DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Do systolic BP and pulse pressure relate to ventricular enlargement?

BACKGROUND AND PURPOSE: To evaluate the association between systolic, diastolic and pulse pressure, and increase in ventricular size (VS). Observations in laboratory animals suggest intraventricular pulse pressure (systolic-diastolic) may play a role in ventricular enlargement. METHODS: Initial magnetic resonance (MR) scans and vascular risk factors evaluation were performed in 1812 Atherosclerosis Risk in Communities participants in 1994-1995. In 2004-2006, 1130 participants underwent repeat MR. VS was rated using a validated nine-point scale. Multiple logistic regression analysis assessed association between blood pressure measures and pulse pressure, and the change between the MR scans of VS controlling for age, sex and race. RESULTS: At baseline 1112 participants (385 black women, 200 black men, 304 white women and 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models pulse pressure at baseline was associated with an increase in VS [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], as was systolic pressure (OR 1.28, 95% CI 1.03-1.58). CONCLUSIONS: Systolic pressure and pulse pressure are associated with future development of increased VS. The findings are consistent with the animal literature that increased pulse pressure predisposes to risk of future increased VS. High pulse pressure might play a role in the pathogenesis of normal pressure hydrocephalus.

Normal-pressure hydrocephalus. Onset of gait abnormality before dementia predicts good surgical outcome.

In 1977, Fisher reported that in patients with possible normal-pressure hydrocephalus (NPH), if the gait abnormality preceded dementia, surgery usually had a favorable outcome and vice versa. We studied this finding in 21 patients shunted for possible NPH. By evaluating serial videotapes of gait, neuropsychological tests, and Katz index ratings, preoperatively and at approximately two months and six months postoperatively, we judged 16 patients improved. In the improved group, the families reported that the gait abnormality preceded the dementia in 11 patients and occurred at the same time in five. In the unimproved group, dementia was noted first in three patients, gait abnormality first in one patient, and gait abnormality and dementia at the same time in one patient. Using Fisher's exact test, we compared the improved and unimproved groups for gait abnormality or dementia onset first and found a significant difference. We conclude that the history of gait abnormality occurring before or after dementia in patients with possible NPH is an important prognostic factor for surgical outcome.

Normal memory after damage to medial thalamus.

We studied two patients with nonhemorrhagic infarcts of the thalamus and assessed their cognitive functions comprehensively using standardized neuropsychological probes. Neither patient had any discernible memory impairment for verbal or nonverbal material. Analysis of magnetic resonance images with a stereotaxic method revealed that one subject had a right-sided lesion involving about 15% of the dorsomedial nucleus (DM). The other had bilateral lesions that affected about 15% of the left DM and less than 5% of the right DM. The mamillothalamic tract appeared intact in both patients. Considering that medial thalamic lesions commonly cause amnesia in human beings as well as nonhuman primates, there are two possible reasons, alone or in combination, that may explain why these patients failed to have amnesia: the amount of DM damage was less than required to cause amnesia; or the amnesia related to thalamic lesions requires damage to a second structure, such as the mamillothalamic tract or the anterior nucleus.

Transient partial amnesia.

A patient struck with transient amnesia was able to write a detailed account of her experiences during the episode and retained partial memory of the event. The analysis of her report permits an unusual view of transient partial amnesia.

Factors associated with hydrocephalus after subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study.

Hydrocephalus is an important complication of subarachnoid hemorrhage (SAH). We analyzed several factors possibly related to hydrocephalus following SAH in 3521 patients from the International Study on the Timing of Aneurysm Surgery. Hydrocephalus was diagnosed on admission computed tomographic (CT) scans in 15% of patients and was thought to be clinically symptomatic in 13.2% of patients. There was a 5.9% overlap between these groups. Using contingency table analysis, we found the following were significantly related to clinical hydrocephalus: increasing age; preexisting hypertension; admission blood pressure measurements; postoperative hypertension; admission CT findings of intraventricular hemorrhage, a diffuse collection of subarachnoid blood, and a thick focal collection of subarachnoid blood; posterior circulation site of aneurysm; focal ischemic deficits; use of antifibrinolytic drugs preoperatively; hyponatremia; admission level of consciousness; and a low score on the Glasgow outcome scale. Using discriminate factor analysis to predict clinical hydrocephalus, the most important variables in order were the following: CT hydrocephalus, intraventricular hemorrhage, admission level of consciousness, presubarachnoid hypertension, increasing age, subarachnoid blood noted on CT scan, posterior circulation aneurysm site, and hypertension postoperatively (canonical correlation = .399). We conclude that the development of hydrocephalus after SAH is multifactorial. Factors that compromise cerebrospinal fluid circulation acutely (eg, intraventricular hemorrhage, hemorrhage from a posterior circulation site of aneurysm, and diffuse spread of subarachnoid blood) contribute to the development of acute hydrocephalus. These same factors, plus the use of antifibrinolytic drugs preoperatively, are also important in the pathogenesis of clinical hydrocephalus, perhaps by promoting subarachnoid fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia following basal forebrain lesions.

