Dentatorubropallidoluysian atrophy in a spanish family: a clinical, radiological, pathological, and genetic study

The object was to describe the clinical, radiological, pathological, and genetic findings in a Spanish family with dentatorubropallidoluysian atrophy (DRPLA). This is an inherited neurodegenerative disease, well recognised in Japan, but with few cases reported from Europe and America and no cases published from Spain. The clinical misdiagnosis of Huntington's disease is not infrequent. Pedigree analysis and clinical data of a family were collected. A genetic study was performed in two patients. Pathological information was obtained from the necropsy of one patient. RESULTS: Pedigree analysis showed an autosomal dominant pattern of inheritance. Age at onset varied from 5 to 55 years. Ataxia and chorea were present in most of the members. Some of these had a long course disease with late dementia. Four patients had seizures and early mental impairment. In one patient, cranial MRI showed cortical, brain stem and cerebellar atrophy, and white matter changes. In another patient, necropsy showed atrophy of the globus pallidus and lipofuscin deposits in dentate and pallidal neuronal cells. Genetic study showed an abnormal CAG triplet expansion in the B37 gene on chromosome 12. As in other cases previously reported, Spanish cases of DRPLA show intrafamilial phenotypic heterogeneity. Clinical and MRI data could differentiate DRPLA from Huntington's disease but definitive diagnosis requires molecular studies. Pathological studies are still necessary to correlate DRPLA brain involvement with the clinical and molecular findings.     

Quantitative magnetic resonance imaging differences between Alzheimer disease with and without subcortical lacunes

Previous reports showed that patients with Alzheimer disease (AD) frequently have coexisting vascular-related pathologies, such as cerebral infarcts and white matter lesions. The aim of this study was to determine the effects of subcortical lacunar infarcts on brain structure in patients with AD. Semi-automated tissue segmentation and volumetry of magnetic resonance imaging data were performed in 38 AD patients without lacunes (AD-L), 24 AD patients with subcortical lacunes (AD+L), and 40 age-matched cognitively healthy subjects without lacunes. The following tissue volumes were quantified, expressed as percentage of total intracranial volume: ventricular cerebrospinal fluid (CSF), sulcal CSF, cortical gray matter (GM), subcortical GM, white matter (WM), white matter signal hyperintensities (WMSH), lacunes, and hippocampus. There was no difference in the Mini-Mental State Examination between the two AD groups. AD+L patients compared with AD-L subjects had significantly greater volumes of WMSH and ventricular CSF spaces (as expected) but smaller sulcal CSF spaces and no significant increase in cortical GM atrophy (both unexpected). In the AD groups, ventricular CSF correlated inversely with cortical GM but not with WM; sulcal CSF correlated inversely with cortical GM and WM. Cognitive impairment was associated with sulcal CSF volume but not with volumes of WMSH or lacunes. In conclusion, the presence of subcortical lacunes in those with AD is associated with more WM lesions and ventriculomegaly but not with cortical atrophy.     

Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease

We performed morphometric analysis of five standardized coronal brain slices at anterior frontal (AF), caudate-putamen-accumbens (CAP), globus pallidus (GP), lateral geniculate nucleus (LGN), and parieto-occipital fissure (OCP) levels in 30 patients with Huntington's disease (HD) and 13 controls. Associated with the 30% mean reduction in brain weight in HD patients (p less than 0.001) were significantly smaller overall cross-sectional areas of brain at all five levels studied, with striking losses in cerebral cortex (21-29%), white matter (29-34%), caudate (57%), putamen (64%), and thalamus (28%) (all p less than 0.005). In addition, the ventricular system was dilated up to 2.5 times normal at CAP, GP, and LGN levels, 9.5 times normal at the OCP level, and 13 times normal at the AF level. Higher grades of severity of HD had greater reductions in the cross-sectional area of the caudate, putamen, thalamus, and cerebral cortex (p less than 0.005-0.001), and larger ventricles (p = 0.08) compared to lower (less severe) grades of HD. The findings confirm and quantitate the severe atrophy of the neostriatum, in addition to demonstrating a severe loss of cerebral cortex and subcortical white matter in HD. The global atrophy of cerebral cortex and white matter observed in all degrees of HD may account for the cognitive and neuropsychiatric impairments which often precede the onset of chorea.     

