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 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 Jacob 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 fourteen 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 the right parietal, disconnecting it from other cortical areas.
Alien limb; corticobasal syndrome
Progressive apraxia of speech (AOS) can result from neurodegenerative disease and can occur in isolation or in the presence of agrammatic aphasia. We aimed to determine the neuroanatomical and metabolic correlates of progressive AOS and aphasia. Thirty-six prospectively recruited subjects with progressive AOS or agrammatic aphasia, or both, underwent the Western Aphasia Battery (WAB) and Token Test to assess aphasia, an AOS rating scale (ASRS), 3T MRI and 18-F fluorodeoxyglucose (FDG) PET. Correlations between clinical measures and imaging were assessed. The only region that correlated to ASRS was left superior premotor volume. In contrast, WAB and Token Test correlated with hypometabolism and volume of a network of left hemisphere regions, including pars triangularis, pars opercularis, pars orbitalis, middle frontal gyrus, superior temporal gyrus, precentral gyrus and inferior parietal lobe. Progressive agrammatic aphasia and AOS have non-overlapping regional correlations, suggesting that these are dissociable clinical features that have different neuroanatomical underpinnings.
apraxia of speech; aphasia; atrophy; Broca’s area; premotor cortex; hypometabolism
There are few studies examining praxis in subjects with primary progressive aphasia. The aim of this study was to examine the pattern and severity of ideomotor apraxia in subjects with logopenic and agrammatic variants of primary progressive aphasia and to determine if the presence of ideomotor apraxia correlated with specific neuroanatomical structural abnormalities. Subjects with primary progressive aphasia were prospectively recruited and classified according to published criteria. Using the apraxia subtest of the Western Aphasia Battery, pattern and severity of ideomotor apraxia was examined in all subjects diagnosed with agrammatic and logopenic variants of primary progressive aphasia. The study included 47 subjects, 21 diagnosed with agrammatic variant of primary progressive aphasia and 26 with logopenic variant primary progressive aphasia. Subjects with agrammatic aphasia were older at onset than the logopenic variant (67.2 versus 61.7 years, p=0.02), but there was no difference in illness duration prior to evaluation. Those with logopenic aphasia showed more cognitive impairment on the Mini-Mental Status Examination (agrammatic=26.7/30, logopenic=22/30, p=0.002), and a trend for more severe language impairment as measured by Western Aphasia Battery-Aphasia Quotient (agrammatic=82.3, logopenic=75.2, p=0.11). Strong correlations were found between Western Aphasia Battery-Aphasia Quotient and total apraxia, instrumental apraxia, and complex apraxia, while average correlation were seen with upper limb apraxia and modest correlation with facial apraxia. After adjusting for age, mental status performance, and Western Aphasia Battery-Aphasia Quotient score, those with agrammatic aphasia had a higher degree of total apraxia (p=0.004), facial apraxia (p=0.03), instrumental apraxia (p=0.0006), and complex apraxia (p=0.0006) than those with logopenic aphasia. The agrammatic variant of primary progressive aphasia was associated with greater praxis deficits but less cognitive impairment than the logopenic variant. The presence of ideomotor apraxia was associated with grey matter loss in the left lateral premotor cortex with extension into the motor cortex. These findings suggest that although some affected areas in the agrammatic and logopenic variants of primary progressive aphasia overlap, there exists an area that is more affected in the agrammatic variant than the logopenic variant that accounts for the greater association of agrammatic aphasia with apraxia.
Primary progressive aphasia; Agrammatic; Logopenic; Apraxia; Ideomotor; Cortical atrophy
Primary progressive apraxia of speech, a motor speech disorder of planning and programming is a tauopathy that has overlapping histological features with progressive supranuclear palsy. We aimed to compare, for the first time, atrophy patterns, as well as white matter tract degeneration, between these two syndromes.
Sixteen primary progressive apraxia of speech subjects were age and gender-matched to 16 progressive supranuclear palsy subjects and 20 controls. All subjects were prospectively recruited, underwent neurological and speech evaluations, and 3.0 Tesla magnetic resonance imaging. Grey and white matter atrophy was assessed using voxel-based morphometry and atlas-based parcellation, and white matter tract degeneration was assessed using diffusion tensor imaging.
