Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease.

OBJECTIVE: Loss-of-function mutations in the progranulin gene (PGRN) were identified in frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). We assessed whether PGRN also contributes to genetic risk for Alzheimer disease (AD) in an extended Belgian AD patient group (n = 779, onset age 74.7 +/- 8.7 years). METHODS: A mutation analysis of the PGRN coding region was performed. The effect of missense mutations was assessed using in silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis. RESULTS: We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p.Cys139Arg and p.Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD. CONCLUSIONS: Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD). Further, we hypothesize that at least some PGRN missense mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.

Paroxysmal neuralgic upper cervical pain attacks: the lower syndrome of cluster headache.

We present a group of seven patients with a lower syndrome (LS) of cluster headache (CH). Seventy-three newly diagnosed patients with CH were subjected to a 9 years follow-up study; 66 patients were classified as upper syndrome (US) and only seven patients (9.5%) as LS. We focus on the characteristics of this group of seven patients with LS and compare them with existing literature. The seven cases with LS illustrate the wider spectrum of clinical manifestations that can occur in CH, namely infraortibal symptoms or these outside the territory of the trigeminal branches such as the upper cervical region or the craniocervical margin. The duration of the attacks can last more than 180 min. The attacks show a circadian/circannual regularity and a stereotypic pattern of symptoms in most of the patients. The severity and duration of the attacks may increase over the years. The neck pain can overshadow all the other symptoms of CH. Because of the regularity of the attacks at particular times of day or night in some patients, even abortive therapy can be used as prevention when taken some hours before the suspected attack. We hypothesize that some patients with LS may represent an anatomical-functional variant of a primary chronic neurovascular pain disorder originating from the central nervous system, with possible involvement of the hypothalamus and the trigeminovascular (TV) system, with inputs from the cervical roots C(0)-C(2). Clinicians should consider CH when pain attacks are located outside the orbitotemporal regions, but fulfil the other diagnostic criteria for CH and should try ergotamine, oxygen, sumatriptan, verapamil, steroids or even combinations in these patients.

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects.

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.

Phonological agraphia following a focal anterior insulo-opercular infarction.

Following a unique infarction, restricted to the left anterior insula and the adjacent part of the intrasylvian frontal opercular cortex, an 83-year-old right-handed patient acutely developed a severe speech disorder that evolved into mere mutism within a few hours. After rapid recovery from mutism, oral language was characterized by severe apraxia of speech. In-depth language investigations further disclosed an isolated, highly selective disturbance of the spelling system (phonological agraphia) which resolved rapidly. One year after onset of neurological symptoms, the apraxia of speech had almost completely receded. The anatomoclinical findings in this first representative of pure and nearly isolated phonological agraphia complement previous neuroanatomical and neurolinguistic accounts of phonological agraphia. The data not only seem to enrich current insights in the anatomical locus for phonological agraphia, they also seem to contribute to a further delineation of the insular role in phonologically mediated aphasic manifestations.

Loss of psychic self-activation after paramedian bithalamic infarction.

BACKGROUND AND PURPOSE: Loss of psychic self-activation has been described after bilateral lesions to the globus pallidus, striatum, and white matter of the frontal lobes, but it is a very rare sign of bithalamic lesions. The exact functional-anatomic mechanism underlying loss of psychic self-activation following bithalamic lesions remains to be elucidated. CASE DESCRIPTION: We present clinical, neuropsychological, structural, and functional neuroimaging data of an 18-month follow-up period of a man with prominent loss of psychic self-activation after coronary arteriography. Except for memory decline, accompanying symptoms remained restricted to the acute phase. The neurobehavioral syndrome consisted mainly of apathy, indifference, poor motivation, and flattened affect, and this remained unchanged during the entire follow-up period. MRI showed a bithalamic infarction involving the nucleus medialis thalami bilaterally. Single-photon emission CT revealed a severe relative hypoperfusion of both thalami, a relative hypoperfusion of both nuclei caudati, and a relative hypoperfusion mesiofrontally. CONCLUSIONS: Single-photon emission CT data support the hypothesis that the neurobehavioral manifestations after bithalamic paramedian infarction are caused by disruption of the striatal-ventral pallidal-thalamic-frontomesial limbic loop. Probably, bilateral disruption at different levels of the striatal-ventral pallidal-thalamic-frontomesial loop may lead to a similar clinical picture consisting of loss of psychic self-activation.