Relation of cerebral small-vessel disease and brain atrophy to mild Parkinsonism in the elderly.

The association between cerebral small-vessel disease, brain atrophy, and the risk and severity of mild parkinsonian signs (MPS) remains unclear. The objective of this study is to examine the effect of lacunar brain infarcts, cerebral white matter lesions (WMLs), and cortical atrophy on the risk and severity of MPS. This study is a cross-sectional community-based cohort study comprising 268 subjects, 65 to 83 years of age, residing in the Augsburg region of southern Germany, and without contraindications for magnetic resonance imaging (MRI) of the brain. Main outcome measures. Subcortical and periventricular WMLs, lacunar brain infarcts, and cortical atrophy determined using a standardized MRI protocol developed for the Rotterdam Scan Study and an established rating scale. MPS, assessed in a standardized neurological examination and based on the Unified Parkinson's Disease Rating Scale motor scale. Lacunar brain infarcts and large subcortical white matter lesions were associated with an elevated risk of resting tremor. More severe cortical atrophy was related to an increased risk of rigidity and bradykinesia. In a linear regression analysis relating each individual MRI measurement with the severity of MPS, the number of lacunar brain infarcts and the degree of brain atrophy were correlated with the severity of resting tremor, whereas the size of subcortical and periventricular WMLs was correlated with the severity of rigidity. A higher degree of brain atrophy was associated with increased severity of either cardinal sign. In our study, presence and volume of lacunar brain infarcts, cerebral WMLs, and cortical atrophy were associated with the risk as well as severity of MPS. Determining the presence of these brain changes using brain imaging might contribute to identify persons at risk for MPS.     

A case of Huntington's chorea with unilateral ectopic gray matter

The authors report a single case of Huntington's chorea associated with a unilateral focus of ectopic gray matter. The patient's symptoms began at age 45 and included typical involuntary jerking movements of all extremities and face. Mental deterioration may have proceeded the choreiform movements. The family history was positive for Huntington's chorea. Pneumoencephalogram showed atrophy of the caudate nuclei bilaterally early in the disease. The patient improved transiently with haloperidol therapy. The major pathologic features included mild generalized cerebral atrophy with marked atrophy of the caudate nuclei and putamen. Within the white matter of the left frontal lobe, there were irregular nodules of ectopic gray matter with an overall diameter of 2 cm. The rarity of either unilateral ectopia or Huntington's chorea alone, makes it impossible to judge if the two lesions might be linked by a common pathologic mechanism. The significance such a linkage might hold is discussed in light of several currently postulate pathologic mechanisms.     

Prefrontal cortical blood flow and cognitive function in Huntington''s disease.

To examine the relationship between cortical physiology and dementia in Huntington's disease, rCBF during three different behavioural conditions, one of which emphasised prefrontal cognition, was determined by xenon-133 inhalation in 14 patients with Huntington's disease and in matched controls. Cortical rCBF was not reduced in Huntington's disease patients even while they manifested overt prefrontal-type cognitive deficits. Caudate atrophy on CT and rCBF were significantly correlated, but only during the prefrontal behaviour where the correlation was positive. These results suggest a qualification of the subcortical dementia concept as applied to Huntington's disease and implicate an interaction between pathology that is subcortical and cognitive function that is cortical.     

Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease

OBJECTIVE: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). BACKGROUND: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. METHODS: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. RESULTS: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. CONCLUSIONS: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.     

