Brain lithium, N-acetyl aspartate and myo-inositol levels in older adults with bipolar disorder treated with lithium: a lithium-7 and proton magnetic resonance spectroscopy study

Objectives:  We investigated the relationship between brain lithium levels and the metabolites N -acetyl aspartate (NAA) and myo -inositol ( myo -Ino) in the anterior cingulate cortex of a group of older adults with bipolar disorder (BD).
Methods:  This cross-sectional assessment included nine subjects (six males and three females) with bipolar I disorder and currently treated with lithium, who were examined at McLean Hospital's Geriatric Psychiatry Research Program and Brain Imaging Center. The subjects' ages ranged from 56 to 85 years (66.0 ± 9.7 years) and all subjects had measurements of serum and brain lithium levels. Brain lithium levels were assessed using lithium magnetic resonance spectroscopy. All subjects also had proton magnetic resonance spectroscopy to obtain measurements of NAA and myo -Ino.
Results:  Brain lithium levels were associated with higher NAA levels [df = (1, 8), Β = 12.53, t  =   4.09, p < 0.005] and higher myo -Ino levels [df = (1, 7), F  =   16.81, p < 0.006]. There were no significant effects of serum lithium levels on any of the metabolites.
Conclusion:  Our findings of a relationship between higher brain lithium levels and elevated NAA levels in older adult subjects with BD may support previous evidence of lithium's neuroprotective, neurotrophic, and mitochondrial function-enhancing effects. Elevated myo -Ino related to elevated brain lithium levels may reflect increased inositol monophosphatase (IMPase) activity, which would lead to an increase in myo -Ino levels. This is the first study to demonstrate alterations in NAA and myo -Ino in a sample of older adults with BD treated with lithium.     

Neuropsychiatric symptoms and brain structural alterations in Fabry disease

Background: Neuropsychiatric symptoms (NPS), mainly cognitive deficits up to dementia and depressive syndromes have been described repeatedly in Fabry disease (FD). However, examinations regarding the pattern, extent, and frequency of the NPS in FD are still lacking. Moreover, the relationship between NPS and brain structural alterations in FD is unknown. The aim of this study was 1) to characterize NPS in a relatively large cohort of adult subjects with FD, and 2) to explore the association of cognitive performance and depressive syndromes with the FD‐typical brain structural findings. Methods: Twenty‐five Fabry patients (age 36.5 ± 11.0) with mild to moderate disease involvement and 20 age, gender‐, and education‐matched healthy controls were extensively studied by neuropsychiatric assessment, structural magnetic resonance imaging, magnetic resonance angiography, and diffusion‐tensor imaging. Results: Patients with FD showed deficits only in the attention domain. Clinically relevant depressive syndromes were noted in 60% of the patients. The subgroup of patients with markedly elevated volumes of white matter lesions (not associated with actual stroke; n = 7) showed slightly more learning and memory deficits, but no higher depression rate compared to less affected patients. Conclusions: Against the prevailing assumption, Fabry patients, even those with marked brain structural alterations, showed only mild cognitive deficits. The high frequency of depression in FD is likely to be related to the burden of this chronic multiorganic hereditary disease, but not to the FD‐typical brain structural alterations. Longitudinal studies are necessary to clear, if the mild cognitive deficits in FD might precede clinically relevant cognitive decline.     

Higher severity of frontal periventricular white matter and basal ganglia hyperintensities in first-ever lacunar stroke with multiple silent lacunes

Background and purpose:  We investigated whether patients with a lacunar infarct (LI) syndrome exhibiting unique LI or multiple LI on magnetic resonance imaging (MRI) examinations differed in terms of topography and severity of white matter hyperintensities (WMH) ratings.
Methods:  Forty consecutive patients with a first-ever acute LI, who presented a lacunar syndrome according to Miller–Fisher's classification were recruited and were classified into a group presenting isolated LI on MRI ( n  = 17) or multiple LI ( n  = 23).
Results:  Despite equivalent demographic, clinical and cognitive characteristics, patients with multiple LI had increased ratings of WMH in frontal, occipital and subcortical regions. No significant correlations could be evidenced between the number of LI and WMH ratings.
Conclusions:  Present findings provide support to previous hypothesis considering single and multiple LI MRI presentations of lacunar infarct patients as distinct entities.     

The neuroimaging of neurodegenerative and vascular disease in the secondary prevention of cognitive decline

Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease(amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.     

