Cholinesterase inhibitors in the clinical management of Alzheimer's disease: importance of early and persistent treatment.

Alzheimer's disease is a neurodegenerative disease that greatly affects the quality of life of patients and their caregivers and places a heavy cost burden on the healthcare system. The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine have a central role in the treatment of Alzheimer's disease in the mild to moderate stages. Clinical trials with ChEIs have demonstrated therapeutic benefits for symptoms of cognition, function and behaviour across the disease course. These agents are most effective when started early in the disease course and used persistently, without treatment gaps. Early recognition of Alzheimer's disease and a global evaluation of treatment effectiveness are therefore essential. This article identifies barriers to early recognition and effective care of patients with Alzheimer's disease and discusses practical strategies to overcome them.

"Organic brain syndromes": an empirical study and critical review.

The authors found that all but 3 of 80 randomly chosen patients in a Veterans Administration hospital who had been given a primary nonspecific neuropsychiatric diagnosis (organic brain syndrome, organic psychosis, chronic brain syndrome, etc.) could be assigned to specific diagnostic categories. Diagnosis was based on chart review and thorough neurological and clinical evaluation. Senile and alcoholic dementia and Korsakoff's syndrome were seen most often, and 15% of the patients were diagnosed as having functional disorders of the mental state. The authors review the organic brain syndrome diagnosis in light of this and other evidence. They believe that fractionation into more specific diagnoses is essential to further understanding of this group of diseases. Use of the general term can result in inappropriate or no treatment; further, it hampers essential psychological, pharmacological, and biomedical research on these disorders.

Intrinsic connections and architectonics of the superior temporal sulcus in the rhesus monkey.

The intrinsic connections of the superior temporal sulcus (STS) in the rhesus monkey were studied by anterograde and retrograde tracer techniques and correlated with a reevaluation of cortical cytoarchitecture. The polymodal region in the upper bank (area TPO) is divisible into four rostral-to-caudal architectonic sectors, exhibiting increasing degrees of laminar differentiation and cellularity as one proceeds caudally. These sectors, including the sulcal proisocortex (area Pro), are tied together in a sequence of reciprocal connections. Each rostrocaudal sector of area TPO also has reciprocal connections with the laterally adjacent area TAa, at the upper rim of the sulcus, and medially adjacent areas PGa and IPa, near the depth. A similar arachitectonic/connectional organization exists for unimodal vision-related cortex in the lower bank of the STS. Here a rostrocaudal sequence of reciprocal connections unites area Pro, rostral and caudal divisions of area TEa, and the extrastriate visual area OAa (MT). Area TEa also has reciprocal connections with adjacent segments of area TEm laterally, at the lower rim of the sulcus, and area IPa, medially, in the depth. In both upper and lower banks, caudal-to-rostral "forwardgoing" connections begin in supragranular layers of cortex and terminate in and around layer IV. Reciprocal, "backgoing" connections take origin from cells in infragranular layers and terminate mainly over the first layer of the caudally adjacent target zone. Orthogonally directed, "side-to-side" projections originate in both supra- and infragranular layers and terminate diffusely over all layers of cortex.

Frontal lobe connections of the superior temporal sulcus in the rhesus monkey.

The frontal lobe connections of different architectonic areas of the superior temporal sulcus (STS) in the rhesus monkey were investigated with the aid of both anterograde and retrograde tracing techniques. The proisocortical area in the rostralmost STS connects with proisocortical regions on the ventral and medial surfaces of the frontal lobe. The frontal lobe projections of polymodal cortex (area TPO) in the upper bank of the STS are organized according to the rostral-to-caudal topography of the sulcus. Rostral TPO interconnects with ventral (areas 13, 12, 11, and 14), medial (areas 24, 32, 14, and 9), and lateral (areas 10, 12, and 46) sectors of the frontal lobe. The mid-portion of polymodal cortex projects to, and receives fibers from, rostral subdivisions of lateral prefrontal cortex, viz. dorsal area 46, areas 9 and 10, whereas the caudal segment of TPO has reciprocal connections with caudal subdivisions (areas 46, 8, and 6) of the lateral frontal lobe. Visual-related zones (areas TEa and TEm) in the rostral lower bank of the STS have connectional relationships with orbitofrontal areas 11 and 12 and lateral frontal areas 46 and 8. A presumed somatic sensory-related area in the rostral depth of the STS (area IPa) projects to orbital (areas 11 and 14) and lateral (areas 46, 10, and 12) sectors of the frontal lobe.

Post-rolandic cortical projections of the superior temporal sulcus in the rhesus monkey.

