Prosopagnosia: face blindness and its association with neurological disorders.

Loss of facial recognition or prosopagnosia has been well-recognized for over a century. It has been categorized as developmental or acquired depending on whether the onset is in early childhood or beyond, and acquired cases can have degenerative or non-degenerative aetiologies. Prosopagnosia has been linked to involvement of the fusiform gyri, mainly in the right hemisphere. The literature on prosopagnosia comprises case reports and small case series. We aim to assess demographic, clinical and imaging characteristics and neurological and neuropathological disorders associated with a diagnosis of prosopagnosia in a large cohort. Patients were categorized as developmental versus acquired; those with acquired prosopagnosia were further subdivided into degenerative versus non-degenerative, based on neurological aetiology. We assessed regional involvement on [18F] fluorodeoxyglucose-PET and MRI of the right and left frontal, temporal, parietal and occipital lobes. The Intake and Referral Center at the Mayo Clinic identified 487 patients with possible prosopagnosia, of which 336 met study criteria for probable or definite prosopagnosia. Ten patients, 80.0% male, had developmental prosopagnosia including one with Niemann-Pick type C and another with a forkhead box G1 gene mutation. Of the 326 with acquired prosopagnosia, 235 (72.1%) were categorized as degenerative, 91 (27.9%) as non-degenerative. The most common degenerative diagnoses were posterior cortical atrophy, primary prosopagnosia syndrome, Alzheimer's disease dementia and semantic dementia, with each diagnosis accounting for >10% of this group. The most common non-degenerative diagnoses were infarcts (ischaemic and haemorrhagic), epilepsy-related and primary brain tumours, each accounting for >10%. We identified a group of patients with non-degenerative transient prosopagnosia in which facial recognition loss improved or resolved over time. These patients had migraine-related prosopagnosia, posterior reversible encephalopathy syndrome, delirium, hypoxic encephalopathy and ischaemic infarcts. On [18F] fluorodeoxyglucose-PET, the temporal lobes proved to be the most frequently affected regions in 117 patients with degenerative prosopagnosia, while in 82 patients with non-degenerative prosopagnosia, MRI revealed the right temporal and right occipital lobes as most affected by a focal lesion. The most common pathological findings in those with degenerative prosopagnosia were frontotemporal lobar degeneration with hippocampal sclerosis and mixed Alzheimer's and Lewy body disease pathology. In this large case series of patients diagnosed with prosopagnosia, we observed that facial recognition loss occurs across a wide range of acquired degenerative and non-degenerative neurological disorders, most commonly in males with developmental prosopagnosia. The right temporal and occipital lobes, and connecting fusiform gyrus, are key areas. Multiple different pathologies cause degenerative prosopagnosia.

Senile plaque-associated transactive response DNA-binding protein 43 in Alzheimer's disease: A case report spanning 16 years of memory loss.

Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming "apple-bite" or "flame-shaped" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.

Diffuse argyrophilic grain disease with TDP-43 proteinopathy and neuronal intermediate filament inclusion disease: FTLD with mixed tau, TDP-43 and FUS pathologies.

Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins - tau, TDP-43 or FUS - forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer's disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called "cherry spots," that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer's type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases.

Cancer in pathologically confirmed multiple system atrophy.

PURPOSE: The aim of this study was to assess whether cancer occurs with increased frequency in multiple system atrophy (MSA). The pathological hallmark of MSA is glial cytoplasmic inclusions containing aggregated α-synuclein, and the related protein γ-synuclein correlates with invasive cancer. We investigated whether these two disorders are associated clinically. METHODS: Medical records of 320 patients with pathologically confirmed MSA seen between 1998 and 2022 were reviewed. After excluding those with insufficient medical histories, the remaining 269 and an equal number of controls matched for age and sex were queried for personal and family histories of cancer recorded on standardized questionnaires and in clinical histories. Additionally, age-adjusted rates of breast cancer were compared with US population incidence data. RESULTS: Of 269 cases in each group, 37 with MSA versus 45 of controls had a personal history of cancer. Reported cases of cancer in parents were 97 versus 104 and in siblings 31 versus 44 for MSA and controls, respectively. Of 134 female cases in each group, 14 MSA versus 10 controls had a personal history of breast cancer. The age-adjusted rate of breast cancer in MSA was 0.83%, as compared with 0.67% in controls and 2.0% in the US population. All comparisons were nonsignificant. CONCLUSION: The evidence from this retrospective cohort found no significant clinical association of MSA with breast cancer or other cancers. These results do not exclude the possibility that knowledge about synuclein pathology at the molecular level in cancer may lead to future discoveries and potential therapeutic targets for MSA.

Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old.

