Signal Alteration of Substantia Nigra on 3.0T Susceptibility-weighted Imaging in Parkinson's Disease and Vascular Parkinsonism.

Recent researches have found that 7 Tesla SWI can detect the alteration of substantia nigra hyperintensity in Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The aim of this study was to investigate whether 3 Tesla SWI (3T SWI) can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in PD and vascular parkinsonism (VP), and whether the evaluation of abnormal signal can be used as a factor in the differential diagnosis of PD and VP. Using 3 Tesla MRI, we evaluated 38 healthy subjects, 33 patients with PD and 34 patients with VP. Two blinded readers independently assessed the images. We found that the dorsolateral nigral hyperintensity was absent in 31 of 33 patients with PD and 15 of 34 patients with VP. The dorsolateral nigral hyperintensity was present in 19 of 34 patients with VP and 35 of 38 healthy controls. Group comparisons of absence of dorsolateral nigral hyperintensity revealed significant differences between the patients with PD and those with VP (P<0.001). The sensitivity of SWI for PD was 93.9% and the specificity was 92.1%. Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for PD. And our study results indicate that 3T SWI can be used as a tool to identify PD and VP.

X-Linked Lymphoproliferative Syndrome Presenting as Adult-Onset Multi-Infarct Dementia.

Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is ∼11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49-year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment. The patient had 2 brothers; 1 died of aplastic anemia at age 13 and another died of diffuse large B-cell lymphoma in his sixties. Exome sequencing of the patient and his older brother identified a novel hemizygous variant in SH2D1A (c.35G>T, p.Ser12Ile), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Molecular modeling and functional analysis showed that this variant had decreased protein stability, similar to other pathogenic missense variants in SH2D1A. The family described in this report highlights the broadly heterogeneous clinical presentations of XLP and the accompanying diagnostic challenges in individuals presenting in adulthood. In addition, this report raises the possibility of a biphasic distribution of XLP cases, some of which may be mistaken for age-related malignancies and autoimmune conditions.

Infartos estratégicos del tálamo: una causa infrecuente de demencia vascular / Strategic infarcts of the thalamus: an uncommon cause of vascular dementia

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Multi-infarct dementia and Alzheimer disease, contribution of cerebral circulation ultrasonography to pathogenesis and differential diagnosis. Value of microembolisation.

OBJECTIVES: Dementias are one of the most serious health and socioeconomic issues. Multi-infarct dementia (MID) and Alzheimer´s type dementia (AD) exhibit differences in cerebrovascular blood flow velocity profiles and in presence of microemboli, detected by transcranial Doppler sonography. MATERIAL AND METHODS: A group of 77 persons was divided into 4 subgroups: 1. subgroup of patients with MID (n=19; 10 male and 9 female, mean age was 74.32±8.30 years); 2. subgroup of patients with AD (n=19; 11 male and 8 female, mean age was 70.37±87.85 years); 3. subgroup of patients with hypertension (n=19; 11 male and 8 female, age adjusted) and 4. sex and age adjusted control group (CG) of 20 persons without hypertension or other serious risk factors. The duplex ultrasonographic examination of extracranial and intracranial circulation was preceded by neurologic, neuropsychological and psychiatric examination. The presence of microemboli was determined using Multi Dop X2 device (maker DWL), 60 minutes monitoring. All patients underwent brain computer tomography (CT) or magnetic resonance imaging (MRI). RESULTS: We found significantly higher incidence (68.4%, p=0.5267) of asymptomatic microemboli in ACM in the group of patients with MID compared to the AD group, the group of patients with hypertension and CG. CONCLUSION: The occurrence of "asymptomatic" emboli in the middle cerebral artery in patients with multi-infarct dementia is higher in the current study. Although these microemboli do not cause immediate symptoms, the evidence suggests, that they may be a risk factor for cognitive impairment, especially for multi-infarct dementia.

Middle Cerebral Artery Pulsatility Index is Associated with Cognitive Impairment in Lacunar Stroke.