Of five patients with damage to the basal forebrain, four had lesions secondary to rupture of anterior cerebral or anterior communicating artery aneurysms, and one to the resection of an arteriovenous malformation. Computed tomographic scans and intraoperative reports confirmed damage to basal forebrain regions, which include septal nuclei, nucleus accumbens, substantia innominata, and related pathways. Behavioral disturbances featured a prominent amnesic syndrome and personality changes. The amnesia was distinguishable from that reported in patients HM and DRB and shared features with that seen in patients with Korsakoff's syndrome. We propose that the memory disorder can be explained by malfunctioning in the hippocampal system, secondary to damage in the basal forebrain structures with which it is strongly interconnected. The dysfunction might, in part, be caused by reduction of specific neurotransmitter innervation because the lesions are likely to damage cholinergic neurons and nearby catecholamine pathways within the basal forebrain.

Computed tomographic and postmortem study of a nonhemorrhagic thalamic infarction.

A 70-year-old man had a stroke and became unconscious. High-resolution computed tomography (CT) with 5-mm cuts disclosed bilateral thalamic infarctions, larger on the left than the right. He died one week later, and a postmortem examination was performed. By plotting the CT on templates constructed to show the different vascular territories of the thalamus, the infarctions were predicted to be in the territories of the interpeduncular profunda arteries. Comparing sagittal reconstructions to the Schaltenbrand and Wahren atlas, the following thalamic nuclei were thought to be involved: dorsomedial, parafascicular, and centrum medianum bilaterally; and reticular, ventroanterior, and ventrolateral on the left. Pathologic study confirmed these findings. We believe that it is possible to predict the vascular territory of thalamic infarctions by plotting the CT on templates showing the different vascular territories of the thalamus. Sagittal reconstructions of CT scans also permit the determination of thalamic nuclei involved in a lesion.

The effect of brain atrophy on cerebral hypometabolism in the visual variant of Alzheimer disease.

BACKGROUND: Brain glucose metabolic rates measured by positron emission tomography can be more affected by partial volume effects in Alzheimer disease (AD) than in healthy aging because of disease-associated brain atrophy. OBJECTIVE: To determine whether the distinct distribution of cerebral metabolic lesions in patients with the visual variant of AD (AD + VS) represents a true index of neuronal/synaptic dysfunction or is the consequence of brain atrophy. SETTING: Government research hospital. DESIGN: Resting cerebral metabolic rate for glucose was measured with positron emission tomography in a cross-sectional study of AD and AD + VS groups and in healthy control subjects. Segmented magnetic resonance images were used to correct for brain atrophy. PATIENTS: Patients with AD + VS had prominent visual and visuospatial symptoms. There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control subjects. MAIN OUTCOME MEASURE: Measurement of the rate of cerebral glucose metabolism. RESULTS: Before atrophy correction, the AD + VS group, compared with the control subjects, showed hypometabolism in primary and extrastriate visual areas and in parietal and superior temporal cortical areas. Compared with the AD group, the AD + VS group showed hypometabolism in visual association areas. After atrophy correction, hypometabolism remained significantly different between patients and controls and between the 2 AD groups. CONCLUSIONS: The reductions in cerebral hypometabolism represent a true loss of functional activity and are not simply an artifact caused by brain atrophy. The different patterns of hypometabolism indicate the differential development of the lesions between the AD and AD + VS groups.

Hippocampal atrophy correlates with clinical features of Alzheimer disease in African Americans.

