Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes.

OBJECTIVE: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. METHODS: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. RESULTS: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. CONCLUSION: PGRN mutations are not a common cause of ALS phenotypes.

Nonvasculitic autoimmune inflammatory meningoencephalitis imitating Creutzfeldt-Jakob disease.

BACKGROUND: Nonvasculitic autoimmune inflammatory meningoencephalitis and Creutzfeldt-Jakob disease can present as rapidly progressive encephalopathies with similar clinical features. Slowing of background rhythm is an electroencephalographic characteristic shown by both, but persistent periodic sharp waves are more specific for Creutzfeldt-Jakob disease and have not been reported in nonvasculitic autoimmune inflammatory meningoencephalitis or related autoimmune meningoencephalitides. OBJECTIVE: To describe a patient with clinical (rapidly progressive myoclonus, dementia, and Parkinsonism) and electroencephalographic findings (persistent periodic sharp waves) that diagnostically suggest Creutzfeldt-Jakob disease. DESIGN AND SETTING: A case report at the Mayo Clinic Arizona, Scottsdale. RESULTS: The patient made a dramatic recovery with resolution of the periodic sharp wave complexes after treatment with high-dose corticosteroids. Our case is the first reported case of a patient with probable nonvasculitic autoimmune inflammatory meningoencephalitis and electroencephalographic periodic complexes suggestive of Creutzfeldt-Jakob disease. CONCLUSION: Rapidly progressive encephalopathy with periodic sharp wave complexes can be associated with a reversible autoimmune syndrome.

Asymmetric cortical degeneration syndromes. A proposed clinical classification.

Twenty-six patients presented with slowly progressive focal neurologic symptoms that conformed clinically to one of three categories: asphasia, perceptuomotor dysfunction, or neuropsychiatric dysfunction. Of 12 patients with progressive aphasia, seven were dysfluent and five were fluent. Nine patients had progressive perceptuomotor impairment due to bilateral parietal lobe atrophy, which also included frontal lobe signs in seven patients and occipital lobe signs in three patients. The right hemisphere was more severely involved in five patients and the left hemisphere in four. Five patients had a progressive neuropsychiatric syndrome, and there was also generalized spasticity in three patients due to frontal lobe atrophy. The clinically suspected anatomic localization of cortical atrophy or hypoperfusion in all three categories was confirmed with neuroimaging techniques. A brain biopsy specimen from one patient showed mild, nonspecific degenerative changes. A clinical classification scheme incorporating our observations as well as the observations of others is presented to aid in the recognition of these syndromes.

Progressive apraxia in clinically discordant monozygotic twins.

OBJECTIVE: To determine disease concordancy in the first identical twin with corticobasal degeneration. The patients were 63-year-old, erythrocyte antigen-confirmed monozygotic male twins who were clinically discordant for progressive apraxia caused by corticobasal degeneration. INTERVENTIONS: Neuropsychologic and kinesiologic testing, magnetic resonance imaging, and positron emission tomographic measurements of cerebral metabolic rate for glucose. RESULTS: The affected twin had lower neuropsychologic and kinesiologic test scores than did his brother, particularly on tests sensitive to right-compared with left-hemisphere function; widespread cerebral atrophy, worst in right parietotemporal cortices; and reduced whole-brain cerebral metabolic rate for glucose, worst in right posterior cortices. The clinically asymptomatic twin had normal neuropsychologic and kinesiologic test scores but performed more poorly on tests sensitive to left- compared with right-hemisphere function; had no abnormalities on magnetic resonance imaging; and had left temporoparietal as well as mild whole-brain hypometabolism. CONCLUSIONS: Corticobasal degeneration may remain clinically discordant in identical twins after 7 years. Positron emission tomography and neuropsychologic findings suggest the possibility of a preclinical stage of corticobasal degeneration. There is generalized cortical atrophy in patients with corticobasal degeneration in addition to focal atrophy.

Giant cell (temporal) arteritis: a treatable cause of multi-infarct dementia.

Dementia occurs infrequently in patients with giant cell (temporal) arteritis (GCA). Three elderly women with biopsy-proven GCA showed abrupt cognitive decline during periods of clinically active GCA, 1 to 6 months after diagnostic temporal artery biopsy, during periods of corticosteroid taper. One patient had additional clinical signs of cerebral infarction and other ischemic phenomena. Reinstitution of higher oral doses of corticosteroids successfully prevented further cognitive losses and permitted gradual but incomplete improvement of cognitive function in 1 patient. Neuropsychologic data from 2 patients 7 to 10 months after temporal artery biopsy suggested multifocal cognitive impairment, and the 3rd patient appeared clinically to be globally, severely demented. Neuroimaging studies revealed multiple areas of infarction, predominantly in the posterior circulation territory. One patient had bilateral vertebral artery occlusions (digital subtraction angiography) and bilaterally reduced carotid system perfusion pressures (oculoplethysmography). There were no associated cardiovascular risk factors or family history of dementia in these patients.