Multicenter long-term follow-up of children with idiopathic West syndrome: ACTH versus vigabatrin

Background and purpose:  Long-term follow-up of children with idiopathic West syndrome (WS) treated with adrenocorticotropic hormone (ACTH) or vigabatrin.
Methods:  Records of 28 normal magnetic resonance imaging (MRI) WS cases were reviewed for seizure development and cognitive outcome in relation to treatment type and lag.
Results:  Average age at disease onset was 5.5 months, and average lag time to treatment was 25 days. Fourteen patients were treated with ACTH (eight early and six late), and 14 with vigabatrin (without delay). Response rates were 88% for ACTH and 80% for vigabatrin. Short-term outcomes for seizure cessation and electroencephalography normalization were identical between the groups. In the long-term, early ACTH treatment was better than the rest combined. Average follow-up time was 9 years. A normal cognitive outcome was achieved in 100% of the early-ACTH group, 67% of the late-ACTH group and 54% of the vigabatrin group ( P  = 0.03). Seizures subsequently developed in 54% of the vigabatrin group, in 33% of the late ACTH group, and 0% of the early ACTH group ( P  < 0.05).
Conclusions:  Idiopathic WS with normal MRI is associated with a good cognitive outcome. Early ACTH treatment, administered within 1 month, yields a better cognitive and seizure outcome than vigabatrin or late ACTH.     

Mania as the first manifestation of Wilson's disease

Background:  Although mental changes are frequent in Wilson's disease, severe psychiatric disorders occur uncommonly and usually accompany the neurological picture. There are few reports in the literature of Wilson's disease patients with typical bipolar affective disorder (BPAD).
Case report:  The authors report the case of a patient with Wilson's disease whose initial manifestation was a manic episode followed by depression. Tremor in the upper limbs appeared one year after the onset of symptoms. The diagnosis of Wilson's disease was established three years after the first symptoms appeared, based on the neuropsychiatric picture, the detection of Kayser–Fleischer rings and the results of diagnostic tests indicating chronic liver disease and copper excess. ATP7B genotyping and magnetic resonance imaging of the brain with proton spectroscopy study were also performed. The patient became asymptomatic two years after starting treatment with penicillamine and remained non-symptomatic controlled during the eight-year follow-up period, without any specific treatment for the BPAD.
Conclusions:  To our knowledge, this is a singular report of a case of Wilson's disease in which a manic episode preceded the onset of neurological symptoms. The association between Wilson's disease and bipolar disorder is discussed.     

Adult-onset Hallervorden-Spatz syndrome presenting as cortical dementia

The authors examined behavioral and pathophysiologic substrates in a patient with adult-onset Hallervorden-Spatz syndrome who presented with insidious cognitive decline but no motor impairment. The authors combined longitudinal case history and serial neuropsychologic testing with functional neuroimaging (positron emission tomography), structural neuroimaging (magnetic resonance imaging), and brain tissue analyses. Serial assessments of a 29-year-old woman showed progressive dementia. Marked cognitive and behavioral deficits were seen on neuropsychologic testing, corresponding to striking cortical abnormalities on positron emission tomography, magnetic resonance imaging, and histopathologic studies. Typical motor manifestations of the disorder did not emerge until the patient was 34 years old, 5 years after the onset of cognitive symptoms. Hallervorden-Spatz syndrome should be considered in the differential diagnosis of progressive cortical dementia in a young adult, even in the absence of motor dysfunction.     

Assessment of dementia in patients with multiple system atrophy

Background and purpose:  We investigated dementia in patients with multiple system atrophy (MSA) in order to characterize the prevalence and nature of impairments in these patients.
Methods:  Fifty-eight MSA patients were recruited in our institution between April 1996 and December 2006 and investigated.
Results:  Of 58 patients, 10 were diagnosed with dementia. There were no significant differences in age at onset, gender, duration of disease, or severity of cerebellar dysfunction between patients with and without dementia. The early and delayed heart to mediastinum (H/M) ratios obtained with ¹²³I-metaidobenylguanidine (MIBG) cardiac scintigraphy were significantly decreased in patients with dementia compared with those without dementia. Of the 10 patients with dementia, three were found to have cognitive decline that preceded onset of motor symptoms. White matter lesions were evident in these patients, whilst frontal atrophy was prominent in patients whose cognitive decline was preceded by onset of motor symptoms.
Conclusions:  Dementia in patients with MSA may be more common than previously thought, furthermore, we speculate that clinical features of dementia in these patients might be heterogeneous.     

