Neuropsychiatric Significance of Subcortical Hyperintensity

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

Subcortical brain systems play an important role in the regulation of a variety of cognitive and emotional processes. The basal ganglia and thalamus, along with the surrounding limbic structures, comprise MacLean’s paleomammalian brain, a region that serves to integrate appetitive drives with approach or avoidance to environmental stimuli. In humans, frontal–subcortical circuits comprise one of the major organizing neural networks in the brain. Discrete pathways connect prefrontal neurons sequentially to caudate, globus pallidus, dorsomedial thalamus, and finally back to the original prefrontal locus. These loop circuits process information supporting executive cognitive functions such as organization, motivation, and social comportment. This region of the brain receives its blood supply from relatively long, small-diameter, penetrating branches of the anterior and middle cerebral arteries. This unique circulatory arrangement is a consequence of the rapid evolutionary expansion of the neocortex and leaves these deep white and graymatter tissues vulnerable to ischemic injury and resulting neuropsychiatric dysfunction. Changes in subcortical white matter and deep gray matter nuclei are often noted in the brains of elderly people. Typically, these changes appear as foci of increased signal (hyperintensity) on T2-weighted magnetic resonance (MR) imaging or as areas of low density (attenuation) on computed tomography (CT) (Figure 1). Such changes were previously interpreted to reflect degeneration of the white matter typical of Binswanger’s disease. More recently, similar changes have been reported in patients with Alzheimer’s disease, in nondemented patients with cerebrovascular disease or psychiatric illness, and in apparently asymptomatic individuals. As a result, important questions are being raised about the frequency, pathophysiology, and potential clinical significance of these subcortical changes. Given the frequent use of brain MR imaging in neuropsychiatry, clinicians and neuroscientists are likely to encounter patients with changes in the subcortical white and gray matter. The purpose of this article is to review relevant data on the occurrence, etiology, and correlates (both clinical and neurobiological) of these subcortical changes. The potential implications of these changes for the pathophysiology of neuropsychiatric disorders will be discussed, with a particular focus on the relationship between subcortical brain changes and aging, cognitive function, and mood in older adults.

To the Editor: The recent article by DeCarli et al1 addresses a somewhat neglected aspect of white matter hyperintensities (WMH), the significance of their anatomical location. The authors argue that the commonly accepted categorization into deep (DWMH) and periventricular (PVWMH) WMH is arbitrary, because the 2 are very highly correlated, and a spatial analysis does not reveal distinct populations. We think that this conclusion is premature, because the categorization depends on a number of factors. The first limitation of their analysis is that they examined individuals in their 70s who presented to a specialty clinic, suggesting that the white matter lesions in their sample were at an advanced stage. If an analogy is drawn from cerebral atrophy in dementia, regional differences in atrophy that are present in the different subtypes of dementia become less prominent in the later stages. In our study of WMH in middle age (60 to 64 years), the correlation of DWMH and PVWMH was much lower ( r =0.621; …