The efferent connections of different cytoarchitectonic areas of the superior temporal sulcus (STS) in the rhesus monkey with parieto-temporo-occipital cortex were investigated using autoradiographic methods. Four rostral-to-caudal subdivisions of cortex (area TPO) in the upper bank of the STS have distinct projection patterns. Rostral sectors (areas TPO-1 and -2) project to the rostral superior temporal gyrus (areas Ts1, Ts2, and Ts3), insula of the Sylvian fissure, and parahippocampal gyrus (perirhinal and prorhinal cortexes, areas TF, TH, and TL); caudal sectors (TPO-3 and -4) project to the caudal superior temporal gyrus (areas paAlt and Tpt), supratemporal plane (area paAc), circular sulcus of the Sylvian fissure (area reIt), as well as medial paralimbic (areas 23, 24, and retrosplenial cortex) and extrastriate (areas 18 and 19) cortexes. Area TPO-1 does not project to the parietal lobe; area TPO-2 projects to the inferior parietal lobule; area TPO-3 to the lower bank of the intraparietal sulcus (IPS) (area POa); and area TPO-4 to medial parietal cortex (area PGm). Vision-related cortex (area TEa) in the rostral lower bank of the STS sends fibers to the rostral inferotemporal region (areas TE1, -2, and -3) and parahippocampal gyrus (perirhinal cortex, areas TF and TL). Visual zones in the caudal lower bank and depth of the sulcus (area OAa, or MT and FST) project to the caudal inferotemporal region (areas TE3 and TEO), lateral preoccipital region (area V4), and lower bank of the IPS (area POa). A zone in the rostral depth of the STS (area IPa) projects to the rostral inferotemporal region, parahippocampal gyrus, insula of the Sylvian fissure, parietal operculum, and lower rim of the IPS (area PG). STS projections to parieto-temporo-occipital cortex have "feedforward," "feedbackward," and "side-to-side" laminar patterns of termination similar to those of other cortical sensory systems. The differential connectivity supports the cytoarchitectonic parcellation of the STS and suggests functional heterogeneity.

Parietal, temporal, and occipital projections to cortex of the superior temporal sulcus in the rhesus monkey: a retrograde tracer study.

The afferent cortical connections of individual cytoarchitectonic areas within the superior temporal sulcus (STS) of the rhesus monkey were studied by retrograde tracer techniques, including double tracer experiments. Rostral superior temporal polysensory (STP) cortex (area TPO-1) receives input from the rostral superior temporal gyrus (STG), cortex of the circular sulcus, and parahippocampal gyrus (PHG) (areas 35, TF, and TL). Mid-STP cortex (areas TPO-2 and -3) has input from the mid-STG, cortex of the mid-circular sulcus, caudal inferior parietal lobule (IPL), cingulate gyrus (areas, 23, 24, retrosplenial cortex), and mid-PHG (areas 28, TF, TH, and TL). Caudal STP cortex (area TPO-4) has afferent connections with the caudal STG, cortex of the caudal insula and caudal circular sulcus, caudal IPL, lower bank of the intraparietal sulcus (IPS), medial parietal lobe, cingulate gyrus, and mid- and caudal PHG (areas TF, TH, TL; prostriate area). The most rostral cortex of the lower bank of the STS (areas TEa and TEm), a presumed visual association area, receives input from the rostral inferotemporal (IT) region; more caudal portions of areas TEa and TEm have afferent connections with the caudal IT region, PHG, preoccipital gyrus, and cortex of the lower bank of the IPS.

Intrinsic connections and architectonics of posterior parietal cortex in the rhesus monkey.

By means of autoradiographic and ablation-degeneration techniques, the intrinsic cortical connections of the posterior parietal cortex in the rhesus monkey were traced and correlated with a reappraisal of cerebral architectonics. Two major rostral-to-caudal connectional sequences exist. One begins in the dorsal postcentral gyrus (area 2) and proceeds, through architectonic divisions of the superior parietal lobule (areas PE and PEc), to a cortical region on the medial surface of the parietal lobe (area PGm). This area has architectonic features similar to those of the caudal inferior parietal lobule (area PG). The second sequence begins in the ventral post/central gyrus (area 2) and passes through the rostral inferior parietal lobule (areas PG and PFG) to reach the caudal inferior parietal lobule (area PG). Both the superior parietal lobule and the rostral inferior parietal lobule also send projections to various other zones located in the parietal opercular region, the intraparietal sulcus, and the caudalmost portion of the cingulate sulcus. Areas PGm and PG, on the other hand, project to each other, to the cingulate region, to the caudalmost portion of the superior temporal gyrus, and to the upper bank of the superior temporal sulcus. Finally, a reciprocal sequence of connections, directed from caudal to rostral, links together many of the above-mentioned parietal zones. With regard to the laminar pattern of termination, the rostral-to-caudal connections are primarily distributed in the form of cortical "columns" while the caudal-to-rostral connections are found mainly over the first cortical cell layer.

Neurochemical and connectional organization of the dorsal pulvinar complex in monkeys.