Ventrolateral and dorsomedial somatosensory association cortex damage produces distinct somesthetic syndromes in humans.

Five somatosensory cortices have distinctive somatotopic representations, cytoarchitecture, and connectivity: primary somatosensory cortex (SI), ventrolateral association cortices (SII, SIII, and SIV), and dorsomedial association cortex (supplementary sensory area). Patients with focal lesions of ventrolateral (n = 5) and dorsomedial (n = 6) somatosensory association cortices (SACs) and hemiparetic (n = 8) and neurologically normal control patients (n = 14) underwent detailed somesthetic testing that encompassed basic, intermediate, and complex (tactile object recognition) somesthetic functions. Dorsomedial lesions acutely caused severe disruption of somesthetic processing and severe apraxia when the area of damage was extensive and involved anterior and posterior cortices. In contrast, ventrolateral lesions caused tactile agnosia. Chronically, sensorimotor function following dorsomedial damage improved considerably. Tactile agnosia following ventrolateral damage, however, was readily detectable for years following onset. Functional differences between ventrolateral and dorsomedial SACs may reflect parallel processing in dual somatosensory systems.

Primary lateral sclerosis: a neuropsychological study.

Nine patients with clinically diagnosed, radiologically supported primary lateral sclerosis underwent cognitive testing. None was demented, but eight had mild cognitive impairment. Performances were most consistently impaired on neuropsychological tests sensitive to frontal lobe functions, followed by tests sensitive to memory. Cognitive testing may be useful in helping to establish a cortical localization in patients with the syndrome of progressive spasticity. There are potential nosologic relations between primary lateral sclerosis and other degenerative frontal lobe syndromes, such as frontal lobe dementia and progressive spasticity with dementia.

Neurologic disease in biopsy-proven giant cell (temporal) arteritis.

Neurologic findings were studied in 166 consecutive patients with biopsy-proven giant cell (temporal) arteritis. Neurologic problems occurred in 51 patients (31%): neuropathies (23), TIA/strokes (12), neuro-otologic syndromes (11), tremor (6), neuropsychiatric syndromes (5), tongue numbness (3), and myelopathy (1). Neuro-ophthalmologic problems occurred in 35 patients (21%): amaurosis fugax (AF) (17), permanent vision loss (PVL) (14), scintillating scotoma (8), and diplopia (3). Abnormalities in large arteries in 52 patients (31%) included bruits and diminished pulses. The carotid artery was involved in 31 patients (bilateral in 58%). Overall, 35% of patients with carotid disease had TIA/stroke, AF, or PVL.

Peripheral neuropathic syndromes in giant cell (temporal) arteritis.

Of 166 consecutive patients with histologically confirmed giant cell (temporal) arteritis (GCA) seen during a 3-year period, 23 (14%) had clinically diagnosed peripheral neuropathic syndromes temporally coincident with clinically active GCA. Electromyography and nerve conduction studies were performed in 16, confirming abnormalities in all. Of the 23 patients, 11 had a generalized peripheral neuropathy, nine had multiple mononeuropathies, and three had a mononeuropathy. The nerves affected as mononeuropathies were the median, ulnar, peroneal, tibial, and sural nerves, and the C-5 and L-5 nerve roots. Angiography, performed in two patients, demonstrated widespread arteritis involving the lower limbs and, after 3 months of oral corticosteroid treatment in one of these patients, an amputation specimen showed chronic arteritis.

Asymmetric cortical degenerative syndromes: clinical and radiologic correlations.

Eight patients presented with slowly progressive focal neurologic syndromes that conformed to one of three clinically defined categories: progressive nonfluent aphasia (three patients), progressive perceptual-motor impairment (four patients), and progressive frontal lobe syndrome (one patient). Planar MRI and MRI-based surface or volume renderings demonstrated focal areas of atrophy that correlated well with clinical deficits. Single-photon emission computed tomography (SPECT) showed areas of cortical hypoperfusion that corresponded to focally atrophic regions revealed by MRI, but abnormal areas with SPECT were larger than those suggested by MRI. MRI and SPECT are useful in defining the regional structural and functional cerebral abnormalities that underlie slowly progressive focal neurologic syndromes caused by asymmetric cortical degeneration.

Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy.

