbens. Implications of these relative rates of age-related volume loss in healthy aging are discussed and merit further research.

Effects of acute levodopa challenge on resting cerebral blood flow in Parkinson’s Disease patients assessed using pseudo-continuous arterial spin labeling

Introduction. Levodopa is the gold-standard for treatment of Parkinson’s disease (PD) related motor symptoms. In this study, we used pseudo-continuous arterial spin labeling (pCASL) to quantify changes in cerebral blood flow (CBF) after acute oral administration of levodopa in PD patients. Materials and Methods. Thirteen patients (3 females, age 66.2 ± 8.7 years) with moderately advanced PD (Hoehn and Yahr stage >2 (median 2.5), disease duration >3 years) were scanned on a 3T Siemens MR scanner before and after oral levodopa administration. Statistical parametric mapping was used to detect drug-induced changes in CBF and its correlation to clinical severity scales. Images were normalized and flipped in order to examine effects on the more affected (left) and less affected (right) cerebral hemispheres across the cohort. Results. Levodopa did not change global CBF but increased regional CBF in dorsal midbrain, precuneus/cuneus, more affected inferior frontal pars opercularis and triangularis, bilateral pre- and postcentral gyri, more affected inferior parietal areas, as well as less affected putamen/globus pallidus by 27–74% (p < 0.05, FWE corrected for multiple comparisons). CBF change was negatively correlated with improvement in bradykinesia UPDRS-III subscore in the more affected precentral gyrus, and total predrug UPDRS-III score in the mid-cingulate region. Drug-induced CBF change in a widespread network of regions including parietal and postcentral areas was also negatively correlated with the predrug rigidity UPDRS-III subscore. Conclusion. These findings are in line with prior reports of abnormal activity in the nigrostriatal pathway of PD patients and demonstrate the feasibility of pCASL as a neuroimaging tool for investigating in vivo physiological effects of acute drug administration in PD.

Maxillary sinus mass: The case for the unerupted third molar ☆ ☆☆ ★

A 50-year-old previously healthy woman sought consultation because of chronic sinusitis. She denied any history of trauma, tooth extraction, or previous dental surgery. Her medical and family histories were not suggestive of Gardner’s syndrome or its possible manifestations (which are associated with embryologic osteogenesis). Extraoral examination revealed no facial asymmetry or swelling. Intraorally, the patient had a complete set of adult teeth with the exception of left and right upper third molars. CT of the sinuses was obtained and demonstrated mild mucosal thickening bilaterally in the maxillary sinuses. CT bone windows (Fig 1) demonstrated a pedunculated lesion isodense to bone and projecting from the lateral wall of the right maxillary sinus. This maxillary sinus mass is also represented in the intraoperative photograph (Fig 2). Taken with a 5-mm trocar used in the canine fossa puncture, the photograph shows the spherical mass we believe to be an unerupted third molar/dentigerous cyst. It is seen cradled in what appears to be a sling of mucosa. Its spheroid form and well-defined perimeter are evident. Although ectopic eruption of teeth in the maxillary antrum is rare, and that involving the third molar is extremely rare,1 third molars have long been known to occur in unusual positions; this has been attributed to the early appearance and activity of the enamel organ—before the development of the tooth germ.2 The spectrum of odontogenic malformations is fairly limited, with a smattering of reports of osteomas and odontomas loosely categorized according to clinical, radiographic, and histologic findings. Osteomas are benign bony proliferations that may lead to displacement and erosion of surrounding tissue. Osteomas of the paranasal sinuses are typically slowgrowing, benign tumors that are incidentally discovered; most are asymptomatic and located in the frontal sinus.3-5 The association between osteoma and Gardner’s syndrome is striking.4 The odontoma in our case is likely best characterized as complex and is thought to develop from the enamel organ or dental lamina, in association with an unerupted tooth.6 An absence of teeth is a concomitant finding. Odontomas may be surrounded by either a fibrous capsule or an enamel (dentigerous) cyst. Experience has demonstrated that, after calcification, they typically remain static for the remainder of the patient’s life.

Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier.

Microtubule‐associated protein tau mutations result in 10–20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimers disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel‐based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome.