Calcification of the basal ganglia: computerized tomography and clinical correlation

During a 1-year period, 4219 consecutive computerized tomograms (CT) were reviewed for basal ganglia calcification; 14 patients with such calcification were identified. Calcifications on CT scan were bilateral in 12 of these cases and unilateral in 2. All bilateral calcifications were symmetric. The globus pallidus was the site of calcification in 13 of the 14 patients. Bilateral dentate nucleus calcification was seen in one patient. Skull radiograms were normal in all but one. Patients had diverse symptoms that were often explained by other findings, suggesting that calcifications may be coincidental and that basal ganglia calcification may not be a nosologic entity. Disturbances of calcium metabolism were not found in these patients, minimizing the pathophysiologic significance of altered calcium metabolism and the need for extensive endocrinologic evaluation. The finding of basal ganglia calcification alone does not justify invasive diagnostic procedures. Extrapyramidal signs may be associated with basal ganglia calcification; parkinsonism associated with basal ganglia calcification differs from idiopathic parkinsonism in being resistant to levodopa therapy.     

Cerebellar calcification on computerized tomography

Cerebellar calcification on CT scan was observed in five patients over a two-year period. It was located bilaterally and symmetrically in the dentate nucleus in all 5 patients and in the cerebellar vermis in one. Calcifications of the basal ganglia and cerebral cortex were associated in two cases each. Skull radiography did not reveal the cerebellar calcifications, and serum calcium levels were normal in all patients. None had symptoms or signs of cerebellar dysfunction, and they had a variety of different clinical diagnoses. Cerebellar calcification may be a form of benign intracerebral calcification.     

A case of pseudohypoparathyroidism with intracerebral calcification

Intracerebral calcifications, especially in the basal ganglia, are observed in many kinds of diseases. A 41-year-old man is reported, who suffered from an acute epidural hematoma and underwent surgery to remove the hematoma. We detected very extensive intracerebral calcification on CT. Laboratory findings revealed hypocalcemia and hyperphosphatemia. General physical examination revealed characteristics typical of pseudohypoparathyroidism. The patient was diagnosed as having pseudohypoparathyroidism type I by the Ellsworth-Howard test. Since the advent of CT, the incidence of basal ganglia calcification has increased. CT is 5 to 15 times more sensitive than skull radiography in the detection of intracerebral calcification. Although many pathological states can cause basal ganglia calcification, most of the calcifications which are recognized on CT scans are physiological. But in cases in which basal ganglia calcifications are recognized also on plain radiographs, various kinds of symptoms including ones of basal ganglia origin are often recognized, and calcifications often extend to regions other than basal ganglia, eg. cerebellum, thalamus, etc. Pseudohypoparathyroidism is a rare disease which presents hypocalcemia, some characteristic physical appearances, and dementia. It is important to decide whether further examinations are necessary or not, when basal ganglia calcification is recognized incidentally on CT scan.     

Psychopathological alterations in cases of symmetrical basal ganglia sclerosis

Psychopathological alterations caused by symmetrical basal ganglia sclerosis of different etiologies are described, involving cases with parathyroid gland/hormone dysfunction (some of them familial), patients after thyroidectomy, and patients with basal ganglia calcification of uncertain etiology. Initial symptomatology in a group of 62 patients is reported; chronic symptoms in another group of 35 patients were evaluated. Estimates of volume of the basal ganglia calcifications were made, in addition to precise topographical localizations by CT. In 40% the initial symptoms noted were psychiatric, compared with 50% who first presented neurological symptoms. In the group of chronic cases practically all showed intellectual impairment. There was a marked preponderance of organic affective syndromes (initially 21%, chronic 65%): the affective chronic patients can be subdivided into 37% depressive, 20% bipolar, 11% manic cases. We could find no direct relationships with regard to etiology, localization, volume or symptoms, except that extensive calcifications occur after parathyroid hormone deficiencies due to thyroidectomy and lead to more severe mental deterioration.     

Substance P receptors are differentially affected in Parkinson's and Alzheimer's disease

Summary We have quantified by receptor autoradiography the number of NK1 receptors, using [¹²⁵I] Bolton-Hunter labeled substance P, in striatum and pallidum (internal (GPi) or external (GPe) segment) of patients suffering from Alzheimer's (AD) and Parkinson's disease (PD). When compared to non-neurologic controls, a significant increase in the number of NK1 sites has been observed in the striatum of PD patients. No significant differences were observed for the GPi and GPe. We observed no significant differences from controls in the number of NK1 sites in the striatum and pallidum of AD cases. However, the number of NK1 sites in the striatum of AD patients was significantly lower than that of PD patients. These results show that the expression of NK1 receptors in the basal ganglia is affected in PD.     