Correlation among subcortical white matter lesions, intelligence and CTG repeat expansion in classic myotonic dystrophy type 1

Objectives –  To analyze the correlation among intelligence, brain magnetic resonance images (MRI) and genotype in classic myotonic dystrophy type 1 (DM1) patients.
Materials and methods –  Seventeen patients with classic DM1 were administered intelligence and neuropsychological tests and brain MRI focusing on a semi-quantitative rating scale of subcortical white matter lesions (WMLs). Statistical analysis was measured to evaluate the correlation among clinical manifestations, intelligence, brain MRI abnormalities, and CTG repeat expansion.
Results –  There were statistically significant correlations between intelligence test and insular WMLs for all DM1 patients and between intelligence quotient and temporal WMLs for those patients with less than 400 of the CTG repeat size. We also documented that temporal WMLs were related to the disease course, and frontal WMLs were correlated with aging in all DM1 patients. However, a poor correlation was found among CTG repeat size and clinical pictures, neuropsychological impairments, and brain MRI abnormalities in all DM1 patients.
Conclusion –  These results suggest that subcortical WMLs are correlated with focal dementia in classic DM1 patients. Temporal and insular WMLs may be responsible for the global intellectual dysfunction of adult DM1 patients.     

Cerebral lesions can impair fMRI-based language lateralization

Purpose:   Several small patient studies and case reports raise concerns that the reliability of functional magnetic resonance imaging (fMRI) may be impaired in the vicinity of cerebral lesions. This could affect the clinical validity of fMRI for presurgical language lateralization. The current study sets out to identify if a systematic effect of lesion type and localization on fMRI exists.
Methods:   We classify lesions typically occurring in epilepsy patients according to (1) their potential to disturb blood oxygenation level dependent (BOLD)–effect generation or detection or to disturb spatial brain normalization, and (2) the proximity of lesions to protocol-specific volumes of interest (VOIs). The effect of lesions is evaluated through the examination of 238 epilepsy patients and a subgroup of 37 patients with suspected unilateral left-language dominance according to the Wada test.
Results:   Patients with fMRI-critical lesions such as cavernomas, gliomas, and mass defects close to VOIs, or with severe atrophy, show lower lateralization indices (LIs) and more often discordant language lateralization with the Wada test than do patients without such lesions.
Discussion:   This study points seriously toward fMRI-language lateralization being sensitive to cerebral lesions. Some lesion types and locations are more critical than others. Our results question the noncritical application of fMRI in patients with cerebral lesions.     

Asymmetrical lateral ventricular enlargement in Parkinson's disease

Background:  A recent case report suggested the presence of asymmetrical lateral ventricular enlargement associated with motor asymmetry in Parkinson's disease (PD). The current study explored these associations further.
Methods:  Magnetic resonance imaging (3T) scans were obtained on 17 PD and 15 healthy control subjects at baseline and 12–43 months later. Baseline and longitudinal lateral ventricular volumetric changes were compared between contralateral and ipsilateral ventricles in PD subjects relative to symptom onset side and in controls relative to their dominant hand. Correlations between changes in ventricular volume and United Parkinson's disease rating scale motor scores (UPDRS-III) whilst on medication were determined.
Results:  The lateral ventricle contralateral to symptom onset side displayed a faster rate of enlargement compared to the ipsilateral ( P  = 0.004) in PD subjects, with no such asymmetry detected ( P  = 0.312) in controls. There was a positive correlation between ventricular enlargement and worsening motor function assessed by UPDRS-III scores ( r  = 0.96, P  < 0.001).
Discussion:  There is asymmetrical lateral ventricular enlargement that is associated with PD motor asymmetry and progression. Further studies are warranted to investigate the underlying mechanism(s), as well as the potential of using volumetric measurements as a marker for PD progression.     