Improved survival of HIV-infected individuals increasingly poses new clinical challenges as they develop diseases associated with aging, such as dementia. Common risk factors (e.g. older age, lower education level, and apolipoprotein ε4 allele [1]) and pathophysiology including chronic immune activation [2,3] have been implicated in Alzheimer's disease and HIV-associated dementia. Although highly-active antiretroviral therapy has led to a decrease in HIV-associated dementia [3], it has been hypothesized that Alzheimer's disease will become epidemic among elderly HIV-infected individuals [4]. Alzheimer's disease in a HIV-infected individual has not been described previously. Case report We report a case of dementia in a 64-year-old male patient with features characteristic of both Alzheimer's disease and HIV-associated dementia (HAD). The patient's history was notable for a diagnosis of HIV infection in 1995, a distant history of intravenous drug use, a history of cytomegalovirus retinitis, and institution of Trizivir (abacavir, lamivudine, zidovudine; GlaxoSmithKline, London, UK) in 2000 with subsequent undetectable viral loads. In June 2006, the patient's son brought him for neuropsychiatric evaluation due to progressive cognitive problems and grief related to his wife's recent death. Mental status examination revealed a poor informant with anosognosia, impaired judgment, apathy, and mild irritability. His thought process was circumstantial and tangential with repetitive themes about the past and his wife. Neurological examination revealed diffuse paratonia in the extremities, slowed coordination and gait, and positive glabellar and palmomental signs. Mini-Mental State Examination (MMSE) [5] score was 25/30 (1.8 SD below adjusted normative score), HIV Dementia Scale (HDS) [6] score was 10/16 (≤10 suggestive of HAD), and Frontal Assessment Battery [7] score was 12/18 (6.6 SD below adjusted normative score). Deficits were detected in memory, including encoding and recall; visual spatial skills; language, particularly word finding; psychomotor speed; and executive function. Remote memory was relatively preserved. Laboratory studies showed HIV RNA levels less than 20 copies/ml, 660 CD4+ T-cells/μl, B12 level of 154 pg/ml (normal 211–911 pg/ml), antibodies to hepatitis C virus (HCV), and undetectable HCV RNA. Serum chemistries, liver function tests, rapid plasma reagin test, urine toxicology, and thyroid stimulating hormone were normal. Brain magnetic resonance imaging (MRI) revealed nonspecific signal abnormalities in the subcortical gray and white matter on T-2 weighted images with atrophy in the cortex, particularly the medial temporal lobes, and the parietal and frontal lobes. Brain positron emission tomography (PET) demonstrated hypometabolism in the parietal and temporal cortices (Fig. 1). Neuropsychological testing revealed mild deficits in executive function and information processing speed and capacity, general impairment across memory domains, and word-finding difficulties on confrontational naming.Fig. 1: Positron emission tomography of the brain. Hypometabolism, which appears as the color blue, was demonstrated in the parietal and temporal cortices and is consistent with Alzheimer's disease. Normal metabolic activity, which appears as the color orange, was observed in the frontal cortices and subcortical structures (basal ganglia and thalami). These findings do not support the presence of HIV-associated dementia, which would be expected to show reduced metabolic activity in subcortical regions.The initial impression was that the patient had dementia due to multiple causes including possible Alzheimer's disease, possible HAD, vitamin B12 deficiency, and possible substance-induced persisting dementia. The ‘possible’ modifiers were applied because the presence of multiple potential causes precluded selection of a single problem, and neuropathological examination is necessary to establish a ‘definite’ diagnosis [8]. Monthly injections restored vitamin B12 levels to normal. Grief was treated with supportive psychotherapy. For Alzheimer's disease, the cholinesterase inhibitor rivastigmine was prescribed. To treat HAD, nevirapine was initiated to optimize antiretroviral penetration into the central nervous system [9]. Two years later, the patient continued to live at home with assistance. His HDS score had improved to 12/16, but cognitive function and apathy had worsened. MMSE score was 20/30 (5.7 SD below adjusted normative score). Repeat neuropsychological testing demonstrated a decline in language and memory skills and information processing speed and capacity, and a mild improvement in immediate recall of information. Memantine, an N-methyl-D-aspartate receptor antagonist approved for the treatment of Alzheimer's disease, was initiated. This is the first report of dementia with features characteristic of Alzheimer's disease in a patient with AIDS. The presence of Alzheimer's disease is supported by the pattern of cognitive decline, specifically memory-encoding deficits with relative preservation of remote memory; anosognosia; apathy; language difficulty; lack of motor deficits on neurological examination; and relatively preserved social behavior. Medial temporal lobe atrophy on MRI is suggestive of Alzheimer's disease, and bilateral parietal–temporal hypometabolism on PET has high specificity for Alzheimer's disease [10]. Concomitant HAD is suggested by the history of AIDS, executive dysfunction and psychomotor slowing, personality change, frontal release signs, slowed coordination and gait, subcortical white matter changes on MRI [11], and improvement in the cognitive features of HAD following addition of nevirapine. This case underscores the challenges of diagnosing dementia in older HIV-infected individuals in whom the presence of multiple predisposing conditions, as well as overlapping clinical syndromes, may lead to complex and ambiguous clinical presentations. As HIV-infected individuals continue to age, it is imperative that HIV specialists become skilled at diagnosing and treating dementia. Acknowledgements Thanks are due to University of Colorado Hospital Nuclear Medicine and Neuroradiology faculty and staff and Craig Nielsen, NP, University of Colorado Hospital, Infectious Disease Group Practice. Informed consent has been obtained from the patient and his family. J.J.K., PharmD, receives support from the National Institute of Health (NIH R21 and U01) and Tibotec Therapeutics (financial support for a research grant only, no consultant fees). L.E.A., MD, receives support as a primary investigator from the Department of Veterans' Affairs Mental Illness Research Education and Clinical Centers and from the National Institute of Mental Health (NIMH RO1). He is a coinvestigator on a Colorado Research to Improve Care Coordination Pilot Grant. E.C., MD, receives support as either a primary or coinvestigator from the National Institute of Health (NIH), including: National Institute of Allergy and Infectious Disease (P01; P30; R21; U01); NIH (UL1); National Heart, Lung, and Blood Institute (R01; R21). There are no conflicts of interest.