Longitudinal atrophy characterization of cortical and subcortical gray matter in Huntington’s disease patients

Huntington's disease (HD) is an inherited neurodegenerative disease with clinical manifestations that involve motor, cognitive and psychiatric deficits. Cross‐sectional magnetic resonance imaging (MRI) studies have described the main cortical and subcortical macrostructural atrophy of HD. However, longitudinal studies characterizing progressive atrophy are lacking. This study aimed to describe the cortical and subcortical gray matter atrophy using complementary volumetric and surface‐based MRI analyses in a cohort of seventeen early HD patients in a cross‐sectional and longitudinal analysis and to correlate the longitudinal volumetric atrophy with the functional decline using several clinical measures. A group of seventeen healthy individuals was included as controls. After obtaining structural MRIs, volumetric analyses were performed in 36 cortical and 7 subcortical regions of interest per hemisphere and surface‐based analyses were performed in the whole cortex, caudate, putamen and thalamus. Cross‐sectional cortical surface‐based and volumetric analyses showed significant decreases in frontoparietal and temporo‐occipital cortices, while subcortical volumetric analysis showed significant decreases in all subcortical structures except the hippocampus. The longitudinal surface‐based analysis showed widespread cortical thinning with volumetric decreases in the superior frontal lobe, while a subcortical volumetric decrease occurred in the caudate, putamen and thalamus with shape deformation on the anterior, medial and dorsal side. Functional capacity and motor status decline correlated with caudate progressive atrophy, while cognitive decline correlated with left superior frontal and right paracentral progressive atrophy. These results provide new insights into progressive volumetric and surface‐based morphometric atrophy of gray matter in HD.     

Pyramidal cell loss in motor cortices in Huntington's disease

Patterns of huntingtin protein aggregation and cortical neuronal loss suggest early involvement of corticostriatal pathways in Huntington's disease. However, theories of pathogenesis of chorea rely on the motor cortices being intact. The motor cortices have not previously been studied at a cellular level in Huntington's disease. We analyzed the neuronal number in the caudate, putamen, and three motor cortical areas in five cases of Huntington's disease and five controls. For each motor cortical region the total neuronal number, number of interneurons, and number of SMI32 immunopositive pyramidal neurons were quantified using previously published techniques and any relationship between cell loss and severity or duration of chorea was examined. The results showed a loss of long projecting SMI32 immunopositive pyramidal neurons in the primary motor cortex with associated morphological changes and suggest a loss of short projecting pyramidal neurons in the premotor cortex. Degeneration in the primary motor cortex correlated with subcortical degeneration. These findings indicate pyramidal cell involvement in Huntington's disease and implicate the degeneration of corticostriatal pathways in the production of chorea.     

Neuropsychological and neuroradiological correlates in Huntington''s disease.

Measurements of cortical and subcortical atrophy were made on CT scans of 34 patients with Huntington's disease. Significant correlations were found between the bicaudate ratio (BCR) and an eye movement scale (r = 0.44, p less than 0.01), and activities of daily living scale (r = 0.57, p less than 0.001) and the Mini-Mental State Exam (r = 0.49, p less than 0.01). No correlations were found between BCR values and severity of chorea or voluntary motor impairment. A detailed neuropsychological evaluation of 18 Huntington's disease patients showed significant correlations between the BCR and Symbol Digit Modalities test (r = 0.65, p less than 0.01), and parts A (r = 0.72, p less than 0.001) and B (r = 0.80, p less than 0.0001) of the Trail Making Test. These data support work in primates that demonstrates the role of the caudate nucleus in cognitive and oculomotor functions, but not in motor control (which is governed by putamino-subthalamic systems). The specific cognitive skills correlated with caudate atrophy in Huntington's disease are those reported in primate work to be served by the frontal-caudate loop system: eye movements, conceptual tracking, set shifting and psychomotor speed.     

