A 34-year-old man with progressive behavioral and language disturbance.
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Adult↗
Biomedical subjects
Joseph E Parisi
Publications and source records attributed to Joseph E Parisi.
Argyrophilic grains: a distinct disease or an additive pathology?
BACKGROUND: Argyrophilic grains (AG) are silver-positive spindle-shaped lesions found at postmortem. Their significance is controversial. OBJECTIVE: To determine clinical correlates of AG and MRI patterns of atrophy that could allow premortem recognition of this pathology. METHODS: Cases with AG were identified from a longitudinal study of aging and dementia. Clinical features were compared between subjects with and without dementia. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in subjects compared to controls. Whole brain volumes (WBV) were compared across groups. RESULTS: Twenty-two cases (14 females; median age at death of 90 years; range: 70-101) with AG were identified. Eight of the 22 were demented. Those with dementia had higher Braak (p=0.02) and lower Mini-Mental State Examination (MMSE) (p=0.002). VBM demonstrated hippocampal atrophy in those with dementia (N=3) but no atrophy in those without (N=9). There was no difference in WBV between groups. CONCLUSION: AG is a feature of old age commonly occurring in non-demented subjects. In this age group, the presence of AG may reduce the threshold for dementia.
Aged↗
Voxel-based morphometry in autopsy proven PSP and CBD.
The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.
Aged↗
Involvement of hypocretin neurons in multiple system atrophy.
Hypocretin/Orexin (Hcrt/Orx) neurons of the posterolateral hypothalamus have been implicated in control of sleep and autonomic function. Sleep disorders and autonomic failure are important manifestations of multiple system atrophy (MSA). We sought to determine whether Hcrt/Orx neurons were involved in this disorder. Hypothalamus was obtained from seven subjects with neuropathologically confirmed MSA, and seven age-matched controls. 50 mum sections obtained throughout the posterior hypothalamus were immunostained for Hcrt-1 and alpha-synuclein. In MSA, there was a marked reduction of the total numbers of Hcrt/Orx neurons compared to controls (1,009 +/- 190 cells in MSA vs. 3,206 +/- 185 in controls, P < 0.0001). There were abundant glial cytoplasmic inclusions in the area of distribution of Hcrt/Orx neurons in MSA. This is the first demonstration of loss of Hcrt/Orx neurons in MSA, which is consistent with a system degeneration of neurons involved in homeostatic function, including sleep and autonomic regulation, in this disorder.
Adult↗
Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study.
We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G-->A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G-->A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease--the 'hypoprogranulinopathies'.
Brain Mapping↗
Differential involvement of hypothalamic vasopressin neurons in multiple system atrophy.
We sought to determine whether there is differential involvement of different groups of hypothalamic arginine-vasopressin (AVP) synthesizing neurons in multiple system atrophy (MSA). Hypothalamus was obtained from five subjects with clinical diagnosis of MSA confirmed neuropathologically and five age-matched controls. Sections were immunostained for AVP, and cells with visible nuclei were counted in the posterior portion of the paraventricular nucleus (PVNp), supraoptic nucleus (SON), magnocellular PVN and suprachiasmatic nucleus (SCN). Sections of the hypothalamus and medulla were also immunostained for tyrosine hydroxylase (TH). There was a significant loss of AVP neurons in the PVNp in MSA compared with controls (17 +/- 3 versus 59 +/- 10 cells/section, P < 0.01). There was preservation of AVP- and TH-immunoreactive neurons in the SON and magnocellular PVN in all MSA cases. In contrast, there was marked depletion of TH-immunoreactive fibres innervating these magnocellular AVP neurons, coincident with a loss of neurons in the A1 area (6 +/- 1 versus 13 +/- 1 cells/section, P < 0.01). There was loss of AVP neurons in the SCN in MSA compared with control cases (14 +/- 3 versus 71 +/- 16 cells/section, P < 0.02). Our results indicate that, in MSA, loss of AVP neurons in the PVNp may contribute to sympathetic failure, whereas loss of catecholaminergic input from the brainstem to the magnocellular AVP neurons may contribute to impaired AVP secretion in response to orthostatic stress. Loss of AVP neurons in the SCN may contribute to impaired circadian regulation of endocrine and autonomic functions.
Aged↗
Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech.
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.
Aged↗
Cognitive impairment and celiac disease.
