Parkinsonisms at onset can be associated to cognitive impairment.

Purpose To evaluate optic nerve and in particular melanopsin retinal ganglion cells (mRGCs) in relation to rest-activity rhythm in Alzheimer disease (AD). Methods Retinal nerve fiber layer (RNFL) thickness measurements by optical coherence tomography were performed in 21 AD and 74 age-matched controls. Actigraphic monitoring was performed in 16 AD patients and 10 age-matched controls. Non-parametric methods were applied to assess interdaily stability (IS), intradaily variability (IV) and relative amplitude (RA) of rest-activity rhythm. We also performed immunohistochemical analysis of mRGCs and axonal count on optic nerve cross-sections in 14 neuropathologically confirmed AD and 13 control post-mortem retinas. Results OCT evaluation showed reduced average (p=0.03) and superior (p=0.005) RNFL thickness in AD patients. Actigraphic monitoring demonstrated an increased IV (p=0.04) and reduced RA (p=0.04) in AD. Furthermore, AD patients were significantly less active during the day (p=0.03). Considering the patients with at least one circadian parameter outside the 2SD from the mean of controls, we found a significant correlation between IV, average (p=0.035), superior (p=0.045) and inferior (p=0.017) RNFL thickness. Melanopsin RGCs density was significantly reduced, independently from age, in AD retinas (p=0.003) and AD optic nerves showed variable degree of age-related axonal loss. Conclusion We demonstrated a subclinical optic nerve involvement in AD patients, both by OCT and histopathology. We also documented rest-activity circadian dysfunction in AD patients. Post-mortem investigation revealed loss of mRGCs and RGCs with a different pattern in AD. The reduction of mRGCs may contribute to circadian rhythm dysfunction in AD.

In previous studies, addressing the association between orthostatic hypotension and cognitive decline, patients underwent neuropsychological evaluation in sitting position, and blood pressure values and cognition were not measured concurrently. Furthermore, no studies assessed the acute effects of orthostatic hypotension on cognitive performances. The aim of our study was to evaluate the effect of a documented fall in systolic blood pressure (SBP) of at least 20 mmHg on a battery of cognitive tests in patients with neurogenic orthostatic hypotension. Ten consecutive patients with neurogenic orthostatic hypotension, normal brain imaging, and a normal Mini Mental State Examination in supine position were enrolled in the study. Patients underwent a detailed neuropsychological assessment (Brief Mental Deterioration battery and computerized tests) over two test sessions: the first while tilted to an angle able to cause a fall of at least 20 mmHg in SBP; the second while supine, after 30 min of rest. Parallel forms of the tests were presented on each testing session. Patients scored significantly worse in the visual search test, analogies test, immediate visual memory, and the measure of global cognitive functioning of Brief Mental Deterioration battery during the orthostatic challenge compared to the supine position. Orthostatic hypotension was associated with a significant worsening of cognitive performances, affecting both global cognitive functioning and specific tasks, mainly exploring executive functions. The assessment of cognitive function in patients with neurogenic orthostatic hypotension should be performed considering the body's position of the subject.

Slowly progressive aphemia (SPA) is a rare focal degenerative disorder characterized by severe dysarthria, frequent orofacial apraxia, dysprosody, phonetic and phonemic errors without global cognitive deterioration for many years. This condition is caused by a degeneration of anterior frontal lobe regions, mainly of the left frontal operculum. We report a case of SPA with a course of 8 years, evaluated by repeated neuropsychological, conventional, and functional MRI examinations. In our case, neuropsychological examinations showed a progressive impairment of speech articulation including dysprosody, phonetic and phonemic errors, and slight writing errors. No global cognitive deterioration was detected and the patient is still completely autonomous. Morphological and functional investigations showed, respectively, a progressive atrophy and progressive impairment of the left frontal region, confirming the role of the opercular region in determining this rare syndrome. During verbal task generation as the cortical activation of this region gradually decreased, the language articulation worsened.