Validation of the cerebellum as a reference region for SPECT quantification in patients suffering from dementia of the Alzheimer type.

In longitudinal brain studies of dementia of the Alzheimer type (DAT), the cerebellum is often used as a reference region for single photon emission computed tomography (SPECT) quantification, which assumes no significant regional influence of physiological fluctuations or pathology. With the use of absolute quantification in DAT patients, reproducibility of cerebellar uptake of technetium-99m-d,l-hexamethylpropyleneamine oxime (HMPAO) was tested and compared with the mean absolute cerebellar tracer uptake value in DAT patients and healthy control subjects. In 13 DAT patients SPECT studies were repeated within 2 weeks to assess reproducibility of cerebellar regional brain uptake (rBU). With calibrated point sources as scaling factors, cerebellar activity was expressed as rBU of HMPAO per cm3 brain tissue in percent of the injected lipophilic dose of 740 MBq (20 mCi). Also, mean cerebellar rBU in patients suffering from DAT was calculated and compared with a previously established database obtained in healthy volunteers. Repeated SPECT studies within a 2-week interval in clinically stable patients resulted in a mean rBU increase of 6.8 +/- 10.3% in the second SPECT study as compared with the first. A similar shift was previously reported in healthy volunteers. Mean cortical cerebellar rBU values in DAT patients and in the healthy reference population concurred, after cumulative corrections for body surface and for a mean brain volume of 1350 ml (obtained in healthy control subjects), showing respective mean values of 53.9 +/- 7.4 and of 52.0 +/- 7.3 x 10(-6) of the injected lipophilic dose 740 MBq (20 mCi) of HMPAO per cm3 of brain tissue. A unidirectional shift in mean absolute cerebellar uptake values occurs between repeat SPECT examinations in DAT patients similar to previous findings in a group of healthy volunteers. The origin of this phenomenon remains elusive but deserves further study with regard to SPECT (semi)quantification in DAT patients. Most interestingly, the presented findings suggest that with the use of HMPAO SPECT in DAT patients the cerebellum remains scintigraphically uninvolved.

From neuronal and vascular impairment to dementia.

This paper reviews aspects of existing knowledge and recent concepts related to the development of vascular dementia which, after Alzheimer's disease, is the most frequent type of dementia. The disorder may result from cerebrovascular disorders, including multi-infarct dementia due to thromboembolic disease, other less common vasculopathies and ischemic brain damage secondary to systemic hypotension. Characteristic clinical features are stepwise cognitive deterioration resulting from repeated strokes and the presence of focal signs and symptoms. The clinical distinction between Alzheimer's disease and vascular dementia may be difficult and strict criteria (NINDS/ AIREN) have recently been adopted as standard guidelines for research studies. Vascular dementia and Alzheimer's disease can co-exist, so-called "mixed dementia", and the presence of cerebrovascular disease may worsen Alzheimer dementia. Indeed, there is often a vascular component in the pathogenesis of dementia. The pathogenesis of vascular dementia is complex. Post-stroke patients are at increased risk; some predisposing or risk factors are the volume, number and site (whether strategic or not) of cerebral injuries, distal field vascular injury with reduced cerebral blood flow, white matter ischemia due to small vessel disease, the co-existence of vascular disease and Alzheimer's dementia, and the presence of cognitive decline prior to stroke. There is increasing evidence of a complex relationship between vascular dementia and Alzheimer's disease. When post-stroke dementia is progressive this may reflect associated Alzheimer's disease either unrecognized or asymptomatic prior to the stroke. The apolipoprotein E4 genotype is a risk factor for ischemic stroke, vascular dementia and Alzheimer dementia. Although dementia is usually irreversible, it is now accepted that cognitive impairment may be delayed, stabilized or sometimes reversed. The treatment of vascular dementia consists of two approaches: preventive measures, including attempts to control risk factors for stroke and the use of antiplatelet agents and/or surgery, and the treatment of cognitive symptoms. Nootropic and vasodilator agents have been reported to improve cognitive impairment from various causes. Ongoing research is attempting to show their specific benefit in vascular dementia.

Case report of a patient with complex partial frontal lobe seizures as a complication of bifrontal lobotomy.

This case report describes an 85 year-old woman who underwent a bilateral frontal lobotomy for presumed schizophrenia 50 years ago. The patient presented with sudden alterations of consciousness accompanied by motionless staring and speech and movement arrest. After 5 to 10 seconds, contact recovered briskly. As there was electrophysiological evidence for a frontal epileptic focus, these fits were classified as complex partial frontal lobe seizures with impairment of consciousness at onset. An aetiological link with the bifrontal lobotomy is probable. At the occasion of this case report, complications of frontal lobotomy are reviewed.