Five patients, age 54 to 80 years, presented between 3 weeks and 18 months after symptomatic onset of progressive cognitive decline, psychosis, and unsteady gait that proved to be due to a steroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitic syndrome. CSF examination showed elevated immunoglobulin (Ig)G index and IgG synthesis rate in all three patients in whom it was checked, and brain biopsy revealed perivascular lymphocytic infiltrates without vessel wall invasion.

Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes.

OBJECTIVE: To determine, in a cross-sectional evaluation of nondemented individuals, if age-related memory decline is influenced by apolipoprotein E (apoE) genotype. BACKGROUND: The apoE-4 allele is an important risk factor for AD. PET in cognitively normal apoE-4 carriers (mean age, 56 years) shows reduced cerebral metabolism suggestive of very early AD that precedes clinically evident memory loss or MRI-based hippocampal atrophy. METHODS: Tests of immediate and delayed recall (primary outcome measures) and other neuropsychological measures (secondary outcome measures) were given to three genetically defined groups of cognitively normal individuals (age, 49 to 69 years) including apoE-4 homozygotes (n = 25), apoE-4 heterozygotes (n = 25, all epsilon3/4), and apoE-4 noncarriers (n = 50). Groups were matched for age, gender, and educational background. Cross-sectional comparisons between the genetic subgroups of the relationship between age and test score were performed for each neuropsychological measure. RESULTS: There were no intergroup differences in mean scores on any neuropsychological measure, but tests sensitive to immediate and delayed recall showed a significant negative correlation with age in the apoE-4 homozygote group relative to the noncarrier group. CONCLUSION: Consistent with previous neuropsychological studies of early AD, this cross-sectional study suggests that age-related memory decline occurs earlier in cognitively healthy apoE-4 homozygotes than in apoE-4 heterozygotes and noncarriers, and precedes clinically detectable AD.

Pathologic heterogeneity in clinically diagnosed corticobasal degeneration.

BACKGROUND: Early reports suggested that corticobasal degeneration (CBD) is a distinct clinicopathologic entity. Because patients have had a fairly consistent constellation of clinical and laboratory findings, many have proposed that the pathologic diagnosis can be surmised with confidence during life. OBJECTIVE: To analyze the pathologic findings in a large series of cases with clinically diagnosed CBD. METHODS: Using the medical research linkage system of the Mayo Clinic for the period January 1990 to December 1997, we identified cases diagnosed during life with CBD who subsequently underwent autopsy. All patients had progressive asymmetric rigidity and apraxia (except one with rigidity but no apraxia) with other findings, suggesting additional cortical and basal ganglionic dysfunction. All cases underwent standardized neuropathologic examination with the distribution and severity of the pathologic changes determined for each case and the pathologic diagnoses based on currently accepted criteria. RESULTS: Thirteen cases were identified. The pathologic diagnoses were CBD in seven, AD in two, and one each for progressive supranuclear palsy, Pick's disease, nonspecific degenerative changes, and Creutzfeldt-Jakob disease. Two cases had negligible basal ganglia and nigral degeneration despite previously having obvious extrapyramidal signs. However, all patients had focal or asymmetric cortical atrophy with coexisting neuronal loss and gliosis with or without status spongiosis, which was maximal in the parietal and frontal cortical regions. CONCLUSIONS: The constellation of clinical features considered characteristic of CBD is associated with heterogeneous pathologies. Furthermore, this syndrome can occur in the absence of basal ganglia and nigral degeneration. The one invariable pathologic abnormality in patients with this syndrome, however, is asymmetric parietofrontal cortical degeneration. At present, accurate diagnosis of CBD requires tissue examination.

The nature of tactile agnosia: a case study.

A chronic tactile agnosic with a small, MRI-documented left inferior parietal infarction underwent detailed somesthetic testing to assess (1) the acquisition of sensory data, (2) the manipulation of somatosensory percept and its association with previous knowledge, and (3) recognition occurring at a deeper taxonomic level. Results suggest that tactile agnosia can arise from faulty high-level perceptual processes, but that the ability to associate tactually defined objects and object parts with episodic memory can be preserved. Consistent with anatomic and physiologic studies in nonhuman primates, inferior parietal cortex (including Brodmann area 40, possibly area 39) appears to serve as a high-level somatosensory region.

Rediscovering tactile agnosia.