Introduction: As therapeutic interventions become available for degenerative dementias (1) there is a need for automated imaging methodologies which can provide in vivo surrogate markers of brain pathological changes. The aim of the present study was to assess the ability of combined MR cortical structure volumetry and DTI to automatically detect regional brain changes in patients with a clinical and neuropsychological diagnosis of Alzheimer disease (AD) and Frontotemporal dementia (FTD). Methods Subjects. As part of an on-going study, patients were recruited from the Ospedale S. Orsola, Bologna, with a clinical/radiological diagnosis of AD or FTD, along with healthy controls of similar ages. All subjects gave written informed consent. Subject characteristics: AD: 9 patients (2 M), ages 67±8 yrs (mean±s.d.); FTD : 7 patients (3 M), ages 64±5 yrs; 7 controls (4 M), ages 66±11 yrs. MR acquisition. All MRI studies were performed on a 1.5 T GE Signa Horizon LX scanner. A conventional T1-weighted (T1W) axial volumetric image was acquired using the FSPGR sequence TI=600 ms; TE=5.1 ms; TR=12.5 ms; 25.6 cm square FOV, 1 mm slice thickness; in-plane resolution=256x256. A DTI SE-EPI image, was also acquired, encoded in 25 directions at b=900 s.mm and one T2-weighted image; TE=89.2 ms; TR=10 s; 32 cm square FOV, 4 mm inter-slice distance; in-plane resolution=192x192; NEX=1. DTI parameter maps of mean diffusivity (MD) were generated using DTIFIT (FSL; 2). Data analysis. Automatic segmentation of the volumetric image was performed using FIRST (2) to bilaterally define seven subcortical gray matter structures (thalamus, putamen, caudate, pallidus, accumbens, hippocampus and amygdala). In addition, five cortical regions (frontal, parietal, temporal and occipital lobes and cerebellum) were defined using an MNI (3) template. Within these regions gray matter was defined using a three-class segmentation of the T1W images All structures were registered onto the DTI maps in two steps using flirt (2), following a previously published method (4). White matter partial volume on DTI images was masked by registering the MNI FA template onto subjects’ own FA map using non-linear registration. Deep gray structures were identified by warping the Harvard-Oxford sub-cortical structure atlas (also defined in MNI coordinate space). A mask excluding CSF was generated from a three-class segmentation of the T2weighted image volume. ROIs of all deep gray and cortical structures was defined in the DTI space by fusing registered FIRST, Harvard-Oxford, and CSF and WM exclusion masks. Volumes and median MD values were calculated. Statistics. Cortical and subcortical volumes were separately corrected for subject age and total brain volume, MD values for age only. Each set of corrected values was then analysed by a full factorial ANOVA including structure and patient group as factors. In addition particular structures of interest (frontal, parietal and temporal lobes and hippocampus) were analysed by one-way ANOVA. Results: Results of the ANOVA analysis were significant (p<0.001) for cortical volume, subcortical volume, cortical MD and subcortical MD, using structure and patient group as factors. However patient group was not a significant factor for subcortical volume. Cross terms (group * structure) were not significant, indicating that group differences did not vary between structures. Differences between groups are summarised in the Table. One way ANOVA revealed a reduction in gray matter volume in patients, in the hippocampus, and the parietal but not frontal or temporal lobes. Individual structures and cortical lobes did not reveal elevated MD. Table. Subject group comparisons for cortical/subcortical volume/MD. Mean ±S.E. * Sig. diff from controls at p<0.05 Group Volume (mL) MD (x10 mm.s) Cortex Subcortical Cortex Subcortical Mean S.E. Mean S.E. Mean S.E. Mean S.E. Controls 203.1 3.0 6.1 0.1 0.802 0.005 0.801 0.006 AD 195.3 2.9 * 6.0 0.1 0.824 0.005 * 0.835 0.006 * FTD 186.4 3.2 * 5.8 0.1 0.829 0.006 * 0.831 0.006 * Discussion: Volumetric structural imaging and DTI are two MR imaging modalities which offer the potential of improving the radiological diagnosis and grading of neurodegenerative diseases, but to achieve this potential in a clinical setting automated methods of image segmentation and analysis are required. In the current study, for both AD and FTD, a highly automated method of image segmentation, combining information from both volumetric and diffusion imaging was able to differentiate patient groups from normal subjects of similar ages. The changes related to diffuse reductions in cortical volume, and diffuse increases in MD in both cortex and subcortical structures. Alterations were much less apparent on examination of individual structures, even those known to be involved in the degenerative pathology. This may be both to the limited number of cases studied so far, and the heterogeneity of the disorder, at least for FTD (5). Even in this limited group of patients this automated segmentation method revealed differences between control subjects and patients. These are expected to increase with the number of subjects in the study database.

Cerebrospinal Venous Fistula Presenting with Cognitive Decline: Systematic Literature Review and Report of Two Cases,

Knowing how and when the degenerative process starts is important in neurodegenerative diseases.We have addressed this issue in fatal familial insomnia (FFI) measuring the cerebral metabolic rate of glucose (CMRglc) with 2-[ 18 F]fluoro-2-deoxy-D-glucose PET in parallel with detailed clinical, neuropsychological examinations and polysomnography with EEG spectral analyses.Nine asymptomatic carriers of the D178N mutation, 10 non-carriers belonging to the same family, and 19 age-matched controls were studied over several years.The CMRglc as well as clinical and electrophysiological examinations were normal in all cases at the beginning of the study.Four of the mutation carriers developed typical FFI during the study but CMRglc and the clinical and electrophysiological examinations remained normal 63, 56, 32 and 21 months, respectively before disease onset.The carrier whose tests were normal 32 months before disease onset was re-examined 13 months before the onset.At that time, selective hypometabolism was detected in the thalamus while spectral-EEG analysis disclosed an impaired thalamic sleep spindle formation.Following clinical disease onset, CRMglc was reduced in the thalamus in all 3 patients examined.Our data indicate that the neurodegenerative process associated with FFI begins in the thalamus between 13 and 21 months before the clinical presentation of the disease.