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-ß plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Neuropathology and emerging biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and alien limb phenomenon. Corticobasal degeneration (CBD) is one of the most common underlying pathologies of CBS, but other disorders, such as progressive supranuclear palsy (PSP), Alzheimer's disease (AD) and frontotemporal lobar degeneration with TDP-43 inclusions, are also associated with this syndrome.In this review, we describe common and rare neuropathological findings in CBS, including tauopathies, synucleinopathies, TDP-43 proteinopathies, fused in sarcoma proteinopathy, prion disease (Creutzfeldt-Jakob disease) and cerebrovascular disease, based on a narrative review of the literature and clinicopathological studies from two brain banks. Genetic mutations associated with CBS, including GRN and MAPT, are also reviewed. Clinicopathological studies on neurodegenerative disorders associated with CBS have shown that regardless of the underlying pathology, frontoparietal, as well as motor and premotor pathology is associated with CBS. Clinical features that can predict the underlying pathology of CBS remain unclear. Using AD-related biomarkers (ie, amyloid and tau positron emission tomography (PET) and fluid biomarkers), CBS caused by AD often can be differentiated from other causes of CBS. Tau PET may help distinguish AD from other tauopathies and non-tauopathies, but it remains challenging to differentiate non-AD tauopathies, especially PSP and CBD. Although the current clinical diagnostic criteria for CBS have suboptimal sensitivity and specificity, emerging biomarkers hold promise for future improvements in the diagnosis of underlying pathology in patients with CBS.

Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.

BACKGROUND AND OBJECTIVE: Individuals with biomarker evidence of ß-amyloid (Aß) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aß-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. METHODS: Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aß PET positivity was defined based on ADNI cutpoints. We identified all Aß-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aß PET (amyloid with low tau [ALT] group) and all Aß-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aß Centiloid, and hippocampal volume. RESULTS: We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aß Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aß Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. DISCUSSION: Aß-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aß cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.

Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations.

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

PSP-like syndrome after aortic surgery in adults (Mokri syndrome).

BACKGROUND: A rare progressive supranuclear palsy-like syndrome seemingly triggered by aortic surgery was first described in 2004. This largest case series to date describes the features of this syndrome. METHODS: We searched the Mayo Clinic electronic medical records using the advanced cohort explorer search engine for patients evaluated for neurologic symptoms after cardiac-aortic surgery in the past 30 years. Data were extracted to Microsoft Excel from the identified patients and included clinical and neuroimaging features and outcomes. RESULTS: Twenty-five patients met the inclusion criteria. All surgeries were performed under thoracic aortic bypass and deep hypothermia. Surgery included aortic aneurysm, aortic valve repair, and/or aortic dissection repair. Surgical records were unavailable, although surgery was documented in the Mayo record as uncomplicated in 60% of cases. In the remaining cases, no particular intraoperative or postoperative complications were documented at a high frequency. A typical triad was documented: supranuclear gaze palsy (SNGP; 100%), gait imbalance (80%), and dysarthria (96%). Part or all of the triad was observed before hospital discharge and stabilized over the course of days-weeks. A second phase of symptom worsening plus new symptoms developed up to a year later; this decline continued for up to several years before stabilization. Delayed epileptic seizures occurred in 32% of patients. Brain MRI revealed only nonspecific findings. CONCLUSION: This syndrome following adult thoracic aortic bypass surgery with deep hypothermia remains unexplained. It follows a biphasic course and is characterized by the triad of SNGP, unsteady gait, and a predominantly ataxic dysarthria.

Neuronal intermediate filament inclusion disease may be incorrectly classified as a subtype of FTLD-FUS.

BACKGROUND: The majority of cases of frontotemporal lobar degeneration (FTLD) are characterized by focal cortical atrophy with an underlying tau or TDP-43 proteinopathy. A subset of FTLD cases, however, lack tau and TDP-43 immuno-reactivity, but have neuronal inclusions positive for ubiquitin, referred to as atypical FTLD (aFTLD-U). Studies have demonstrated that ubiquitin-positive inclusions in aFTLD-U are immuno-reactive for fused in sarcoma (FUS). As such, the current nosology for this entity is FTLD-FUS, which is thought to include not only aFTLD-U, but also neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease. OBJECTIVE: To compare pathological features of cases of aFTLD-U and NIFID. METHODS: We reviewed the neuropathology of 15 patients (10 males and 5 females; average age at death 54 years (range 41-69 years)) with an antemortem clinical diagnosis of a frontotemporal dementia and pathological diagnosis of aFTLD-U (n=8) or NIFID (n=7). Sections were processed for immunohistochemistry and immunoelectron microscopy with FUS, TDP-43, and α-internexin (αINX) antibodies. RESULTS: Eight cases had pathologic features consistent with FTLD-FUS, with severe striatal atrophy (7/8 cases), as well as FUS-positive neuronal cytoplasmic and vermiform intranuclear inclusions, but no αINX immuno-reactivity. Five cases had features consistent with NIFID, with neuronal inclusions positive for both FUS and αINX. Striatal atrophy was present in only 2 of the NIFID cases. Two cases had αINX-positive neuronal inclusions consistent with NIFID, but both lacked striatal atrophy and FUS immunoreactivity. Surprisingly, one of these two NIFID cases had lesions immunoreactive for TDP-43. DISCUSSION: While FUS pathology remains a prominent feature of aFTLD-U, there is pathologic heterogeneity, including rare cases of NIFID with TDP-43- rather than FUS-positive inclusions.