All progressive supranuclear palsy subjects had typical occulomotor/gait impairments but none had speech apraxia. Both syndromes showed grey matter loss in supplementary motor area, white matter loss in posterior frontal lobes and degeneration of the body of the corpus callosum. While lateral grey matter loss was focal, involving superior premotor cortex, in primary progressive apraxia of speech, loss was less focal extending into prefrontal cortex in progressive supranuclear palsy. Caudate volume loss and tract degeneration of superior cerebellar peduncles was also observed in progressive supranuclear palsy. Interestingly, area of the midbrain was reduced in both syndromes compared to controls, although this was greater in progressive supranuclear palsy.
Although neuroanatomical differences were identified between these distinctive clinical syndromes, substantial overlap was also observed, including midbrain atrophy, suggesting these two syndromes may have common pathophysiological underpinnings.
Progressive supranuclear palsy; apraxia of speech; voxel-based morphometry; diffusion tensor imaging; midbrain
Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists.
We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities.
Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions.
OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option.
Dopamine; Othello's syndrome; Parkinson's disease; Delusion
We aimed to determine if there is an association between teaching and the development of progressive speech and language disorders (SLDs). Occupation was compared between 100 patients with a progressive SLD, 404 Alzheimer’s dementia patients, and the 2008 US census. In SLDs the most common occupation was teacher (22%), versus 8% in Alzheimer’s dementia. The odds ratio of being a teacher in SLDs compared to Alzheimer’s dementia was 3.4 (95% CI=1.87, 6.17). No differences were observed in the frequency of other occupations. The frequency of teachers was higher in SLDs compared to the US census; odds ratio of 6.9 (95% CI=4.3, 11.1). Farming, forestry and fishing occupations were more frequent in SLDs compared to the US census. We identified an association between progressive SLDs and the occupation of teaching. Since teaching is a communication demanding occupation, teachers may be more sensitive to the development of speech and language impairments.
Alzheimer’s; dementia; aphasia; teacher; occupation
Most subjects with logopenic primary progressive aphasia (lvPPA) have beta-amyloid (Aβ) deposition on Pittsburgh Compound B PET (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line-plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on F18-fluorodeoxyglucose PET, and presence and distribution of microbleeds and white matter hyperintensities (WMH) were assessed.
Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions, and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.
Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA, and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.
Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
We aimed to assess associations between clinical, imaging, pathological and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into three groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared to left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.
Frontotemporal dementia; frontal lobes; MRI; asymmetry; microtubule associated protein tau; progranulin; C9ORF72; pathology
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe
To discuss apraxia of speech (AOS) as it occurs in neurodegenerative disease (progressive AOS, or PAOS) and how its careful study may contribute to general concepts of AOS and help refine its diagnostic criteria.
The paper summarizes our current understanding of the clinical features and neuroanatomical and pathologic correlates of PAOS and its relationship to primary progressive aphasia (PPA). It addresses similarities and differences between PAOS and stroke-induced AOS that may be relevant to improving our understanding of AOS in general.
PAOS is clinical disorder that should be distinguished from PPA. Its recognition is important to clinical care provided by speech-language pathologists, but it also has implications for neurologic localization and diagnosis, and prediction of underlying pathology and histochemistry. The clinical features of PAOS and stroke-induced AOS have not been explicitly compared, but they may not be identical because PAOS does not follow a vascular distribution, the brunt of cortical pathology is in the premotor and supplementary motor area, and its onset, rather than acute, is slowly progressive with potential for adaptation to gradual impairment. Careful description and study of PAOS may be a valuable source of information for refining our understanding of AOS in general.
apraxia of speech; progressive apraxia of speech; primary progressive aphasia; motor speech programming
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
To report three patients with history of transient global amnesia who developed primary progressive aphasia.
Three patients presenting to the Neurology clinic with language complaints
Tertiary care center
We describe three patients with a history of transient global amnesia who were subsequently diagnosed with primary progressive aphasia. All patients had recurrent attacks of transient global amnesia. The diagnoses of primary progressive aphasia were supported by speech pathology evaluations, neuropsychometric testing and imaging findings. PET scans, for example, revealed left posterior frontal hypometabolism in one patient, predominately left temporal-parietal hypometabolism in another while single-photon emission computed tomography demonstrated decreased perfusion in the anterior left temporal and frontal lobe in the third.