Eighty-four patients with damage to various levels of the nervous system, ranging from the peripheral nerves to the cerebral cortex, underwent somesthetic assessment in order to determine the degree to which basic and complex perceptual and motor disorders affect tactile object recognition (TOR) and to determine whether TOR can be impaired in the absence of more basic sensorimotor imperception. The results suggest that (1) basic and intermediate disorders of somesthetic function impair TOR but are commensurately more severe for any given degree of TOR impairment in patients with peripheral lesions than in patients with cortical lesions; (2) neither hemiparesis nor hemianopia alone precludes normal TOR; (3) hemineglect contributes substantially to TOR impairment; (4) impairment of TOR can occur in the absence of more basic somesthetic dysfunction and constitutes tactile agnosia; (5) tactile agnosia is a subtle, nondisabling disorder that should be distinguished from the nonagnosic, severe and disabling disorder, astereognosis; and (6) tactile agnosia results from unilateral damage to parietotemporal cortices, possibly including the second somatosensory cortex, in either hemisphere.

Bilateral impairment of somesthetically mediated object recognition in humans.

Thirty adult patients (six in each of five groups--neurologically normal, lacunar infarct-related hemiparesis, unilateral thalamic lacunar infarction, right cortical infarction with mild left hemineglect, and extensive right cortical infarction with severe left hemineglect) were asked to perform various tasks that encompassed basic and intermediate somatosensory functions and tactile and visual object recognition. Patients with thalamic and cortical infarctions had severe impairment of contralateral hand-mediated somatosensory functions in all three categories of somesthetic tasks, although patients with cortical infarction were more impaired on the object recognition task than were patients with thalamic infarction. Patients with extensive damage to the right hemisphere and severe left hemineglect also had impairment of somesthetically mediated object recognition in the ipsilateral hand despite normal basic and intermediate somatosensory function and visually mediated object recognition analogous to unilateral tactile agnosia. All other groups had normal ipsilateral tactile object recognition.

Associative anomia: dissociating words and their definitions.

A 60-year-old woman, in whom magnetic resonance imaging and single photon emission computed tomography confirmed the presence of chronic damage to the left temporal lobe, had pure anomia with sparing of other language and cognitive functions. She could independently access lexical knowledge (words) and semantic knowledge (word definitions). We postulate that her anomia was due to a failure to associate lexical and semantic knowledge.

Chronic inflammatory meningoencephalitis should not be mistaken for Alzheimer's disease.

We describe two patients with a chronic encephalopathy that clinically resembled dementia but that resolved after oral administration of high-dose corticosteroid therapy. Both patients had serologically documented Sjögren's syndrome, a diagnosis that was further supported by biopsy of a salivary gland in one. Neither patient had radiologic evidence of vasculitis of the central nervous system. In one patient, meningeal and brain biopsy specimens showed perivascular inflammatory lymphocytic infiltrates. Chronic inflammatory meningoencephalitis is a treatable cause of chronic encephalopathy that should be clinically distinguished from dementia associated with Alzheimer's disease.

Simultanagnosia as the initial sign of degenerative dementia.

In a study of 10 patients with degenerative brain disease that manifested as simultanagnosia, our aims were (1) to elucidate their clinical, neuropsychologic, and radiologic findings to determine whether these patients might represent a group distinguishable from those with typical Alzheimer's disease and (2) to help clinicians recognize this entity. All patients were initially examined by ophthalmologists because of visual difficulties, and the simultanagnosia remained undiagnosed until nonophthalmologic complaints developed. Optic ataxia developed in six patients, and all patients had mildly impaired eye movements. All 10 patients could identify colors appropriately. Nine patients had language deficits (anomia, decreased auditory comprehension, alexia, and agraphia) but were fluent and had relative preservation of sentence repetition, and four performed in the normal range on a test of associative fluency. Two patients scored in the normal range on memory tests, all had preserved insight, and nine had no family history of degenerative dementia. The mean age at onset of the disorder was 60 years (range, 50 to 69). Neuroimaging disclosed prominent bilateral occipitoparietal atrophy in nine patients and generalized atrophy in one. With this unusual but consistent clinical, neuropsychologic, and anatomic profile, these patients are clinically distinguishable from those with typical Alzheimer's disease, but until a specific cause has been found, we cannot be certain that they constitute a specific biologic entity. Clinicians should consider this diagnosis in relatively young patients who have slowly progressive nonocular visual complaints.

Neurologic aspects of giant cell (temporal) arteritis.

Headache is the most frequent symptom for which a patient with giant cell arteritis (GCA) presents to a neurologist. Amaurosis fugax and ischemic optic neuropathy are well-recognized complications. Less commonly recognized neurologic complications include transient ischemic attacks, cerebral infarctions, acute confusional states (due to multi-infarct dementia), ischemic cervical myelopathy, and ischemic mononeuropathies. Because patients with GCA generally respond well to corticosteroid therapy, prompt diagnosis can minimize neurologic damage.