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease

We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology.     

Substance P-like immunoreactivity in brains with pathological features of Parkinson's and Alzheimer's diseases

Substance P is found in both the basal ganglia and cerebral cortex in mammalian brain. In the present study postmortem concentrations of substance P-like immunoreactivity (SP-LI) were measured in the globus pallidus, substantia nigra and 22 cortical regions in a group of demented patients with neuropathological features of both Parkinson's disease (PD) and Alzheimer's disease (AD), and from neurologically normal controls. There were no significant changes in the globus pallidus but concentrations were significantly reduced by 44% in the substantia nigra compacta in the PD patients. In cerebral cortex small (20-30%) significant reductions of SP-LI were found in the PD patients in 7 of 22 cortical regions examined. These results are similar to changes found in AD alone and provide further evidence that the dementia of PD is frequently related to the coincidence of PD and AD.     

Prevalence and vascular risk factors of basal ganglia calcifications in patients at risk for cerebrovascular disease

Background and purposeRisk factors for and meaning of basal ganglia calcifications outside Fahr syndrome are poorly understood. We aimed to assess the prevalence of basal ganglia calcifications and the association with vascular risk factors.Materials and methods1133 patients suspected of acute ischemic stroke from the Dutch acute stroke (DUST) study who underwent thin-slice unenhanced brain CT were analyzed. Basal ganglia calcifications were scored bilaterally as absent, mild (dot), moderate (multiple dots or single artery) and severe (confluent). Uni- and multivariable logistic regression analysis was used to determine possible risk factors (age, gender, history of stroke, smoking, hypertension, diabetes mellitus, hyperlipidemia, body mass index (BMI), renal function and family history of cardiovascular disease under 60 years) for presence of basal ganglia calcifications and ordinal regression analysis for severity of basal ganglia calcifications.ResultsMean age was 67.4 years (SD: 13.8), 56.8% were male. 337 (29.7%) patients had basal ganglia calcifications, of which 196 (58%) were mild, 103 (31%) moderate, 38 (11%) severe. In multivariable logistic regression analysis, age (OR: 1.02, 95% CI 1.01–1.03, P < 0.01) and BMI (OR: 0.95, 95% CI 0.91–0.98, p 0.01) were significantly associated with the presence of basal ganglia calcifications. Ordinal regression analysis gave comparable results. Age (OR: 1.02, 95% CI 1.01–1.03, P < 0.01) and BMI (OR: 0.95, 95% CI 0.92–0.99, P 0.01) were significantly associated with severity of basal ganglia calcifications.ConclusionsIn this study with patients suspected of acute ischemic stroke, basal ganglia calcifications were common and significantly associated with older age and lower BMI.     

Nerve growth factor receptor immunoreactivity within the nucleus basalis (Ch4) in Parkinson's disease: reduced cell numbers and co-localization with cholinergic neurons.

In a effort to better define the role cholinergic basal forebrain neurons play in human cognitive processes, a quantitative assessment of cholinergic nucleus basalis (Ch4) neurons was carried out in 5 patients with Parkinson's disease (PD; 4 non-demented and 1 demented) and 4 age-matched controls using nerve growth factor (NGF) receptor immunohistochemistry as a direct marker for cholinergic basal forebrain neurons. Virtually all (greater than 90%) NGF receptor-containing neurons co-localize with the specific cholinergic marker choline acetyltransferase (ChAT) within the nucleus basalis in PD. NGF receptor-containing neurons were reduced on average by 68% (range 38.6-87.4%) in the non-demented PD cases and by 88.6% in the demented PD patient. Loss of these neurons was heterogeneous across the nucleus basalis subfields with only the anterolateral and posterior Ch4 subregions demonstrating significant reductions of NGF receptor-containing neurons. The reduction in NGF receptor-containing neurons was accompanied by a decrease of acetylcholinesterase (AChE) containing fibers within temporal cortex and in some cases ChAT immunoreactivity in the basolateral amygdaloid nucleus. The numerous non-cholinergic AChE-rich pyramidal cells which were observed throughout the cortex of aged controls were also virtually absent in PD. Although PD patients exhibited severe reductions in Ch4 neurons, few neuritic plaques or neurofibrillary tangles were observed within the PD cortex or Ch4 and similar numbers of these AD-type pathologies were seen within age-matched controls. This suggests that Ch4 degeneration alone is not sufficient to induce such cytoskeletal abnormalities and that the neuron loss seen within Ch4 in AD and PD may be mediated through different processes. These results, coupled with the extensive basic and clinical literature linking acetylcholine and memory function, further indicate that Ch4 degeneration without additional cortical and/or subcortical pathology is not sufficient to impair cognition in PD. Perhaps additional pathology must be superimposed upon nucleus basalis degeneration to induce dementia in humans.     