Behavioral effects of vigabatrin correlated with whole brain gamma-aminobutyric acid metabolism in audiogenic sensitive rats.

The present study evaluates dose-dependent behavioral effects of acutely or subacutely administered single doses of vigabatrin (gamma-vinyl gamma-aminobutyric acid, gamma-vinyl GABA, CAS 60643-86-9) in audiogenic sensitive rats, in correlation with whole brain GABA metabolism. There was a discrepancy in timing between behaviorally observed maximal antiepileptic protection (4 h after i.p. administration of gamma-vinyl GABA) and on the other hand maximal inhibition of GABA-transaminase activity and maximal increase of whole brain GABA content (24 h after i.p. administration of gamma-vinyl GABA). This suggests that the antiepileptic properties of gamma-vinyl GABA not only depend on GABA-ergic neurotransmission. A possible explanation is a gamma-vinyl GABA-induced decrease of excitatory amino acids or increased glycine concentrations in the brain.

Perfusion and thallium single photon emission computed tomography in herpes simplex encephalitis.

This is the first report on 201thallium-single photon emission computed tomography (201Tl-SPECT) brain scan of a patient with herpes simplex encephalitis (HSE). The presented 201Tl-SPECT observations are correlated with 99mtechnetium hexamethylpropylene amine oxime (99mTc-HMPAO) perfusion SPECT and magnetic resonance imaging (MRI) findings. Brain 99mTc-HMPAO perfusion SPECT reveals a hyperperfusion in the right temporal lobe with extension to the parietal lobe and a hypoperfusion in the ipsilateral occipital lobe. 201Tl-SPECT shows a fixation in the right temporal lobe coinciding with the gadolinium enhancement on MRI. The right occipital lesion shown by gadolinium captation on MRI and hypoperfusion on 99mTc-HMPAO perfusion SPECT was not evident on the 201Tl SPECT. These findings could illustrate that the lesions might be different pathophysiologically.

Primary cerebral lymphoma visualised by means of In-111-pentetreotide scintigraphy.

Primary lymphoma of the central nervous system, until recently representing about 1% of all brain tumours, shows a dramatically increased incidence in the general population as well as in high-risk groups (immunocompromised, AIDS), and may rise up to 6% in a population of AIDS patients. The clinical presentation is variable and cannot reliably be distinguished from other intracerebral tumours. At present, CT and MRI are the methods of choice for diagnosing cerebral lymphomas. However, their characteristics are not specific. The radiological picture may suggest glioma, meningioma, metastatic carcinoma or even a cerebrovascular accident. A labelled somatostatin analogue (pentetreotide) has been proposed as a new tracer for the imaging of somatostatin receptors, which have been identified by immunocytochemical or radioimmunoassay techniques in several organ systems. Somatostatin receptors were also identified in surgical biopsy samples from patients with Hodgkin and non-Hodgkin lymphoma and extracerebral lymphoma has already been visualised in vivo by means of In-111-labelled pentetreotide. While CT images of the brain showed a regression of the tumour after radiotherapeutic treatment, the scintigraphic images showed persistence of the tumoural tissue, corresponding with the clinical evolution and outcome. Furthermore, the absence of extra-cerebral lymphoma tissue, seen on the whole body images, was confirmed by post-mortem examination. To our knowledge, this is the first report of a primary intracerebral lymphoma visualised by means In-111-pentetreotide.

Discriminative use of SPECT in frontal lobe-type dementia versus (senile) dementia of the Alzheimer's type.