There may be a relationship between recurrent transient global amnesia and the development of primary progressive aphasia.
Neuroimaging has played an important role in the characterization of the frontotemporal dementia (FTD) syndromes, demonstrating neurodegenerative signatures that can aid in the differentiation of FTD from other neurodegenerative disorders. Recent advances have been driven largely by the refinement of the clinical syndromes that underlie FTD, and by the discovery of new genetic and pathological features associated with FTD. Many new imaging techniques and modalities are also now available that allow the assessment of other aspects of brain structure and function, such as diffusion tensor imaging and resting state functional MRI. Studies have utilized these recent techniques, as well as traditional volumetric MRI, to provide further insight into disease progression across the many clinical, genetic and pathological variants of FTD. Importantly, neuroimaging signatures have been identified that will improve the clinician’s ability to predict underlying genetic and pathological features, and hence ultimately improve patient diagnosis.
Magnetic Resonance Imaging; Diffusion Tensor Imaging; Resting-state functional MRI; behavioral variant frontotemporal dementia; semantic dementia; agrammatic; apraxia of speech; C9ORF72 hexanucleotide repeat; progranulin; tau; TDP-43; fused in Sarcoma; atrophy; white matter tracts; functional connectivity
Recently, we evaluated two patients with corticobasal syndrome (CBS) who reported symptom onset after limb immobilization. Our objective was to investigate the association between trauma, immobilization and CBS.
The charts of forty-four consecutive CBS patients seen in the Mayo Clinic Alzheimer Disease Research Center were reviewed with attention to trauma and limb immobilization.
10 CBS patients (23%) had immobilization or trauma on the most affected limb preceding the onset or acceleration of symptoms. The median age at onset was 61. Six patients manifested their first symptoms after immobilization from surgery or fracture with one after leg trauma. Four patients had pre-existing symptoms of limb dysfunction but significantly worsened after immobilization or surgery.
23 percent of patients had immobilization or trauma of the affected limb. This might have implications for management of CBS, for avoiding injury, limiting immobilization and increasing movement in the affected limb.
Corticobasal syndrome; plasticity; immobilization
Atypical variants of Alzheimer’s disease (AD) have been pathologically defined based on the distribution of neurofibrillary tangles; hippocampal sparing (HpSp) AD shows minimal involvement of the hippocampus and limbic predominant (LP) AD shows neurofibrillary tangles restricted to the medial temporal lobe. We aimed to determine whether MRI patterns of atrophy differ across HpSp AD, LP AD and typical AD, and whether imaging could be a useful predictor of pathological subtype during life.
In this case-control study, we identified 177 patients who had been prospectively followed in the Mayo Clinic Alzheimer’s Disease Research Center, were demented during life, had AD pathology at autopsy (Braak stage ≥ IV, intermediate-high probability AD) and an antemortem MRI. Cases were assigned to one of three pathological subtypes (HpSp n=19, typical n=125, or LP AD n=33) based on neurofibrillary tangle counts and their ratio in association cortices to hippocampus, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss across groups, and to controls.
The severity of medial temporal and cortical grey matter atrophy differed across subtypes. The most severe medial temporal atrophy was observed in LP AD, followed by typical AD, and then HpSp AD. Conversely, the most severe cortical atrophy was observed in HpSp AD, followed by typical AD, and then LP AD. A ratio of hippocampal-to-cortical volume provided the best discrimination across all three AD subtypes. The majority of typical AD (98/125;78%) and LP AD (31/33;94%) subjects, but only 8/19 (42%) of the HpSp AD subjects, presented with a dominant amnestic syndrome.
Patterns of atrophy on MRI differ across the pathological subtypes of AD, suggesting that MR regional volumetrics reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype during life.
US National Institutes of Health (National Institute on Aging)
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.
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.
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.
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.
Few studies have assessed parkinsonian motor features features across variants of primary progressive aphasia (PPA). Our objective was to compare degree of parkinsonian motor features features between two PPA variants.