The purpose of this study was to examine the relationship between signal hyperintensities--a probable marker of underlying pathology--on T2-weighted magnetic resonance brain scans and neuropsychological test findings in elderly depressed and normal subjects. Elderly subjects with a DSM-III-R diagnosis of major depression (N=41) and normal elderly comparison subjects (N=38) participated in a magnetic resonance imaging study (1.0-T) of signal hyperintensities in periventricular, deep white matter, and subcortical gray matter. Hard copies of scans were rated in random order by research psychiatrists blind to diagnosis; the modified Fazekas hyperintensity rating scale was used. Cognitive performance was independently assessed with a comprehensive neuropsychological battery. Clinical and demographic differences between groups were assessed by t tests and chi-square analysis. Relationships between neuropsychological performance and diagnosis and hyperintensities and their interaction were analyzed by using analysis of covariance, with adjustment for age and education. Elderly depressed subjects manifested poorer cognitive performance on several tests than normal comparison subjects. A significant interaction between hyperintensity location/severity and presence/absence of depression on cognitive performance was found: depressed patients with moderate-to-severe deep white matter hyperintensities demonstrated worse performance on general and delayed recall memory indices, executive functioning and language testing than depressed patients without such lesions and normal elderly subjects with or without deep white matter changes. Findings validate cognitive performance decrements in geriatric depression and suggest possible neuroanatomic vulnerabilities to developing particular neuropsychological dysfunction in depressed subjects.

Methylmalonic acidemia (MMA) is a severe, heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism with a poor prognosis that can cause brain damage. Identifying the magnetic resonance imaging (MRI) findings of MMA might help to make accurate diagnoses earlier in the disease course and exploring the relationship between neuropsychological scores and MRI findings, when therapy is more effective and to improve therapeutic efficacy. Cerebral MRI studies from 37 children with MMA were evaluated by a neuroradiologist. Clinical and imaging data were collected from each patient. All tests were performed during routine investigations and in accordance with the ethical principles of the Declaration of Helsinki. Informed consent was obtained from the guardians of all patients for inclusion in the study. The most common and significant findings were periventricular white matter changes (78.4%), ventricular dilation (29.7%) and cerebral atrophy (40.5%). According to the developmental quotient, the 37 patients were divided into the normal intelligence subgroup (NI, developmental quotient ≥ 85) and the low intelligence subgroup (LI, developmental quotient < 85). The incidence of corpus callosal thinning, cortical atrophy, subcortical white matter changes, and ventricular dilation (grades 0–3) was significantly higher in the LI subgroup than in the NI subgroup (P < 0.05). The incidence of no-mild and moderate-severe ventricular dilation was significantly higher in the LI subgroup than in the NI subgroup (P < 0.05). Ventricular dilatation, cerebral atrophy, white matter changes, and corpus callosal thinning are the main MRI abnormalities in MMA patients, and these manifestations are significantly correlated with delayed development in children.