Deep white matter hyperintensities in patients with bipolar depression,unipolar depression and age-matched control subjects

Objective:  Hyperintensities in the white matter of the brain (DWH) and in the periventricular area (PVH) seen on magnetic resonance imaging (MRI) have been reported to be more frequent in patients with bipolar disorder (BP) than in normal subjects. To examine this further we compared MRI of patients with BP with age-matched patients with major depressive disorder (unipolar depression, UP) and healthy control subjects.
Methods:  T2 weighted axial and coronal brain MRI scans were obtained from 13 patients in the depressive phase of BP, 11 with current UP and 19 age-matched control subjects. The degree of DWH and PVH present in each scan was determined using a standardized scoring method.
Results:  The PVH ratings were similar in the three groups of subjects. However, proportionately more BP patients had higher DWH scores than either UP patients or controls. Although this difference did attain statistical significant, a main effect of age was noted. Further, subjects over the age of 50 were under-represented in the UP group.
Conclusions:  Notwithstanding the small total sample size and relative lack of older subjects in the UP group, the fact that almost twice as many BP patients showed more severe DWH suggests that patients with BP may be more vulnerable to develop these changes than UP patients and healthy controls.     

1H-MR spectroscopy indicates prominent cerebellar dysfunction in benign adult familial myoclonic epilepsy

Purpose :  To investigate the neurochemical pattern in patients with benign adult familial myoclonic epilepsy (BAFME/FAME), an inherited form of myoclonic epilepsy, by proton magnetic resonance (MR) spectroscopy (¹H-MRS).
Methods :  Eleven BAFME patients from three families showing linkage to 2p11.1-q12.2 were compared with 11 age-matched healthy control subjects.
Results :  MR imaging of all the patients and healthy subjects exhibited no structural abnormalities on detailed visual assessment. However, compared with healthy subjects, patients with BAFME displayed elevated choline/creatine ratio in the cerebellar cortex (p  =  0.01), whereas there was no significant difference for the other ratios. No ¹H-MRS values in the frontal and occipital cortex differed significantly in the patients compared with the healthy controls. No correlation was detected between ¹H-MRS values and disease duration (p  =  −0.35) as well as myoclonus severity (p  =  −0.48).
Conclusions :  Our findings suggest that the cerebellum is a prominent site of dysfunction in BAFME. The abnormal choline concentrations could reflect changes in the chemical and functional nature of cell membranes. ¹H-MRS was able to detect brain changes also in patients with recent disease onset and may be a useful tool supporting the diagnosis based on familial and electrophysiologic data. The relationship between cortical tremor and the cerebellum is also discussed.     

Very early onset and greater vulnerability in schizophrenia: A clinical and neuroimaging study

Although schizophrenia has been diagnosed in children, this group of disorders has received too little attention in the clinical and research literature. Preliminary data suggest that early onset schizophrenia (EOS) and very early onset schizophrenia (VEOS) tend to have a worse outcome than adult onset schizophrenia, and seem to be related to a greater familial vulnerability, due to genetic, psychosocial, and environmental factors. Recently, advanced neuroimaging techniques have revealed structural and functional brain abnormalities in some cerebral areas. This paper reports on a case diagnosed as VEOS, with premorbid year-long psychopathological history. The patient showed atypical proton magnetic resonance spectroscopy findings, and normal brain and spine computer tomography and brain magnetic resonance images.     

Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton magnetic resonance spectroscopy in vivo

The brain morphology and chemistry of seven children with late infantile (4/7) and juvenile (3/7) forms of metachromatic leukodystrophy (MLD) were investigated by magnetic resonance imaging (MRI) and localized proton magnetic resonance spectroscopy (MRS). Patients who were examined at least 6 months after the onset of symptoms (6/7) had severe leukodystrophic changes on MRI. Proton MRS revealed a marked reduction of the neuronal markerN-acetylaspartate in white and grey matter and elevated lactate in demyelinated areas. In contrast to other leukodystrophies MLD patients showed a generalized increase of brainmyo-inositol (2- to 3-fold in white matter), indicating a specific role in the pathophysiology of demyelination in MLD.     

Smaller pituitary volume in adult patients with obsessive–compulsive disorder

Aims:  Another structure in the obsessive–compulsive disorder (OCD) circuit may be the pituitary gland because of the fact that limbic–hypothalamic–pituitary–adrenal (LHPA) axis abnormality has been reported in patients with OCD. There has been only one prior study, however, concerning pituitary volumetry, in which the sample was a pediatric group. The purpose of the present study was therefore to investigate this in an adult OCD patient group using magnetic resonance imaging (MRI).
Methods:  Pituitary volume was measured in 23 OCD patients and the same number of healthy control subjects. Volumetric measurements were made on T1-weighted coronal MRI, with 2.40-mm-thick slices, at 1.5 T, and were done blindly.
Results:  A statistically significantly smaller pituitary volume was found in OCD patients compared to healthy controls (age and intracranial volume as covariates). With regard to gender and diagnosis, there was a significant difference in pituitary gland volume ( F  = 4.18, P  < 0.05). In addition, post-hoc analysis indicated near-significant difference in men with OCD as compared with women with OCD ( P  = 0.07) and significant difference between control men and control women ( F  = 10.96, P  < 0.001).
Conclusions:  Taking into consideration that the prior study found decreases in pituitary volume in pediatric patients with OCD as compared with healthy control subjects, future large MRI studies should investigate pituitary size longitudinally, with a careful characterization of hypothalamo-pituitary-adrenal (HPA) function in conjunction with anatomic MRI evaluation.     