BACKGROUND AND PURPOSE: Pulsatility index (PI) of the middle cerebral artery is postulated to reflect the vascular resistance in the artery distal of the probe, and has been reported to increase in small vessel disease, diabetes mellitus, ageing, and dementia. Lacunar infarcts are considered to be related to cognitive impairment. We therefore conducted a study to assess the association between cognitive impairment and PI in patients with a lacunar infarct. METHODS: Consecutive patients presenting with an acute lacunar syndrome who were admitted to the stroke unit were enrolled. The patients were examined with Doppler ultrasonography of the intracranial arteries, and the PI of the middle cerebral artery was recorded. Cognitive function was evaluated by mini-mental state examination (MMSE), clock drawing test, and trail making test (TMT) A and B. RESULTS: Among the 113 patients included, 85 patients had an acute lacunar infarct and 28 had one or more nonlacunar infarcts. The mean PI was 1.46 (SD = .33). PI was significantly (P < .05) associated with MMSE, TMT A and TMT B in patients with lacunar infarct, even after adjustment for multiple patient characteristics (age, sex, prestroke hypertension, smoking, previous stroke, and diabetes). CONCLUSIONS: PI was associated with the cognitive performance in patients with lacunar infarcts and a lacunar syndrome. An elevated PI may be related to impairment in several cognitive domains. These findings suggest that transcranial Doppler ultrasonography could be an adjunct tool for early diagnosis of cognitive impairment after stroke.

Vascular cognitive impairment in small vessel disease: clinical and neuropsychological features of lacunar state and Binswanger's disease.

BACKGROUND: ischaemic cerebrovascular small vessel disease (SVD) is a prevalent and under-diagnosed condition that triggers vascular cognitive impairment (VCI). OBJECTIVE: to describe the neuropsychological and clinical profiles in SVD (Binswanger's disease, BD; lacunar state, LS) from the clinician's perspective at the VCI stage. METHODS: a total of 1257 patients admitted to a tertiary center with a diagnosis of stroke, neuroradiological vascular disease, cognitive impairment/dementia, during a 13-year period were investigated. We prospectively assessed cognition in a subset of 141 patients with VCI (LS n = 28, BD n = 69, large vessel disease-LVD-n = 44) with MMSE, CAMDEX-H, WAIS-R, EXIT-25 and Trail making test. RESULTS: executive dysfunction (ECD) (n = 89, 91.7% versus n = 10, 22.7%; P < 0.001) and gait disturbances (n = 74, 76.3% versus n = 15, 34.1%; P < 0.001) characterized SVD. Prior strokes (n = 9, 9.3% versus n = 23, 52.3%; P < 0.001) and embologenous cardiopathy (n = 39, 40.2% versus n = 28, 63.6%; P < 0.04) featured LVD cases. BD was defined by hypertension (n = 52, 75.4% versus n = 30, 44.1%; P < 0.001), ECD (n = 65, 94.2% versus n = 34, 47.2%; P < 0.001) and VCI onset with cognitive impairment but not strokes (n = 44, 63.8% versus n = 34, 50%; P < 0.01). CONCLUSIONS: ECD and a frontal gait are SVD's clinical landmarks in our sample. LS and BD cases share a similar cognitive profile.

Autosomal dominant leukoencephalopathy with mild clinical symptoms due to cerebrovascular dysfunctions: a new disease entity?

A family with cerebrovascular dysfunctions and extensive white matter lesions was presented. The proband had suffered migraine. His brother showed syncopal episodes and migraine. His mother also suffered severe migraine with aura, and had transient hemiparesis during pregnancy. Their brain MRIs, being quite similar to each other, revealed diffuse bilateral deep white matter lesions, with no changes in serial follow-up. His grandmother showed similar white matter changes on CT, consistent with autosomal dominant inheritance. Lesions were considered to be due to chronic vasogenic edema based upon increased apparent diffusion coefficient (ADC) values on diffusion-weighted imaging, normal spectrum ratio of metabolites on (1)H MR spectroscopy, and decreased regional cerebral blood flows on single-photon emission CT (SPECT). A deficiency of genetically determined factors contributing to the autoregulation of small blood vessels might possibly lead to both clinical symptoms and white matter lesions through the breakdown of the blood-brain barrier and resultant vasogenic edema. Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was suspected, neither NOTCH3 mutation nor granular osmiphilic material (GOM) in the arteriole walls were detected. Further accumulation of similar cases is necessary to establish the possibility of a new familial leukoencephalopathy.

Effects of CT-localized scalp round-needling on the blood rheology, NO and NOS of patients with multiple infarctional dementia.

OBJECTIVE: To observe the short-term therapeutic effects of CT-localized scalp round-needling on the blood rheology, nitric oxide (NO) and nitric oxide synthetase (NOS) of patients with multiple infarctional dementia. METHODS: 89 cases of multiple infarctional dementia were randomly divided into an electro-round-needling group (57 cases), and a western medication group (32 cases). The therapeutic effects, including the effects on the blood rheology, NO and NOS, were observed. RESULTS: After receiving same courses of treatment, both the electro-round-needling group and the western medication group showed significant differences in the various kinds of indexes (P < 0.05-0.01). CONCLUSION: The CT-localized scalp round-needling is an effective therapy for multiple infarctional dementia.