Binswanger's disease is a subacute form of hypertensive encephalopathy characterized by patchy-confluent myelin loss of the deep hemispheric white matter, associated with marked regressive changes of the oligodendrocytes and variable astroglial reaction. To understand the distribution and the specificity of astrocyte pathology in Binswanger's disease we quantified reactive and degenerating astrocytes in different regions of the deep and subcortical white matter and of the cerebral cortex. Sections of frontal, temporal, parietal, and occipital lobes of 12 histologically proven cases of Binswanger's disease were immunostained with antibodies to glial fibrillary protein (GFAP) and to metallothionein I and II (MT-I-II), markers which specifically identify normal and reactive astrocytes. Control tissues were from 6 elderly patients without neurological diseases. The brains of Binswanger's disease were characterized by few and lightly immunostained astrocytes in the deep white matter, but normal and reactive astrocytes, strongly immunoreactive for GFAP and MT-I-II, were prominent in the subcortical white matter and the cerebral cortex. However, the relative distribution of GFAP positive and MT-I-II positive astrocytes was significantly different between the cerebral cortex and the subcortical white matter, the MT-I-II positive astrocytes being more frequent in the cerebral cortex, and the GFAP positive astrocytes in the subcortical white matter (p < 0.02). The GFAP and MT-I-II expressions in subsets of reactive astrocytes in the cortico-subcortical layers together with regressive astroglial changes in the deep white matter suggest that the dynamic plasticity of astroglia is topographically and biochemically differentiated in vascular dementia of Binswanger type.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about thepersistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

Subcortical white matter builds neural connections between cortical and subcortical regions and constitutes the basis of neural networks. It plays a very important role in normal brain function. Various studies have shown that white matter deteriorates with aging. However, due to the limited spatial resolution provided by traditional diffusion imaging techniques, microstructural information from subcortical white matter with normal aging has not been comprehensively assessed. This study aims to investigate the deterioration effect with aging in the subcortical white matter and provide a baseline standard for pathological disorder diagnosis. We apply our newly developed multi-shot high resolution diffusion tensor imaging, using self-feeding multiplexed sensitivity-encoding, to measure subcortical white matter changes in regions of interest of healthy persons with a wide age range. Results show significant fractional anisotropy decline and radial diffusivity increasing with age, especially in the anterior part of the brain. We also find that subcortical white matter has more prominent changes than white matter close to the central brain. The observed changes in the subcortical white matter may be indicative of a mild demyelination and a loss of myelinated axons, which may contribute to normal age-related functional decline.

We investigated the histopathologic correlates of white matter changes in Alzheimer's disease (AD) patients (n = 6) and controls (n = 9) using postmortem MRI. White matter changes were rated on a 0 to 3 scale in 51 regions. Histopathologically, we subjectively rated the loss of myelinated axons in the deep and periventricular white matter, denudation of the ventricular ependyma, gliosis, width of the perivascular spaces, and leptomeningeal congophilic angiopathy; we measured structural changes in the walls of the blood vessels in the white matter in micrometers. The AD brains displayed significantly more white matter hyperintensities on MRI than controls. Histopathologically, the denudation of the ventricular ependyma and the gliosis were significantly more severe in AD than in controls, and there was a trend toward more loss of myelinated axons in the deep white matter in the AD brains (p = 0.07). The MRI abnormalities correlated with the loss of myelinated axons in the deep white matter (r' = 0.37; p < 0.01) and with the denudation of the ventricular lining (r' = 0.54; p < 0.01). We could not find any evidence for arteriolosclerosis, but the mean thickness of the adventitia of the arteries of the deep white matter in AD almost doubled the value in control brains (p = 0.0009). We conclude that white matter abnormalities in AD patients and controls consist of loss of myelinated axons, probably caused by arterial changes and breakdown of the ventricular lining. Since imaging/histopathologic correlation was similar in AD patients and controls, these changes probably represent some form of accelerated aging.

Ischemic brain injury in hemodialysis patients: which is more dangerous, hypertension or intradialytic hypotension?