Cortical pathology and cognitive impairment in multiple sclerosis

Cognitive impairment constitutes a relevant clinical aspect of multiple sclerosis (MS). Depending on the disease phase and type, 40-65% of MS patients develop various degrees of cognitive dysfunction. Pathological and MRI studies have failed to demonstrate the existence of a strict relationship between cognitive impairment and subcortical white matter pathology. The correlation is also poor when MRI metrics of whole brain (white plus gray matter) atrophy are considered. Over the last decade, increasing observations have provided evidence of a primary role of cortical pathology - that is, inflammatory focal lesions (cortical lesions) and atrophy (cortical thickness) - in determining global and/or selective cognitive disability in MS. By applying a new semi-automated software (Freesurfer) to analyze the global and regional cortical thickness and the double inversion recovery sequence to identify cortical lesions, it has been observed that specific cognitive deficits, such as memory impairment, attention deficits and reduced mental processing speed, could be better explained by cortical structural abnormalities rather than subcortical white matter lesions. Therefore, MRI evaluation of cortical pathology should be included in the routine examination of MS patients, especially those with initial signs/symptoms of cognitive dysfunctions.     

Extrastriatal dopamine D(2) receptor binding in Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the high-affinity dopamine D(2) receptor radioligand [(11) C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D(2) receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D(2) receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D(2) receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D(2) receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.     

Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease

Morphometric analysis of standardized gross cerebral slices from 16 patients with end-stage Alzheimer's disease (AD), 14 controls without neuropathological lesions or neurological disease, and 4 neurologically intact nondemented patients with histopathological lesions of AD was used to measure cross-sectional areas of cerebral cortex, white matter, subcortical nuclei, and the ventricular system. In AD, there was global cerebral atrophy of both cortex and white matter, selective atrophy of the amygdala and hippocampus, and ex vacuo hydrocephalus. In addition, in half the cases of AD, white matter atrophy was associated with overt histopathological evidence of patchy rarefaction of fibers and gliosis. Patients with preclinical AD had prominent and selective shrinkage of white matter comparable to that observed in AD, yet their cortical areas were normal. These observations suggest that white matter degeneration is an intrinsic component of AD. Moreover, its presence in preclinical AD where cortical atrophy is not evident indicates that cytoskeletal abnormalities associated with axonal degeneration may precede and perhaps cause the cortical atrophy observed in clinically manifested AD.     

脑皮质下小血管病变与脑萎缩的相关性分析

目的探讨脑皮质下小血管病变与脑萎缩的相关性。方法通过10例临床确诊为脑萎缩的病人的调查,收集其临床基本资料及头颅磁共振成像(magnetic resonance imaging,MRI)的结果及图像,评判其脑皮质下小血管的病变情况。结果所有病例颅脑MRI均发现显著的弥漫性脑白质病变(white matter lesions,WML)和多发的脑腔隙性梗死灶(lacunarinfarcts,LI)。结论颅脑MRI提示,脑皮质下小血管病变与脑萎缩共存,提供了其与脑萎缩可能有关的临床依据。     

Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency

We examined brain magnetic resonance imaging (MRI) in a cohort of seven patients with ornithine transcarbamylase deficiency (OTCD), and correlated MRI findings with clinical manifestations. Seven patients with OTCD, aged 3-27 years, all with a missense mutation, were involved in the study. We classified the OTCD patients clinically into four stages. MR study was performed with a 1.5-T superconducting magnet during asymptomatic periods. MRI revealed white matter lesions in two patients with an advanced clinical stage, i.e. T1 and T2 prolongated round lesions in the deep white matter and posterolateral angle of the lateral ventricle in one patient; small foci of T2 and T1 prolongation in the subcortical white matter in another. Parenchymal lesions, and cerebral and cerebellar atrophy were not found in the other five patients. MRI might be normal in the early stage of the disease, and progress in proportion to the clinical stage of OTCD. OTCD should be considered as a differential diagnosis of small foci in the white matter in children.     

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.     

Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures.