Interrater reliability and accuracy in identifying ischemic strokes using computed tomography scans in people with dementia.

OBJECTIVES: To assess the reliability and interobserver agreement of stroke identification on neuroimaging in patients presenting with dementia. DESIGN: Comparison study between neurologists, radiology reports, and autopsy. SETTING: Dementia registry within a health maintenance organization. PARTICIPANTS: Dementia patients with computed tomography (CT) scans obtained near the time of diagnosis and postmortem neuropathological examinations (N=99). MEASUREMENTS: Three neurologists independently read CT scans for the presence and locations of strokes. Radiology reports from these scans were reviewed. The results from neurologists, radiologists, and autopsies were compared. RESULTS: The positive predictive value for CT-observed strokes compared with their presence on autopsy was 0.44 to 0.49, regardless of the specialty of the observer. Strokes were present at autopsy in 46 of 99 cases. Agreement between neurologists on the presence of strokes was fair to moderate (kappa=0.27-0.56). Less agreement was found between neurologists and radiologists (kappa=0.00-0.11). Results improved slightly when each case was evaluated as any stroke present versus no stroke on imaging (kappa=0.34-0.75) or for the presence of multiple strokes (kappa=0.17-0.69). CONCLUSION: There is only fair to moderate agreement between observers regarding the identification of strokes on CT scans in patients presenting with dementia. Furthermore, strokes identified on imaging were present on pathology only half the time.

Pathological validation of a CT-based scale for subcortical vascular disease. The OPTIMA Study.

The validity of a computed tomography (CT)-based rating scale that separately rates leukoaraiosis, patchy lesions, and lacunes was tested using neuropathological findings collected on 87 subjects enrolled in the Oxford Project to Investigate Memory and Ageing. The CT-based score (range 0-64) was associated with both small vessel disease (p = 0.015) and microinfarcts (p = 0.002) on pathology. A sum score of subcortical cerebrovascular disease (CVD) on pathology was computed, 0 indicating absent/mild small vessel CVD and no microinfarcts, 1 moderate small vessel CVD or microinfarcts, and 2 and higher both conditions or severe small vessel CVD. Subjects with a sum score of 0 were decreasing with increasing severity of CT-based score (64, 46, and 25% in those with CT-based scores of 0, 1-38, and 39 and higher), while those with a sum score of 2 and higher were increasing (0, 14, and 44%; p = 0.002). A standardized assessment of subcortical CVD on CT films can be compounded into a unique score that is in good agreement with neuropathology. This supports the validity of the CT-based visual rating scale as a valid tool to detect subcortical vascular changes in elderly persons.

Retinal abnormalities in CADASIL: a retrospective study of 18 patients.

BACKGROUND: CADASIL is an inherited small vessel disease related to Notch3 gene mutations. AIM: To report retinal findings in symptomatic CADASIL patients. METHODS: Assessment of visual acuity (VA), testing of visual fields (VF), funduscopic examination (FE), and fluorescein angiography (FA) were carried out in 18 symptomatic patients. RESULTS: No visual symptoms were presented by our patients. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients. VF were normal except for a right hemianopia in one subject due to ischemic stroke. FE and FA revealed significant abnormalities in seven other subjects (mean age: 55 years; range: 39-74): nerve fibre loss (n = 4), cotton wool spots (n = 3), sheathed arteries (n = 1), and tortuous arteries (n = 1). Only one patient with both tortuous arteries and nerve fibre loss had multiple vascular risk factors, and another patient with cotton wool spots was a current smoker. DISCUSSION: FE and FA revealed silent retinal abnormalities in CADASIL patients with nerve fibre loss in 22% and cotton wool spots in 17%. The presence of these abnormal retinal findings does not seem related to the severity of the disorder but may be considered as peripheral markers of this genetic disease.

Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients.

BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in the CADASIL patients was significantly lower in both frontal (P=0.019) and occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.

[Observation on efficacy of CT positioning scalp circum-needling combined with Chinese herbal medicine in treating poly-infarctional vascular dementia].