CONTEXT: Imaging measurements may aid in the characterization and diagnosis of patients with Alzheimer disease (AD). Most research studies, however, have been performed on predominantly white study groups despite the fact that there may be biological differences in AD between African American and white patients. OBJECTIVE: To measure hippocampal volume in African American patients with AD and to correlate these measurements with the presence of AD and neuropsychological test performance. DESIGN: Survey study. SETTING: Academic center. PARTICIPANTS: Fifty-four healthy African American subjects and 32 African American patients with AD were studied. Hippocampal volumes were measured in all subjects from magnetic resonance images using established methods. MAIN OUTCOME MEASURE: Correlations were assessed between hippocampal volume and demographic variables, clinical group membership, and neuropsychological performance. RESULTS: The hippocampi of patients were atrophic with respect to those of healthy subjects (P<.01). Significant direct correlations were present between hippocampal volumes and performance on several different neuropsychological tests (r>0.5 and P<.01 for every test evaluated) when patients and healthy subjects were combined. CONCLUSIONS: Hippocampal atrophy is a feature of AD in African Americans as it is in white subjects. The neuropsychological-hippocampal volume correlations indicate that hippocampal volume measurements do represent a measure of the structural substrate of functional impairment in AD.

Callosal apraxia.

A 39-year-old right-handed woman suffered a ruptured pericallosal aneurysm. Serial MRI studies showed damage to the genu and most of the body of the corpus callosum but not the splenium. Both supplementary motor areas (SMA) appeared intact. We studied the patient's praxis performance at intervals over a 4-month period with a standardized battery. The study suggests that apraxia seen in patients with callosal lesions is probably due to the callosal damage, not to the usually associated SMA lesion. Our findings support Liepmann's idea that the left hemisphere is dominant for praxis in both hands. We propose, however, that the dominance effect is related to the type of test given and varies among individuals. As regards the latter, in some individuals the left hemisphere is strongly dominant for motor tasks, while in others it is less so. As regards the type of test, the most enduring left-hand apraxia is seen in verbal, not visuomotor tests.

Idiopathic normal pressure hydrocephalus and systemic hypertension.

Nineteen patients with idiopathic normal pressure hydrocephalus (NPH) were treated with intraventricular shunts. Ten of the 14 who improved and 14 of the total group had systemic hypertension. The prevalence of hypertension in both the improved and whole NPH groups was significantly greater than in a control group with dementia (N = 122) and the published prevalence of hypertension in the US population for this age group. Four possible mechanisms for this association are discussed.

Symptomatic congenital hydrocephalus in the elderly simulating normal pressure hydrocephalus.

In a series of 30 older patients shunted for symptomatic hydrocephalus, we found 3 with a head circumference at or greater than the 98th percentile. In 2, we demonstrated deterioration over 6 and 12 months by serial videotaping of gait and neuropsychological testing. In the 3rd, serial lumbar punctures over a 6-month period gave temporary improvement. In each, CTs showed ventriculomegaly without transependymal flow. One patient had an Arnold-Chiari type I abnormality identified by MRI. All had systemic hypertension. CSF pressure monitoring showed CSF pressure greater than 15 mm Hg 39% of the time in 1 patient, and 100% in another. All improved with ventriculoperitoneal shunting. Patients with probable compensated congenital hydrocephalus who functioned well throughout most of their lives may become symptomatic as they age but improve with shunt surgery. The head circumference should be measured in all older hydrocephalic patients.

Variables predicting surgical outcome in symptomatic hydrocephalus in the elderly.

We prospectively studied 30 older patients who had shunt surgery for symptomatic hydrocephalus and measured outcome using serial videotaping of gait, neuropsychological testing, and the Katz index of activities of daily living. Twenty-three patients improved and 7 did not. Using univariate analysis and the Fisher exact test, we found that the following variables were significantly related to outcome: (1) time B-waves present on 24-hour CSF pressure record; (2) anterior/posterior ratio on slice 4 of regional cerebral blood flow study; (3) duration of dementia prior to surgery; and (4) gait abnormality preceding dementia. The following variables showed a trend towards significance: (1) time CSF pressure greater than 15 mm Hg; and (2) scoring either pass or fail on the Multilingual Visual Naming Test. We conclude that several variables are significantly associated with surgical outcome in symptomatic hydrocephalus in the elderly and can be used in deciding whether to recommend surgery.

Nonhemorrhagic infarction of the thalamus: behavioral, anatomic, and physiologic correlates.