Immunohistochemical study of the striatal efferents and nigral dopaminergic neurons in parkinsonism-dementia complex on Guam in comparison with those in Parkinson's and Alzheimer's diseases.

A comparative topographical immunohistochemical analysis was performed on the basal ganglia (including the substantia nigra) in Guamanian parkinsonism-dementia complex, idiopathic Parkinson's disease (PD), and Alzheimer's disease (AD). The striatal projection neurons and their efferent fibers were examined by using antibodies to calcineurin, methionine-enkephalin, and substance P. Tyrosine hydroxylase served as a marker for nigrostriatal dopaminergic neurons. The basal ganglia of patients with parkinsonism-dementia complex reacted strongly with all of the antibodies and the reaction products exhibited a normal distribution pattern. These findings suggest that the striatal output system is well preserved in patients with this disease. Similar results were obtained in patients with AD or PD. However, as compared to the patients with AD or PD, patients with parkinsonism-dementia complex showed severe reduction (greater than 90%) in the number of dopaminergic neurons in both the lateral and the medial portions of the substantia nigra. In view of the functional cortico-subcortical loops, these findings could explain the parkinsonian features and in part the cognitive impairment that occur in parkinsonism-dementia complex on Guam.     

Differential memory and executive functions in demented patients with Parkinson''s and Alzheimer''s disease.

Selected aspects of verbal memory and executive function were compared in 11 demented Parkinson's disease (PD) patients and 11 Alzheimer's disease (AD) patients with equally severe dementia, with 11 healthy controls matched for age and education. Semantic and episodic memory were impared in all patients compared with controls, but to a relatively greater degree in AD patients than in those with PD. In contrast, demented PD patients were relatively more compromised on executive tasks. These findings, taken in the context of the neuropathological and neurochemical overlap between demented PD and AD patients, suggest that differences in neurobehavioural patterns in patients with these diseases are relative, rather than absolute.     

Brain iron deposition fingerprints in Parkinson's disease and progressive supranuclear palsy

It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2' maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2' values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2' values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients.     

Encephalopathy with calcifications of the basal ganglia in children. A reappraisal of Fahr's syndrome with respect to 14 new cases

Calcifications of the basal ganglia are described under the heading of "Fahr's syndrome". The clinical pattern is variable and the syndrome may be sporadic or familial. This study describes a personal series of 14 cases of encephalopathy with calcification of the basal ganglia and reviews the literature cases. A four-group classification is proposed. The first group includes encephalopathy, microcephaly, dwarfism, retinal degeneration or optic atrophy, symmetrical patchy demyelination with calcifications and probable autosomal recessive inheritance. Some cases have an early onset, a rapid evolution. Others have a later onset, longer course and retinal degeneration. In the second group, the children suffer from a congenital encephalopathy or a cerebral palsy without clear deterioration, without short stature, ocular impairment or persistent CSF abnormalities. This group has not been reported in the literature. The cases do not seem to be genetic. The precise cause in unknown but a sporadic non progressive anoxo-ischemic, or viral prenatal disease is suggested. In the third group, the association of encephalopathy, microcephaly, and persistent CSF lymphocytosis, has a high recurrence rate. The pathogenesis is still a matter of dispute. The fourth group is characterized by autosomal dominant calcifications of the basal ganglia with or without neurological abnormalities. Finally calcium metabolism disorders and mitochondrial encephalomyopathy may be associated with calcifications of the basal ganglia.     