Magnetic resonance (MR) imaging features of white matter lesions, often seen in the elderly, are correlated with histologic findings. Dilatation of perivascular spaces is seen, especially in the frontal and/or parietal subcortical white matter; the spaces are less than 3 mm in diameter and have sharp margins with no perifocal abnormality. Old lacunar infarcts are larger than 3 mm in diameter and are irregularly shaped and accompanied by perifocal myelin pallor and gliosis. Periventricular hyperintensity, including cap and rim, histologically shows myelin pallor, dilatation of perivascular spaces, discontinuity of the ependymal lining, and subependymal gliosis. Deep and subcortical white matter hyperintensity reflects myelin pallor and dilatation of perivascular spaces. Diffuse white matter lesion, seen in Binswanger's disease, shows myelin pallor and tissue rarefaction associated with loss of myelin and axons. U-fibers are usually well preserved. Severe arteriosclerosis and arteriolosclerosis are usually seen in the white matter. Knowledge of the pathologic features of incidental changes in white matter helps in understanding MR imaging findings.

A 39-year-old woman with systemic sclerosis/systemic lupus erythematosus overlap syndrome was admitted with fever. This followed a second course of pulsed intravenous cyclophosphamide for relapse of lupus nephritis WHO class IV with crescents. Her past history included Raynaud’s phenomenon, pulmonary fibrosis, oesophageal dysmotility and membranous glomerulonephritis causing nephrotic syndrome 8 years previously. She had also had seizures in pregnancy associated with pre-eclamptic toxaemia. During the admission, her blood pressure rose to 170/100mmHg. She developed cortical blindness followed by status epilepticus. A head computed tomography (CT) scan showed bilateral subcortical white matter changes in the posterior lobes, suggestive of posterior leukoencephalopathy. A magnetic resonance imaging (MRI) scan showed high T2 signal in the left cerebellar white matter and both occipital poles involving grey and white matter (Figure 1). A magnetic resonance venogram (MRV) was normal (Figure 2). Her blood pressure was controlled with intravenous nitrates and prostacyclin. Her symptoms resolved rapidly. A repeat MRI scan 2 weeks later showed resolution of some of the changes (Figure 3). A repeat renal biopsy showed crescent formation in two glomeruli with no evidence of malignant hypertension. Three weeks later, her blood pressure rose once again to a maximum of 150/90mmHg. She re-developed the cortical blindness, generalized hypertonicity and grand mal seizures. A thirdMRI scan showed that the findings of posterior leukoencephalopathy had mostly resolved, but there were now new bright subcortical white matter changes in the right preand postcentral gyri, both middle frontal gyri and the left superior frontal gyrus, suggesting the possibility of an acute vasculitis (Figure 4). Once again the MRV was normal. Aggressive blood pressure control and immunosuppression with mycophenolate mofetil led to a resolution of all neurological symptoms and signs, and recovery of renal function over the ensuing 8 weeks. She remains well with immaculate blood pressure control and maintenance mycophenolate mofetil as immunosuppression.

Characterization of cerebral white matter lesions of HTLV-I-associated myelopathy/tropical spastic paraparesis in comparison with multiple sclerosis and collagen-vasculitis: a semiquantitative MRI study

Despite the reduction in the incidence of brain metastases following prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC), the use of this modality is still controversial due to the lack of improvement in survival and the appearance of neurotoxicity in long-term survivors. Moreover, the optimum dose, fraction size, and timing are not known. From 1980 to 1988, 70 patients with limited stage SCLC underwent PCI after or during multimodality treatment of their primary tumor. Most of these patients (75.7%) received an unconventional ultrarapid high-dose course of 17 Gy in two fractions over 3 days. Long-term (range 60-138 months) survivors (n = 16) were invited to have a complete neurological evaluation including computed cranial tomography (CCT), 99mTc-HMPAO single photon emission computerized tomography (SPECT) scan, electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychometry. Delayed neurologic complications or psychometric impairment was observed in 46% of patients. One or more abnormalities were detected by CCT in all patients, and the presence of neurologic complications seemed to correlate with periventricular and subcortical white matter changes. A strong correlation was found between CCT and SPECT periventricular white matter changes. Although the incidence of late neurologic toxicity following this rapid course of irradiation was high, clinical findings were less severe than expected, and all the patients were capable of self-care.