OBJECTIVE: To observe the short-term effect of patients with poly-infarctional vascular dementia (PIVD) treated by CT positioning scalp circum-needling (SCN) combined with Chinese herbal medicine. METHODS: Eighty-nine patients of PIVD were enrolled and divided into the treated group (n = 57) and the control group (n = 32). They were all treated with oral taking of Fuyuan mixture (FYM, consisted of ginseng, medlar, salvia, bitter cardamon, etc). To the treated group, SCN was applied additionally with the unilateral area around the reflecting region (localized by CT) in scalp as main needling points and Ganshu, Shenshu, Zusanli, Hegu as supplementary points. Two courses of SCN were performed. The changes of clinical symptoms, intelligence and hemorrheological characteristics in patients were analysed. RESULTS: After two courses of treatment, the total effective rate in the treated group was 96.5%, which was better than that in the control group (75.0%), with significant difference (u = 2.423, P < 0.01); HDS scores increased in both groups after treatment, showing significant difference as compared with that before treatment (P < 0.01), hemorrheologic parameters were also apparently improved. CONCLUSION: CT positioning SCN combined Chinese herbal medicine treatment has definite therapeutic effect in treating PIVD.

Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study.

UNLABELLED: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel disease caused by mutations in the NOTCH3 gene. As in sporadic small-vessel disease, ischemic lesions are largely confined to subcortical structures, whereas the cortex is spared. CADASIL, therefore, may serve as a model to study subcortically induced remote effects. The purpose of this study was to evaluate with (18)F-FDG PET whether regional cerebral metabolic rate of glucose (rCMRglc) is altered in CADASIL patients and, if so, whether there is evidence of subcortically induced disconnection. METHODS: Eleven CADASIL patients (7 women, 4 men; mean age, 55.8 +/- 6.7 y) without cortical lesions on brain MR images underwent PET after intravenous injection of 120 MBq (18)F-FDG, with calculation of rCMRglc according to a previously published method. For further processing, patient studies were registered to a template of a healthy control group and region-of-interest-based and voxelwise comparisons were performed. RESULTS: In CADASIL patients, mean rCMRglc was significantly reduced in all cortical and subcortical structures, compared with the values in healthy volunteers. In the subcortical gray matter, metabolic rates, given as the percentage of the mean of healthy volunteers, were 49.7%, 65.3%, and 51.6% in the caudate, putamen, and thalamus, respectively. Among cortical structures, the values were 66.9%, 67.9%, 67.2%, and 76.5% for the frontal, parietal, temporal, and occipital lobes, respectively. On an individual level, most patients showed marked asymmetry and inhomogeneities of cortical glucose metabolism. In 6 (55%) CADASIL patients, there was evidence of crossed cerebellar diaschisis. CONCLUSION: This study showed that cortical glucose metabolism is significantly lower in CADASIL patients than in healthy volunteers. The observed decrease in rCMRglc may in part be explained by a reduction of cerebral blood flow and neuronal loss. In addition, our data provide evidence of remote effects secondary to the functional disruption of subcortical fiber tracts in this particular type of small-vessel disease.

Incipient CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited. OBJECTIVE: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years. DESIGN: Clinical characterization and blinded survey comparing MCs with non-MCs. SETTING: Referral center. PARTICIPANTS: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria. METHODS: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale. RESULTS: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps. CONCLUSIONS: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.

[CADASIL: a case with clinical, radiological, histological and genetic diagnoses]. / CADASIL: un caso con diagnóstico clínico, radiológico, histológico y genético.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease. The onset of clinical symptoms occurs with migraine with aura, transient ischemic attacks, recurrent subcortical ischemic infarcts, neuropsychiatric changes reaching subcortical dementia. Brain magnetic resonance images show multiple deep cerebral infarcts in white matter and basal ganglia and diffuse leukoencephalopathy. Neuropathologic hallmark consists of deposition of small electron dense granular patches related to the basement membrane of vascular smooth muscle cells with degeneration of smooth muscle cells and media and luminal obliteration. Recently, the genetic characteristics of this disorder have been reported. Missense mutations in notch3 gene localized in chromosome 19 are involved in its pathogenesis. Only three families from Spain have been reported. Here we describe a patient with typical clinical symptoms, neuroimaging and pathology of CADASIL. C406T (Arg110Cys) mutation in notch3 gene was found. We comment on the clinical symptoms of different members of the patient's family.

A novel mutation (C67Y)in the NOTCH3 gene in a Korean CADASIL patient.

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.

A Novel Mutation (C67Y) in the NOTCH3 Gene in a Korean CADASIL Patient

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.