We studied five patients with nonhemorrhagic thalamic infarction with neuropsychological tests, CT, and somatosensory evoked responses (SERs). The three patients with left thalamic lesions had abnormalities of language, memory, visuospatial processing, intellect, and personality-changes compatible with dementia. The two patients with right thalamic lesions were not aphasic and did not have verbal memory defects, but were otherwise comparable. Four lesions occurred in the tuberothalamic artery territory and one in the deep interpeduncular artery territory. SERs revealed a delay in the first negative peak after P14 in the tuberothalamic patients, and a delay in the third negative peak (N60) in all patients.

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.

Progressive aphasia in a patient with Pick's disease: a neuropsychological, radiologic, and anatomic study.

Although Pick's disease is generally considered as a dementia characterized by signs of frontal lobe dysfunction, it can present with selective language defects rather than with cognitive decline. In this study, we report prospective and serial clinical, neuropsychological, and neuroradiologic observations in a 59-year-old man whose prominent disturbance was in the retrieval and learning of names denoting concrete entities and actions. Postmortem study confirmed the diagnosis of Pick's disease and revealed that neuronal loss and gliosis were most prominent in left anterior temporal cortices. The findings are in keeping with evidence that the left anterior temporal cortices and interconnected hippocampal system are critically involved in the learning and retrieval of verbal lexical items. The evidence from this patient, along with similar evidence from the literature we reviewed, suggests that when patients present with a progressive aphasia characterized by anomia, Pick's disease should be considered as the probable diagnosis.

Unilateral pallidotomy for Parkinson's disease: comparison of outcome in younger versus elderly patients.

We studied the effects of medial pallidotomy in the first 20 consecutive patients with Parkinson's disease (PD) undergoing this MRI/electrophysiologically guided procedure at our institution. The mean age of patients was 65.5 years (median 66.5) and none suffered any serious complications. Pallidotomy significantly improved motor function in both "on" and "off" states as measured by Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and timed tests (Purdue pegboard and counter tapping) in the arm contralateral to surgery 3 months postoperatively. Patients also improved in terms of activities of daily living, reflected by improved UPDRS activity of daily living and complications of therapy scoring and reduced levodopa-induced dyskinesias; six of 11 patients who could not walk in an "off" state prior to surgery could do so postoperatively. The total UPDRS score improved by 22% from preoperative values. The aforementioned improvements occurred similarly in patients greater than (n = 11) or less than 65 years (n = 9) at surgery. Neuropsychological measures indicated that although the majority of cognitive function remains unchanged in right-handed PD patients following dominant (left) hemisphere pallidotomy, mild specific declines in word generation are present. The findings of this study suggest that unilateral pallidotomy is safe and associated with improved motor functioning in elderly as well as younger PD patients experiencing significant disability despite optimal medical therapy.

Elevated gonadotropin levels in patients with Alzheimer disease.

OBJECTIVE: To determine whether gonadotropin levels are elevated in patients with Alzheimer disease (AD). PATIENTS AND METHODS: We measured luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels from stored plasma samples from 284 patients seen at a tertiary care center. We also reviewed their medical charts to record age and estrogen use in the women. The primary aim of our study was to determine whether gonadotropin levels were elevated in 134 patients with AD compared with levels from 45 patients with frontotemporal dementia (FTD) and 105 cognitively normal controls. RESULTS: Although overlap between LH and FSH levels was considerable, LH (P=.046) and FSH (P=.007) were significantly elevated in estrogen-free women with AD (LH: median, 26.3 IU/L; interquartile range, 14.9-34.6 IU/ L; FSH: median, 62.0 IU/L; interquartile range, 45.9-78.5 IU/L) compared with normal controls (LH: median, 20.1 IU/L; interquartile range, 13.7-25.3 IU/L; FSH: median, 47.7 IU/L; interquartile range, 34.1-57.5 IU/L). Levels of LH were also significantly higher (P=.03) in estrogen-free women with AD compared with women with FTD (LH: median, 20.7 IU/L; interquartile range, 19.0-28.5 IU/L; FSH: median, 53.3 IU/L; interquartile range, 27.6-77.9 IU/ L). When we controlled for age, no differences in LH and FSH were observed in men with AD compared with normal controls. CONCLUSIONS: Gonadotropin levels are elevated in some patients with AD, ie, women not taking estrogen. Elevated gonadotropin levels may have a role in the production of amyloid-beta protein, which is related to formation of senile plaques. Therefore, elevated gonadotropin levels may be involved in the pathogenesis of AD.

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.