Patterns of Magnetic Resonance Imaging Abnormalities in Symptomatic Patients With Krabbe Disease Correspond to Phenotype

BackgroundInitial magnetic resonance imaging studies of individuals with Krabbe disease were analyzed to determine whether the pattern of abnormalities corresponded to the phenotype.MethodsThis was a retrospective, nonblinded study. Families/patients diagnosed with Krabbe disease submitted medical records and magnetic resonance imaging discs for central review. Institutional review board approval/informed consents were obtained. Sixty-four magnetic resonance imaging scans were reviewed by two neuroradiologists and a child neurologist according to phenotype: early infantile (onset 0-6 months) = 39 patients; late infantile (onset 7-12 months) = 10 patients; later onset (onset 13 months-10 years) = 11 patients; adolescent (onset 11-20 years) = one patient; and adult (21 years or greater) = three patients. Local interpretations were compared with central review.ResultsMagnetic resonance imaging abnormalities differed among phenotypes. Early infantile patients had a predominance of increased intensity in the dentate/cerebellar white matter as well as changes in the deep cerebral white matter. Later onset patients did not demonstrate involvement in the dentate/cerebellar white matter but had extensive involvement of the deep cerebral white matter, parieto-occipital region, and posterior corpus callosum. Late infantile patients exhibited a mixed pattern; 40% had dentate/cerebellar white matter involvement while all had involvement of the deep cerebral white matter. Adolescent/adult patients demonstrated isolated corticospinal tract involvement. Local and central reviews primarily differed in interpretation of the early infantile phenotype.ConclusionAnalysis of magnetic resonance imaging in a large cohort of symptomatic patients with Krabbe disease demonstrated imaging abnormalities correspond to specific phenotypes. Knowledge of these patterns along with typical clinical signs/symptoms should promote earlier diagnosis and facilitate treatment.     

Smaller amygdala is associated with anxiety in patients with panic disorder

Aims:  Anxiety a core feature of panic disorder, is linked to function of the amygdala. Volume alterations in the brain of patients with panic disorder have previously been reported, but there has been no report of amygdala volume association with anxiety.
Methods:  Volumes of hippocampus and amygdala were manually measured using magnetic resonance imaging obtained from 27 patients with panic disorder and 30 healthy comparison subjects. In addition the amygdala was focused on, applying small volume correction to optimized voxel-based morphometry (VBM). State–Trait Anxiety Inventory and the NEO Personality Inventory Revised were also used to evaluate anxiety.
Results:  Amygdala volumes in both hemispheres were significantly smaller in patients with panic disorder compared with control subjects (left: t = −2.248, d.f. = 55, P  = 0.029; right: t = −2.892, d.f. = 55, P  = 0.005). VBM showed that structural alteration in the panic disorder group occurred on the corticomedial nuclear group within the right amygdala (coordinates [x,y,z (mm)]: [26,−6,−16], Z score = 3.92, family-wise error-corrected P  = 0.002). The state anxiety was negatively correlated with the left amygdala volume in patients with panic disorder (r = −0.545, P  = 0.016).
Conclusions:  These findings suggested that the smaller volume of the amygdala may be associated with anxiety in panic disorder. Of note, the smaller subregion in the amygdala estimated on VBM could correspond to the corticomedial nuclear group including the central nucleus, which may play a crucial role in panic attack.     

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: an in vivo1H MRS study

Objectives:  While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy (¹H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N -acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr).
Methods:  Thirty-two medication-free BD subjects (33.8 ± 10.2 years) and 32 matched controls (33.8 ± 9.0 years) underwent a short echo-time (TE = 30 ms) ¹H MRS. An 8-cm³ single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo -inositol, and glutamate were obtained, using the water signal as an internal reference.
Results:  BD subjects had lower Cr + PCr [ F _(1,62) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [ F _(1,62) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites.
Conclusions:  These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.