Atrophy of cortical and subcortical gray matter is apparent in Huntington's disease (HD) before symptoms manifest. We hypothesized that the white matter (WM) connecting cortical and subcortical regions must also be affected early and that select clinical symptoms were related to systems degeneration. We used diffusion tensor magnetic resonance imaging (DTI) to examine the regional nature of WM abnormalities in early HD, including the preclinical period, and to determine whether regional changes correlated with clinical features. We studied individuals in early stages (HD), presymptomatic individuals known to carry the genetic mutation that causes HD (Pre-HD), and matched healthy controls. DTI indices of tissue integrity were obtained from several regions of interest, including the corpus callosum (CC), internal capsule (IC), and basal ganglia, were compared across groups by t tests, and were correlated to cognitive and clinical measures. WM alterations were found throughout the CC, in the anterior and posterior limbs of the IC, and in frontal subcortical WM in HD subjects, supporting the selective involvement of the pyramidal tracts in HD; a similar distribution of changes was seen in Pre-HD subjects, supporting presymptomatic alterations. There was a significant relationship between select DTI measures and cognitive performance. Alterations in diffusion indices were also seen in the striatum that were independent of atrophy. Our findings support that WM alterations occur very early in HD. The distribution of the changes suggests that these changes contribute to the disruption of pyramidal and extrapyramidal circuits and also support a role of compromised cortical circuitry in early cognitive and subtle motor impairment during the preclinical stages of HD.     

Cerebral atrophy in myotonic dystrophy: a voxel based morphometric study

Brain involvement in myotonic dystrophy type 1 (DM1) is characterised by cortical atrophy and white matter lesions. We compared the magnetic resonance imaging derived grey matter maps of 22 DM1 patients with those of matched, healthy controls using voxel based morphometry to evaluate the extension of global and regional cortical atrophy in DM1, as well as its relationships with clinical and genetic features. Patients had significantly reduced brain tissue volumes. Grey matter volume was inversely correlated with age; this inverse correlation was significantly stronger in DM1 than in controls. Neither the clinical and genetic characteristics nor white matter lesions were correlated with cortical atrophy. Grey matter atrophy was located mainly in the bilateral frontal and parietal lobes, in the bilateral middle temporal gyrus, and in the left superior temporal and occipital gyrus.     

The topographic distribution of brain atrophy in Huntington's disease and progressive supranuclear palsy

Summary The topographic distribution of brain atrophy was quantified by image analysis of fixed coronal brain slices from 12 patients dying with Huntington's disease (HD) and from 4 other patients dying with progressive supranuclear palsy (PSP). In HD, atrophy was maximal within the caudate nucleus, putamen and globus pallidus. However, the cerebral cortex was also atrophied with reductions in cross-sectional area within frontal, temporal and parietal lobes. In general, more white matter than grey matter was lost leading to an elevation in the grey/white matter ratio. The amygdala and thalamus were reduced in area. In PSP, lesser reductions in cortical area than those of HD were seen, these again being mostly due to a loss of white matter, resulting in an elevation of the grey/white ratio. The globus pallidus and thalamus were decreased in area, but no changes in the caudate nucleus and putamen were measured.Supported in part by an intercalated BSc studentship (RO) from the Medical Research Council     

Is “subcortical dementia” a recognizable clinical entity?

The concept of "subcortical dementia" is controversial, lacking clinical validation and having only a questionable pathological basis. Over 100 patients with Alzheimer's, Parkinson's or Huntington's disease, subdivided into three functional disability stages, were given a brief quantitative neuropsychological assessment. Patients with Huntington's or Parkinson's disease were less intellectually impaired than those with Alzheimer's disease at each functional stage. Criteria for dementia were present in all of the Alzheimer's patients but in only half of the Huntington's and Parkinson's disease groups. Patients with similar overall intellectual function scores had no distinct pattern of neuropsychological test performance. Depression, absent in patients with Alzheimer's disease, was present in half the patients with Huntington's and Parkinson's disease and was correlated with intellectual decline. The concept of subcortical dementia is misleading. The pattern of neuropsychological impairment is not distinct, and the neuropathological basis of dementia in these diseases may result from a combination of cortical and subcortical degeneration.