UNLABELLED: Dementia of the Alzheimer's type [(S)DAT] and dementia with frontal features (FLD) are nosological entities with different prognoses and presumed pathophysiology. There is a need for noninvasive differential diagnostic tools. To evaluate whether SPECT perfusion imaging could discriminate between these neurodegenerative disorders, we performed a comparative study. METHODS: SPECT scans using 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO) of 21 patients with FLD were compared with those obtained in a group of 19 age- and severity-matched patients suffering from (S)DAT. Brain SPECT perfusion deficits were scored by visual qualitative analysis with respect to location, lateralization and severity. A total severity score of cerebral hypoperfusion (maximal value = 18) was calculated by adding all severity scores (scored between 0 and 3; 0 = no perfusion deficit; 1 = 13%-30% hypoperfusion; 2 = 30%-50%, hypoperfusion and 3 = > 50% hypoperfusion including breaching of the cortex) for right and left frontal, parietal and temporal lobes. Moreover, bifrontal hypoperfusion (Fa) was scored, yielding a value between 0 and 6 by adding the two frontal severity scores. RESULTS: No significant correlation was found between MMSE scores and total severity scores on SPECT. A statistically significant correlation was found between the Middelheim frontality score and frontal severity score. Statistically more significant bilateral hypoperfusion of the parietal lobes was found in the (S)DAT group. Conversely, bifrontal hypoperfusion was found more in the FLD group. Stepwise logistic regression analysis identified the severity of bifrontal hypoperfusion as the most significant contributing parameter to correctly classifying (S)DAT versus FLD on SPECT. The probability of predicting (S)DAT based on the SPECT scan is calculated with the following formula: [equation: see text] Using this equation, a value above 0.5 was predictive for (S)DAT and a calculated value under 0.5 was predictive for FLD. Using this model, 81% of the FLD group and 74% of the (S)DAT were correctly classified. CONCLUSION: Technetium-99m-HMPAO SPECT may help in discriminating FLD from (S)DAT. Bifrontal hypoperfusion was found to be the most powerful predictor of clinical classification. Further validation of the presented logistic regression model is warranted.

Focal neurocognitive dysfunctions in abstinence delirium: a case report.

Due to abrupt interruption of hidden benzodiazepine-use, a 68-year-old woman developed a full-blown abstinence delirium characterized by epileptic seizures and progressive focal neurocognitive symptoms. The evolution of such rare neuro-linguistic phenomena as an echoism, palilalia and glossomania associated with a progressive visuo-perceptive syndrome and a visual hallucinosis are for the first time reported within the context of withdrawal. Notwithstanding the lack of any neuroradiological evidence for a morphological lesion in the clinically expected brain regions, the anatomo-clinical hypothesis of a focal frontal and parieto-occipital dysfunction was explicitly corroborated by repeated 99mTc-HMPAO SPECT findings.

Cerebellar induced aphasia: case report of cerebellar induced prefrontal aphasic language phenomena supported by SPECT findings.

A 73-year-old right-handed man with ischemic infarction in the vascular territory of the right arteria cerebellaris superior is described. In the acute phase he presented with cerebellar and brainstem symptoms, followed within a few days by a paresis of the right arm and unexpected language disturbances of aphasic origin. The core features of the aphasic syndrome corresponded to a diagnosis of Luria's dynamic aphasia, complicated by expressive and receptive agrammatism. During one year follow-up the ataxia and paretic symptoms disappeared but the slightly ameliorated aphasic syndrome and the sensory disturbances in the left hemicorpus persisted. In the absence of any neuroradiological evidence for a structural lesion in the left frontal language areas, the hypothetical causative role of the right cerebellar lesion on the contralateral prefrontal aphasic symptomatology is advocated and supported by positive 99mTc-hexamethylpropyleneamine oxime single-photon emission-computed tomography findings, revealing a focal hypoperfusion in the clinically suspected areas. In our case, this phenomenon of so-called 'crossed cerebello-cerebral diaschisis', reflecting the distant functional impact of the right cerebellum on the contralateral prefrontal cortical areas, is for the first time associated with an aphasiologic substrate. The co-occurrence of a right cerebellar lesion and an aphasic syndrome forms the first clinical illustration of the pathophysiological hypothesis of a deactivation of prefrontal left hemisphere language functions due to the loss of excitatory impulses through cerebello-ponto-thalamo-cortical pathways.

Dementia paralytica in a fifteen-year-old boy.

A 15-year-old boy, whose history revealed an unremarkable pregnancy, birth and neonatal period and who had shown a normal motor and mental development, presented at the hospital with deterioration of cognitive functions since the age of 7. He was bedridden with manifest ataxia involving all limbs, anisocoria and a sluggish to absent pupil reaction to light. Syphilis serology was positive with a Venereal Disease Research Laboratory (VDRL) titer of 1:256 and a Treponema pallidum Haemagglutination Assay (TPHA) titer of 1:163840. Cerebrospinal fluid (CSF) protein concentration was 55 mg/dl and CSF-leucocyte count was 14/mm3 (85% mononuclear cells). CSF-VDRL-titer was 1:16. A diagnosis of congenitally acquired dementia paralytica was made, since the boy's parents' clinical exam and serology results were suggestive for latent syphilis. Although cognition was still very much deteriorated five months following penicillin treatment, clinical examination revealed partial recuperation. Screening for syphilis should be part of routine testing in every subject presenting with cognitive deterioration, regardless of age.