Objectives: To describe wake-sleep and body core temperature (t°) rhythm abnormalities in two patients with bilateral paramedian thalamic calcifications. Methods: Patients underwent (18F)FDG PET scans and 24 hour polygraphic recordings of wake-sleep and t°. Results: PET showed bilateral thalamic hypometabolism in both patients with additional basal ganglia or mesiolateral frontal and cingular hypometabolism. Wake-sleep studies showed abnormal sleep organisation and in the case with frontal and limbic PET hypometabolism, pre-sleep behaviour associated with “subwakefulness” EEG activities, lack of EEG spindles and K complexes, and features of status dissociatus. The t° rhythms showed increased mesor in both (37.4°C and 37.75°C) and inverted rhythm in one patient. Conclusions: Paramedian thalamic structures and interconnected, especially frontal and cingular, areas play a part in the organisation of the wake-sleep cycle and attendant autonomic functions.

Depression and cognition are intricately related. Depression per se can cause cognitive impairment, mainly affecting attention, psychomotor activity and memory. The possible symptoms are: involvement in the strategic processes when a superior effort in task execution is needed, slowing of motor and ideational activity, deficits in concentration with more sensitivity to interference alteration of episodic memory, mainly autobiographical, especially when the affective tonality of the memorandum is not congruent with that of mood. Many organic diseases and lesions (mainly those in the left frontal cerebral regions) are responsible for depressive symptoms. The spectrum between depression and dementia includes patients with depression without dementia, with dementia without depression, with depressive pseudodementia and with depression during the course of dementia. Differential diagnosis among these entities is often difficult. In a group of 151 patients referred to our Center we found that about half of the demented patients were depressed, in particular women. Old age and low education are significantly related to dementia but not to depression which does not alter global cognitive measures. Our data confirm that dementia is associated with an increase in depression. Whereas depression can cause selective cognitive deficit, it does not seem to influence global intellectual functioning. Nevertheless, depression may be a potential risk factor for developing dementia.

We recently reported in Brain (Lugaresi et al., 1998) 20 cases of idiopathic recurrent stupor due to endozepine-4 accumulation in the blood.Samples obtained from nine of these patients were analysed by gas chromatography-mass spectrometry to rule out contaminating synthetic benzodiazepines (Rothstein et al., 1992).All these samples contained endozepine-4 concentrations high enough to account for the stuporous state of the patients.The other 11 cases of idiopathic recurring stupor were diagnosed on the basis of clinical criteria alone since they were identical to the patients with documented endozepine-4 accumulation.All presented the same clinical picture and EEG pattern (low amplitude, unreactive, background activity) during stupor and a reversal of the stuporous state after flumazenil administration (awakening and EEG normalization).Again, toxicological immunoenzymatic tests failed to detect even traces of synthetic benzodiazepines.We subsequently investigated a cluster of nine patients presenting recurrent stuporous attacks with almost simultaneous onset which had occurred in a restricted rural area near Lucca in Tuscany.Except for the extraordinary clustering in time and space, these patients were in all respects similar to the sporadic idiopathic recurring stupor patients previously encountered by us.The stuporous episodes in fact lasted 1-2 days and were followed by confusion and amnesia; ictal EEG was characterized by the typical low voltage, 13-14 Hz background activity, and flumazenil administration led to transient awakening and EEG normalization.Routine toxicological immunoenzymatic assay had ruled out the presence of benzodiazepines.However, in the meantime, a newer more specific toxicological assay, liquid chromatography-mass spectrometry, had become available to us.Because of the unusual epidemiology, we used this technique to re-analyse blood samples from the Tuscan patients.This time we detected in the blood of all of these patients the benzodiazepine lorazepam which had not

Recurring stupor can be caused by repeated metabolic, toxic or structural brain disturbances. Recently, cases of recurring stupor, with fast EEG activity were shown to display increased endogenous benzodiazepine-like activity during the episodes of stupor. Patients with recurring stupor underwent extensive metabolic and toxicologic screening, EEG and brain imaging. Endozepines and exogenously administered benzodiazepines were assayed in plasma and CSF by means of mass spectrometry. Flumazenil, a benzodiazepine antagonist was administered and the behavioural and EEG responses monitored. Treatment with oral flumazenil was attempted in selected cases. Twenty patients were found with recurring stupor. Episodes had begun between ages 18 and 67 years, and in nine patients, had disappeared spontaneously after 4-6 years with symptoms. Stupor lasted hours or days. Onset of the episodes and frequency were unpredictable. Patients were normal between attacks. Stupor was characterized by initial drowsiness, staggering and behavioural changes, followed by deep sleep and spontaneous recovery with post-ictal amnesia. Biochemical screening and brain imaging were always normal. Ictal EEG showed fast background activity, and flumazenil transiently awoke the patients and normalized the EEG. In the nine cases examined, endozepine-4 levels were increased during the stupor. Oral flumazenil reduced the frequency of the attacks in three of these nine patients. Recurring episodes of stupor may be due to increased endozepine-4. We propose the term 'endozepine stupor' for such episodes. Endozepine-4 is an endogenous ligand for the benzodiazepine recognition site at the GABAA receptor, with unknown molecular structure.

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake‐sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio‐dorsal and anterior‐ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mai seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein‐gene.