Parkinsonian motor features were assessed with the Unified Parkinson’s Disease Rating scale in prospectively recruited PPA subjects, classified based on recently published criteria. Comparisons across groups were performed with Fisher’s exact test for binary data and Mann-Whitney U test for continuous data.
Twenty-three PPA subjects were diagnosed with logopenic (n=11) or nonfluent/agrammatic (n=12) aphasia. There were no significant differences in illness duration (agrammatic=3.4 years; logopenic=3.3 years) or age at onset (nonfluent/agrammatic =67.3; logopenic=62.0), but those with logopenic aphasia were more impaired on Mini-Mental State Examination (21.7/30 points vs. 26.1/30; p=0.04). In contrast, those with logopenic aphasia had fewer parkinsonian motor features than those with agrammatic aphasia (5.7/132 vs. 16.8/132; p=0.003) which was driven by bradykinesia (p=0.02) and speech facial/expression (p=0.04); less so rigidity (p=0.06). Dysarthria was more frequent in the nonfluent/agrammatic subgroup.
Nonfluent/agrammatic subjects have more parkinsonian motor features than logopenic subjects, likely reflecting underlying tau pathology in the agrammatic variant.
Parkinsonism; primary progressive aphasia; logopenic aphasia; agrammatic aphasia; extrapyramidal
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
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 a standardized MRI which was evaluated using VBM. 17 patients with bvFTD were recruited and 11 were included in the study and compared to 11 age and gender matched controls. Six were excluded for lack of MRI at 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 grey 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 likely reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.
Frontotemporal dementia; magnetic resonance imaging; obsessive behavior; compulsive behavior
Evaluating the integrity of white matter tracts with diffusion tensor imaging may differentiate primary lateral sclerosis from progressive supranuclear palsy.
Thirty-three prospectively recruited subjects had standardized evaluations and diffusion tensor imaging: 3 with primary lateral sclerosis who presented with features suggestive of progressive supranuclear palsy, 10 with probable or definite progressive supranuclear palsy, and 20 matched controls. We compared fractional anisotropy of the corticospinal tract, superior cerebellar peduncle and body of the corpus callosum between groups.
Both the primary lateral sclerosis and progressive supranuclear palsy subjects showed reduced fractional anisotropy in superior cerebellar peduncles and body of the corpus callosum compared to controls, but only primary lateral sclerosis subjects showed reductions in the corticospinal tracts. A ratio of corticospinal tract/superior cerebellar peduncle best distinguished the disorders (p<0.02).
The corticospinal tract/superior cerebellar peduncle ratio is a marker to differentiate primary lateral sclerosis from progressive supranuclear palsy.
Progressive supranuclear palsy; primary lateral sclerosis; motor neuron disease; diffusion tensor imaging
The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer’s disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer’s type.
A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer’s type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups.
Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer’s type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer’s type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume.
Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer’s type and both modalities provide excellent discrimination between groups.
Adult-onset primary lower limb dystonia (AOPLLD) has been reported as an early sign of Parkinson’s disease (PD) or Parkinson-plus syndrome in case series. No prior systematic analysis has assessed clinical clues predicting later development of PD or Parkinson-plus syndrome.
We identified patients with AOPLLD from medical records. We excluded patients who had not been diagnosed by a neurologist, and who had a pre-existing diagnosis of PD, psychogenic, or secondary dystonia. Records were subdivided into those who later developed PD or Parkinson-plus disorders and those who did not. The following clinical characteristics were compared between the two groups: dystonia onset age, type of dystonia, levodopa response, anticholinergic response, and family history of Parkinsonism or tremor.
Twenty-two AOPLLD patients were identified: 77% female; the median dystonia onset age was 53 years. Eight (37%) developed Parkinson’s disease; 2 (9%) developed corticobasal syndrome. Twelve patients (54%) did not develop Parkinsonism after a median follow-up period of 1.5 years. There was a significant difference in leg dystonia levodopa response between the two groups (p = 0.02).
In patients with AOPLLD, leg dystonia with levodopa response is associated with the future development of PD.
Dystonia; Parkinson’s disease; leg dystonia; levodopa