OBJECTIVE: To characterize the clinical, radiological, and electrophysiological laboratory profiles and histological features of patients who developed cognitive impairment temporally associated with celiac disease. DESIGN: Case series. SETTING: Referral center. PATIENTS: Patients with the onset of progressive cognitive decline within 2 years of symptomatic onset or with a severe exacerbation of biopsy-proved adult celiac disease were identified from the Mayo Clinic medical records from January 1, 1970, to December 31, 2005. Patients were excluded if an alternate cause of their cognitive impairment was identified. RESULTS: Thirteen patients (5 women) were identified. The median age at cognitive impairment onset was 64 years (range, 45-79 years), which coincided with symptom onset or exacerbation of diarrhea, steatorrhea, and abdominal cramping in 5 patients. Amnesia, acalculia, confusion, and personality changes were the most common presenting features. The average initial Short Test of Mental Status score was 28 of a total of 38 (range, 18-34), which was in the moderately impaired range. The results of neuropsychological testing suggested a trend of a frontosubcortical pattern of impairment. Ten patients had ataxia, and 4 of them also had peripheral neuropathy. Magnetic resonance imaging of the head showed nonspecific T2 hyperintensities, and electroencephalography showed nonspecific diffuse slowing. Deficiencies in folate, vitamin B(12), vitamin E, or a combination were identified in 4 patients, yet supplementation did not improve their neurological symptoms. Three patients improved or stabilized cognitively with gluten withdrawal. A detailed histological analysis revealed nonspecific gliosis. CONCLUSIONS: A possible association exists between progressive cognitive impairment and celiac disease, given the temporal relationship and the relatively high frequency of ataxia and peripheral neuropathy, more commonly associated with celiac disease. Given the impact for potential treatment of similar cases, recognition of this possible association and additional studies are warranted.
Aged↗
Frontotemporal lobar degeneration without lobar atrophy.
BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal inclusions (FTLD-U) is the most common form of frontotemporal dementia. Neuronal loss and gliosis in cornu ammonis 1 and the subiculum of the hippocampus are features of hippocampal sclerosis (HpScl), which occurs in many cases of FTLD-U. OBJECTIVE: To determine if there were any clinical or magnetic resonance imaging correlates of HpScl in FTLD-U. DESIGN: We reviewed demographics and clinical features of 24 cases of FTLD-U and subjectively assessed the severity of neuronal loss and frequency of ubiquitin-positive neuronal lesions in the frontal and temporal cortices and the dentate gyrus of the hippocampus. SETTING: Mayo Clinic, Rochester, Minn. Patients Twenty-six cases were identified from the medical records linkage system query that met clinical criteria and had autopsy material available for additional studies. Two cases were excluded from further analysis after pathologic studies revealed coexisting Alzheimer disease, leaving 24 cases included in the study. Cases were subdivided based on the presence or absence of HpScl. MAIN OUTCOME MEASURES: Patterns of gray matter atrophy were assessed in cases of FTLD-U with and without HpScl using voxel-based morphometry. RESULTS: Six of the 24 cases of FTLD-U did not have HpScl. No differences were found in demographic or clinical features, including disease duration, between cases with and without HpScl; however, voxel-based morphometry analysis revealed minimal cortical atrophy in cases without HpScl, which was significantly different from the pattern of moderate to severe frontal and temporal lobe atrophy in FTLD-U with HpScl. This finding was in keeping with histopathologic observations. CONCLUSIONS: Despite similar clinical features, cases of FTLD-U with HpScl differ from those without HpScl with respect to pathologic findings and structural imaging. Specifically, FTLD-U without HpScl showed on average minimal or no cortical atrophy, even at end-stage disease. Consequently, FTLD-U without HpScl does not conform to the proposed FTLD staging scheme, is underrecognized, and may have different genetic and environmental underpinnings.
Aged↗
Clinically undetected motor neuron disease in pathologically proven frontotemporal lobar degeneration with motor neuron disease.
BACKGROUND: Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is a pathological entity characterized by motor neuron degeneration and frontotemporal lobar degeneration. The ability to detect the clinical signs of dementia and motor neuron disease in pathologically confirmed FTLD-MND has not been assessed. OBJECTIVES: To determine if all cases of pathologically confirmed FTLD-MND have clinical evidence of frontotemporal dementia and motor neuron disease, and to determine the possible reasons for misdiagnosis. METHOD: Review of historical records and semiquantitative analysis of the motor and extramotor pathological findings of all cases of pathologically confirmed FTLD-MND. RESULTS: From a total of 17 cases of pathologically confirmed FTLD-MND, all had clinical evidence of frontotemporal dementia, while only 10 (59%) had clinical evidence of motor neuron disease. Semiquantitative analysis of motor and extramotor pathological findings revealed a spectrum of pathological changes underlying FTLD-MND. Hippocampal sclerosis, predominantly of the subiculum, was a significantly more frequent occurrence in the cases without clinical evidence of motor neuron disease (P<.01). In addition, neuronal loss, gliosis, and corticospinal tract degeneration were less severe in the other 3 cases without clinical evidence of motor neuron disease. CONCLUSIONS: Clinical diagnostic sensitivity for the elements of FTLD-MND is modest and may be affected by the fact that FTLD-MND represents a spectrum of pathological findings, rather than a single homogeneous entity. Detection of signs of clinical motor neuron disease is also difficult when motor neuron degeneration is mild and in patients with hippocampal sclerosis.