Resting state functional connectivity of the subthalamic nucleus in Parkinson's disease assessed using arterial spin‐labeled perfusion fMRI

Neurophysiological changes within the cortico‐basal ganglia‐thalamocortical circuits appear to be a characteristic of Parkinson's disease (PD) pathophysiology. The subthalamic nucleus (STN) is one of the basal ganglia components showing pathological neural activity patterns in PD. In this study, perfusion imaging data, acquired noninvasively using arterial spin‐labeled (ASL) perfusion MRI, were used to assess the resting state functional connectivity (FC) of the STN in 24 early‐to‐moderate PD patients and 34 age‐matched healthy controls, to determine whether altered FC in the very low frequency range of the perfusion time signal occurs as a result of the disease. Our results showed that the healthy STN was functionally connected with other nuclei of the basal ganglia and the thalamus, as well as with discrete cortical areas including the insular cortex and the hippocampus. In PD patients, connectivity of the STN was increased with two cortical areas involved in motor and cognitive processes. These findings suggest that hyperconnectivity of the STN could underlie some of the motor and cognitive deficits often present even at early stages of the disease. The FC measures provided good discrimination between controls and patients, suggesting that ASL‐derived FC metrics could be a putative PD biomarker. Hum Brain Mapp 36:1937–1950, 2015. © 2015 Wiley Periodicals, Inc .     

Natural killer cell proliferation and circulating cytokines in patients with bilateral basal ganglia calcification

Ten adult patients with symmetrical calcifications in the bilateral basal ganglia (diagnosed as physiological calcifications) were analyzed for lymphocyte subsets and cytokines. Increased number of natural killer (NK) cells were identified in the peripheral blood of seven patients by lymphocyte subset analysis. Tumor necrosis factor-alpha was detected in the sera of five patients and interferon-gamma was detected in one patient. In summary, NK cell propagation and circulating cytokines, particularly tumor necrosis factor-alpha, may be involved in the etiology of basal ganglia calcification.     

Time estimation in Parkinson's disease and degenerative cerebellar disease

With functional MRI, we recently identified fronto-cerebellar activations in predicting time to reach a target and basal ganglia activation in velocity estimation, that is, small interval assessment. We now tested these functions in patients with Parkinson's disease (PD) and degenerative cerebellar ataxia. They watched a ball that repeatedly appeared, moved, and disappeared. Velocity, stop locations, and predicted target locations as well as time to reach a target were indicated. Compared with controls, PD patients showed impaired velocity estimation (momentary mode) whereas temporal prediction was selectively impaired in cerebellar ataxia patients. The latter highlights feed-forward processing within fronto-cerebellar circuitry. Impaired velocity estimation in PD fits the concept of a basal ganglia clock function.     

Pallidal gap junctions‐triggers of synchrony in Parkinson's disease?

Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin‐36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin‐36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin‐36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin‐36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia. © 2014 International Parkinson and Movement Disorder Society     

A prospective study of patients with CT detected pallidal calcifications.

In a prospective study pallidal calcification was detected in 30 of 1478 (2%) adult patients, on CT brain scans. In 8 cases (26%), the calcifications were detected either years after, or during the course of, conditions known to cause basal ganglia calcification, including AIDS in four cases. Eight patients (three with AIDS) had disturbances of calcium and phosphorus metabolism. It was concluded that: a) pallidal calcification is not uncommon and aetiological factors may be recognised more often than previously reported; b) AIDS is emerging as a significant cause of pallidal calcification in young adults, and c) in AIDS and other conditions, abnormal calcium and phosphate metabolism may act in conjunction with local vascular changes.     

Cerebello-basal ganglia connectivity fingerprints related to motor/cognitive performance in Parkinson's disease

IntroductionThe role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD.MethodsWe included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition.ResultsThe PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10⁻³), although partially mediated by motor performance (p = 8.2 × 10⁻³).ConclusionFC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD.     

Language recovery following subthalamic nucleus stimulation in Parkinson's disease

Neuropsychological consequences of stimulation of the subthalamic nucleus for treatment of drug-resistant Parkinson's disease (PD) have been studied previously. However, no detailed investigations of linguistic function modifications have been carried out. We studied four consecutive patients with PD who underwent chronic bilateral stimulation of the subthalamic nuclei. Neuropsychological and linguistic evaluations were performed before and 2 weeks after surgery. Linguistic abilities were studied also 1 year after surgery with stimulators both off and on. Intraphrasal hesitation pauses, phonemic paraphasias and morpho-syntactic errors were significantly reduced and lexical retrieval improved with stimulation of the subthalamic nuclei. Implicit linguistic phenomena, mainly occurring within basal ganglia circuitry, benefited by recovery of functional equilibrium within basal nuclei and between overall basal ganglia circuitry and cerebral cortex.