Uptake of AV-1451 in meningiomas.

AIM: AV-1451 is an imaging agent labeled with the positron-emitting radiolabel Fluorine-18. 18F-AV-1451 binds paired helical filament tau (PHF-tau), a pathology related to Alzheimer's disease. In our study of AV-1451 uptake in the brains of cognitively normal subjects, we noted a case of a meningioma with visually significant uptake of AV-1451. OBJECTIVE: We initiated the present retrospective study to further examine cases of meningioma that underwent AV-1451 imaging. METHODS: We searched the patient records of 650 patients who had undergone AV-1451 at our institution for the keyword "meningioma" to identify potential cases. PET/CT and MRI results were visually reviewed and semi-quantitative analysis of PET was performed. A paired student's t test was run between background and tumor standard uptake values. Fisher's exact test was used to examine the association between AV-1451 uptake and presence of calcifications on CT. RESULTS: We identified 12 cases of meningioma, 58% (7/12) of which demonstrated uptake greater than background using both visual analysis and tumor-to-normal cortex ratios (T/N + 1.90 ± 0.83). The paired student's t test revealed no statistically significant difference between background and tumor standard uptake values (p = 0.09); however, cases with a T/N ratio greater than one showed statistically higher uptake in tumor tissue (p = 0.01). A significant association was noted between AV-1451 uptake and presence of calcifications (p = 0.01). CONCLUSION: AV-1451 PET imaging should be reviewed concurrently with anatomic imaging to prevent misleading interpretations of PHF-tau distribution due to meningiomas.

Brain tau deposition linked to systemic causes of death in normal elderly.

The relationship between causes of death and 4 major neurodegenerative brain proteins (beta-amyloid, tau, alpha-synuclein, and the TAR DNA-binding protein of 43 kDa (TDP-43) were assessed in 94 cognitively normal elderly participants that died without a neurodegenerative disease. There was an association between tau and causes of death (p = 0.01). Tau in the brain was associated with a reduced likelihood of dying from systemic cancers (p = 0.046), and with an increased likelihood of dying from pulmonary (p = 0.03) and gastrointestinal (p = 0.049) diseases. There were no associations between beta-amyloid, alpha-synuclein, or TDP-43 and causes of death. Tau deposition in the brain may have a relationship with systemic causes of death, including cancer, in the cognitively normal elderly.

Coprophagia in neurologic disorders.

We report on the unusual behavior of coprophagia (eating one's own feces) in neurologic disorders. The Mayo Clinic Health Sciences-computerized clinical database was queried for all patients evaluated at our institution between 1995 and 2015 in which coprophagia was documented in the medical records. Twenty-six patients were identified of which 17 had coprophagia. Of the 17 patients, five were excluded due to age at onset less than 10 years, leaving 12 adult patients for this study. The median age at onset of coprophagia in the 12 patients was 55 years (range 20-88 years), and half were female. Additional behaviors were common including scatolia (fecal smearing), hypersexuality, aggression, and pica (eating objects of any kind). Coprophagia was associated with neurodegenerative dementia in six patients, developmental delay in two, and one each with seizures, steroid psychosis, frontal lobe tumor, and schizoaffective disorder. Brain imaging in the six patients with dementia showed moderate-to-severe medial temporal lobe atrophy, as well as mild frontal lobe atrophy. Autopsy examination was performed in one patient and revealed frontotemporal lobar degeneration pathology. Many different behavioral and pharmacologic therapies were implemented, yet only haloperidol was associated with discontinuation of the behavior. Coprophagia is associated with different neurologic disorders, particularly neurodegenerative dementias. The behavior may be related to medial temporal lobe atrophy, similar to the Klüver-Bucy syndrome. Haloperidol appears to be effective in treating the behavior, at least in some patients.

Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations.

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.

Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS.

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.

The alien limb phenomenon.

Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome. Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies. We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011. One hundred and fifty patients with alien limb were identified. Twenty-two were followed in the Alzheimer's Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n = 108), stroke (n = 14), Creutzfeldt Jakob disease (n = 9), hereditary diffuse leukoencephalopathy with spheroids (n = 5), tumor (n = 4), progressive multifocal leukoencephalopathy(n = 2), demyelinating disease (n = 2), progressive dementia not otherwise specified (n = 2), posterior reversible encephalopathy syndrome (n = 1), corpus callosotomy (n = 1), intracerebral hemorrhage (n = 1) and thalamic dementia (n = 1). Ten of 14 cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimer's Disease Research Center cohort, 22 had alien limb, and 73 % had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p = 0.004). These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially right parietal, disconnecting it from other cortical areas.

MRI characteristics and scoring in HDLS due to CSF1R gene mutations.

OBJECTIVE: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. METHODS: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. RESULTS: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. CONCLUSION: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.