Adult↗
Neuropathologic features of amnestic mild cognitive impairment.
BACKGROUND: The neuropathologic substrate of amnestic mild cognitive impairment (aMCI) is not known. OBJECTIVE: To determine the neuropathologic features of patients who died while their clinical classification was aMCI. DESIGN: Cohort study. SETTING: Community based. PARTICIPANTS: Sixty-six individuals, including 15 who had memory impairment beyond that allowed for aging but who were not demented, were studied along with 28 clinically healthy individuals and 23 patients with probable Alzheimer disease (AD) for comparison. MAIN OUTCOME MEASURES: Standard neuropathologic techniques and classification according to Khachaturian, Consortium to Establish a Registry for Alzheimer Disease, and National Institute on Aging-Reagan criteria were used to analyze autopsy tissue from 15 individuals who died while their clinical diagnosis was aMCI. For comparison, autopsy data on age-matched groups of clinically healthy individuals and patients with probable AD were analyzed. RESULTS: Most patients with aMCI did not meet the neuropathologic criteria for AD, but their pathologic findings suggest a transitional state of evolving AD. All the patients with aMCI had pathologic findings involving medial temporal lobe structures, likely accounting for their memory impairment. In addition, there were many concomitant pathologic abnormalities, including argyrophilic grain disease, hippocampal sclerosis, and vascular lesions. CONCLUSIONS: The neuropathologic features of aMCI matched the clinical features and seemed to be intermediate between the neurofibrillary changes of aging and the pathologic features of very early AD.
Aged↗
Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia.
BACKGROUND: The pathologic outcome of patients diagnosed with mild cognitive impairment (MCI) following progression to dementia is poorly understood. OBJECTIVE: To determine the pathologic substrates of dementia in cases with prior diagnosis of amnestic MCI. DESIGN AND SETTING: Community-based cohort. PATIENTS: Thirty-four subjects followed up prospectively as part of a community-based study who were diagnosed with amnestic MCI, progressed to clinical dementia, and underwent subsequent postmortem brain analysis. MAIN OUTCOME MEASURES: Neuropathologic analyses resulted in assignment of a primary pathologic diagnosis and included staging of Alzheimer pathologic abnormalities and identification of contributing vascular disease, Lewy bodies, and argyrophilic grains. RESULTS: Although the majority of subjects progressed both clinically and pathologically to Alzheimer disease (AD), 10 (29%) of them developed non-AD primary pathologic abnormalities. All of the cases were found to have sufficient pathologic abnormalities in mesial temporal lobe structures to account for their amnestic symptoms regardless of the cause. Most subjects were found to have secondary contributing pathologic abnormalities in addition to primary pathologic diagnoses. No significant differences between subjects with and without neuropathologically proven AD were detected in demographic variables, apolipoprotein E genotype, or cognitive test measures at onset of MCI, onset of dementia, or last clinical evaluation. CONCLUSIONS: The neuropathologic outcome of amnestic MCI following progression to dementia is heterogeneous, and it includes AD at a high frequency. Complex neuropathologic findings including 2 or more distinct pathologic entities contributing to dementia may be common in community-based cohorts. Neither demographic variables nor cognitive measures had predictive value in determining which patients diagnosed with MCI will develop the neuropathologic features of AD.
Aged↗
Cognitive measures predict pathologic Alzheimer disease.
BACKGROUND: Neuropsychologic testing is often used to infer neuropathologic processes, but clinicopathologic correlations for individual cognitive measures are based on a small number of published studies. OBJECTIVE: To examine the usefulness of the age- and education-adjusted Mayo Cognitive Factor Scales (MCFS) obtained at participants' initial assessments for predicting the presence or absence of pathologic Alzheimer disease (AD). DESIGN: This was a longitudinal study of a cohort of elderly patients with and without cognitive complaints who were followed up until death. Mayo Cognitive Factor Scales age- and education-adjusted standard scores from the participants' initial evaluations were used to calculate classification accuracy statistics for neuropathologic AD diagnosis obtained approximately 6 years after testing. Subjects with non-AD diagnoses or substantial non-AD-related changes were excluded from the study. SETTING: Academic medical center. PARTICIPANTS: One hundred two participants were evaluated clinically and underwent neuropathologic examination at autopsy. All were part of the Mayo Clinic Alzheimer's Disease Patient Registry or Alzheimer Disease Research Center. RESULTS: All Mayo Cognitive Factor Scale scores were significantly correlated with AD criteria. Logistic regression modeling including Mayo Cognitive Factor Scales Verbal Comprehension and Retention indices revealed high positive predictive value with moderate sensitivity and specificity for pathologic AD. CONCLUSION: Neuropsychologic test scores at initial evaluations were predictive of pathologic AD.