SPECT findings in an unusual case of visual hallucinosis.

A 64-year-old right-handed man acutely developed elementary visual hallucinations (monochromatic, moving geometrical figures), visual illusions (distortion of the right side of faces) with achromatopsia and blurred vision restricted to the left visual hemi-field. CT of the brain before and after administration of contrast medium and a repeat examination 2 months later showed no abnormalities, while brain mapping (power analysis of EEG) demonstrated theta wave slowing of the curve over the posterior part of the right hemisphere. 99mTC HMPAO SPECT of the brain, however, demonstrated an area of definite focal hypoperfusion in the right occipito-temporal region. Echo-Doppler-duplex and continuous wave examination of the cervical arterial blood vessels disclosed bilateral discrete atheromatous plaques that did not affect the blood flow. Transoesophageal echocardiography demonstrated slight mitral valve insufficiency. Cerebral angiography showed an occlusion of the right posterior cerebral artery. After the visual hallucinations had subsided, SPECT showed partial normalization of the right occipito-temporal perfusion. In the absence of CT evidence for a structural lesion in the clinically suspected areas, only functional imaging revealed an obviously significant lesion. This case furthermore demonstrates that SPECT can contribute to the identification of the pathophysiology underlying visual hallucinosis.

Actigraphic evaluation of handedness.

The utility of an objective evaluation of motor activity, actigraphy, was examined in the evaluation of handedness. Hand preference was assessed in a homogeneous group of 190 young volunteers using the Edinburgh Inventory (EI). The EI distribution obtained in the population studied was comparable with distributions cited in the literature. Simultaneous actigraphic recordings from both wrists were made in 58 of these subjects for 20 h, starting at 1000 h, using an epoch length of 4 s. Care was taken to include comparable numbers of right- and left-handers (based on EI score) in this subgroup. Two actigraphic parameters were defined. One of these, the Activity Index (AI[x]), is a measure of the difference in total motor activity between right and left wrist. The other, Movement Index (MIy[x]) is a measure of the difference in movement pattern. AI[x] showed a moderate but significant correlation with EI (r = 0.36, P < 0.005). The correlation between MIy[x] and EI was high (r = 0.65, P < 0.0001). Rebinning of the data into 60 s epochs decreased the degree of linear correlation between MIy[x] and EI. We conclude, in contrast to a previous study, that actigraphy can be used to discriminate between dominant and non-dominant hands; that the difference in movement pattern between right and left hand is larger than the difference in total motor activity; and that epoch lengths shorter than the conventional 60 s are more sensitive for this kind of discrimination.

Technetium-99m HMPAO SPET in acute supratentorial ischaemic infarction, expressing deficits as millilitre of zero perfusion.

A comparative interim analysis was performed of clinical parameters, computed tomographic (CT) scan results and technetium-99m hexamethylpropylene amine oxime single-photon emission tomography (SPET) findings obtained within 12 h of acute supratentorial ischaemic infarction. First, the applicability for SPET semiquantification in this study of the "method of Mountz", simultaneously accounting for extent and degrees of hypoperfusion by expressing deficits as millilitre of zero perfusion, was considered. Next, the relative contributions of perfusion SPET and CT scan in the acute stage of ischaemic infarction were compared in 27 patients (mean age 68.8 years). Finally, the correlation of SPET lesions with clinical parameters at onset was evaluated. The method of Mountz represents a workable, accurate virtual parameter, with the assumption that the contralateral brain region remains uninvolved. Interobserver reproducibility in 12 SPET studies, with lesions varying between 6 and 369 cc, showed a correlation coefficient r of 0.99. In practice, because of inconstant distribution of activities in the brain, the method can only be applied slice by slice and not on the total global volume. While the mean delay since the onset of symptomatology was approximately 7 h for both SPET and CT scan, SPET showed lesions concordant with the clinical neurological findings in 100% and CT scan in only 48%. One could hypothesize that SPET examinations performed later would show larger functional defects, because of the development of additional functional changes secondary to biochemical alterations. However, in this regard no statistically significant differences were found between two subproups, taking the median of delay before SPET examination as cut-off.(ABSTRACT TRUNCATED AT 250 WORDS)