Aged↗
Rates of cerebral atrophy in autopsy-confirmed progressive supranuclear palsy.
OBJECTIVE: To determine the rates of cerebral atrophy and ventricular expansion in six patients with autopsy confirmed progressive supranuclear palsy (PSP) and multiple antemortem volumetric head MRI scans. METHODS: This study uses the boundary shift integral to determine rates of cerebral atrophy and ventricular expansion in six patients with pathologically confirmed PSP compared with six age- and sex-matched control subjects. RESULTS: Patients with PSP had a rate of cerebral atrophy and ventricular expansion of 1.3 and 7.0% per year compared with 0.4 and 1.8% in control subjects. INTERPRETATION: These rates provide a benchmark that can be used to monitor future treatment response in PSP.
Aged↗
Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment.
A previous autopsy study of patients with amnestic-type mild cognitive impairment (MCI) suggested an overrepresentation of argyrophilic grain disease (AGD). We studied 34 patients who had diagnoses of amnestic MCI during progression to dementia and who came to autopsy. Neuropathologic evaluation included routine histochemical and immunohistochemical methods, including a 4-repeat tau-specific marker (ET3). AGD was found in association with a variety of neuropathologic diseases in 18 (53%) cases but was the primary pathologic finding in only one (3%) case. ET3 allowed the detection of AGD in 5 additional cases missed using standard techniques. Cases with AGD were significantly older than those without (mean, 94 vs 84 years; p < 0.004, rank sum test). No significant differences were found between groups for other demographic variables, association of AGD with neuropathologic findings of Alzheimer disease, Lewy body, or cerebrovascular disease, or global measures of cognitive function, although there was a nonsignificant trend towards worsening cognitive status in cases with AGD. AGD is a common pathologic finding in subjects who have been diagnosed with amnestic MCI.
Aged↗
Histopathologic findings of malformations of cortical development in an epilepsy surgery cohort.
CONTEXT: Malformations of cortical development (MCDs) are an important cause of pharmacoresistent epilepsy and are frequently diagnosed in surgical pathology. The lack of uniform tissue processing and standard histopathologic nomenclature to describe MCDs has resulted in diagnostic ambiguity. OBJECTIVE: To describe the immunohistochemical findings of MCDs from a relatively large surgical epilepsy cohort and incorporate terminology that more adequately reflects the histopathologic findings into a contemporary classification of MCD. DESIGN: Utilizing the Mayo Clinic Rochester Surgical Pathology Database and patient records, 53 patients with previous intractable epilepsy and a known malformation of cortical development were identified. All of the cohort's paraffin embedded surgical specimens were resectioned and stained with hematoxylin-eosin, Luxol fast blue/cresyl violet, neurofilament protein, and glial fibrillary acidic protein. Each specimen was reviewed histologically and categorized according to a proposed focal MCD classification scheme that substitutes cytoarchitectural dysmorphism for cortical dysplasia and architectural disorganization for microdysgenesis. RESULTS: An MCD was recognized in 49 patients and grouped into 1 of the following 4 categories: (1) cytoarchitectural dysmorphism with balloon cells (n = 19), (2) cytoarchitectural dysmorphism without balloon cells (n = 12), (3) architectural disorganization (n = 8), or (4) polymicrogyria (n = 9). CONCLUSIONS: The histopathologic features of focal MCD in a large epilepsy surgical cohort by using practical immunohistochemistry and a contemporary MCD classification scheme are described. It is proposed that the term focal cortical dysplasia be renamed as focal malformations of cortical development.
Adolescent↗
The pathology of multiple sclerosis: evidence for heterogeneity.
The idiopathic inflammatory demyelinating diseases (IIDDs) consist of a broad spectrum of disorders that vary in their clinical course, regional distribution, and pathology. Though pathology of these demyelinating disorders demonstrates extensive interindividual heterogeneity, there is notable homogeneity within individual patients. The relation between the diverse underlying pathology of IIDDs and the various clinical, paraclinical, and radiological findings is unclear. Finding less-invasive clinical or paraclinical surrogate markers, which accurately and reliably predict the underlying distinct pathologies within the family of IIDDs, can potentially guide future therapies that better target specific pathogenic mechanisms.
Central Nervous System↗
Cortical demyelination and diffuse white matter injury in multiple sclerosis.
Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.
Acute Disease↗