To investigate the organization of the dorsal pulvinar complex, patterns of neurochemical staining were correlated with cortico-pulvinar connections in macaques (Macaca mulatta). Three major neurochemical subdivisions of the dorsal pulvinar were identified by acetylcholinesterase (AChE) histochemistry, as well as immunostaining for calbindin-D(28K) and parvalbumin. The dorsal lateral pulvinar nucleus (PLd) was defined on histochemical criteria as a distinct AChE- and parvalbumin-dense, calbindin-poor wedge that was found to continue caudally along the dorsolateral edge of the pulvinar to within 1 mm of its caudal pole. The ventromedial border of neurochemical PLd with the rest of the dorsal pulvinar, termed the medial pulvinar (PM), was sharply defined. Overall, PM was lighter than PLd for AChE and parvalbumin and displayed lateral (PMl) and medial (PMm) histochemical divisions. PMm contained a central "oval" (PMm-c) that stained darker for AChE and parvalbumin than the surrounding region. The neurochemically defined PLd was labeled by tracer injections in the inferior parietal lobule (IPL) and dorsolateral prefrontal cortex but not the superior temporal gyrus (STG). Label within PMl was found after prefrontal and IPL and, to a lesser extent, after STG injections. The PMm was labeled after injections of the IPL and STG, but only sparsely following prefrontal injections. The histochemically distinct subregion or module of PMm, PMm-c, was labeled only by STG injections. Overlapping labeling was found in dorsal pulvinar divisions PMl and PLd following paired IPL/prefrontal, but not IPL/STG or these particular STG/prefrontal, injections. Thus, PLd may be a visuospatially related region whereas PM appears to contain several types of territories, some related to visual or auditory inputs, and others that receive directly converging input from posterior parietal and prefrontal cortex and may participate in a distributed cortical network concerned with visuospatial functions.

Chemoarchitectonics and corticocortical terminations within the superior temporal sulcus of the rhesus monkey: evidence for subdivisions of superior temporal polysensory cortex.

Cortex of the upper bank of the superior temporal sulcus (STS) in macaque monkeys, termed the superior temporal polysensory (STP) region, corresponds largely to architectonic area TPO and is connectionally distinct from adjacent visual areas. To investigate whether or not the STP region contains separate subdivisions, immunostaining for parvalbumin and neurofilament protein (using the SMI-32 antibody) was compared with patterns of corticocortical terminations in the STS. Chemoarchitectonic results provided evidence for three caudal-to-rostral subdivisions: TPOc, TPOi, and TPOr. Area TPOc was characterized by patchy staining for parvalbumin and SMI-32 in cortical layers IV/III and III, respectively. Area TPOi had more uniform chemoarchitectonic staining, whereas area TPOr had a thicker layer IV than TPOi. The connectional results showed prefrontal cortex in the location of the frontal eye fields (area 8) and dorsal area 46 projected in a columnar pattern to all cortical layers of area TPOc, to layer IV of TPOi, and in a columnar fashion, with a moderate increase in density in layer IV, to TPOr. In TPOc, columns of frontal connections showed a periodicity similar to that of the SMI-32 staining. The caudal inferior parietal lobule (area 7a) and superior temporal gyrus projected to each subdivision of area TPO, displaying either panlaminar or fourth-layer terminations. In addition to STP cortex, parvalbumin and SMI-32 immunostaining allowed identification of caudal visual areas of the STS, including MT, MST, FST, and V4t. These areas received first- and sixth-layer projections from prefrontal cortex and area 7a.

Overlapping and nonoverlapping cortical projections to cortex of the superior temporal sulcus in the rhesus monkey: double anterograde tracer studies.

To examine how fibers from functionally distinct cortical zones interrelate within their target areas of the superior temporal sulcus (STS) in the rhesus monkey, separate anterograde tracers were injected in two different regions of the same hemisphere known to project to the STS. Paired injections were placed in dorsal prearcuate cortex and the caudal inferior parietal lobule (IPL), interconnected regions that are part of a hypothesized distributed network concerned with visuospatial analysis or directed attention; in a presumed auditory region of the superior temporal gyrus (STG) and in extrastriate visual cortex, the caudal IPL and lower rim of the intraparietal sulcus; and in dorsal prearcuate cortex and the STG. Overlapping and nonoverlapping projections were then examined in STS visual and polysensory areas. Prefrontal and parietal fibers directly overlapped extensively in area MST and all subdivisions of presumed polysensory cortex (areas TPOc, TPOi, and TPOr), although nonoverlapping connections were also found. Although STG and IPL fibers targeted all TPO subdivisions, connections were to nonoverlapping, but often adjacent, columns. Paired prefrontal and STG injections revealed largely nonoverlapping vertical columns of connections but substantial overlap within layers VI and I or areas TPOc and TPOi. The findings suggest that area TPO contains differently connected modules that may maintain at least initial segregation of visual versus auditory inputs. Other modules within area TPO receive directly converging input from the posterior parietal and the prefrontal cortices and may participate in a distributed cortical network concerned with visuospatial functions.

Fingerprint pattern differences in early- and late-onset primary degenerative dementia.

The frequency distribution of major fingerprint patterns (ulnar or radial loops, arches, and whorls) was studied in 47 men with early-onset (aged, less than or equal to 64 years), 35 men with late-onset primary degenerative dementia (aged, greater than or equal to 65 years), and 100 control subjects (aged, 29 to 78 years). Patients with an early, but not those with a late, onset of dementia had significantly more ulnar loops than the control group. This finding, along with other data, is interpreted as indicating that there may be a biologic basis for distinguishing these two forms of dementia.

A comparison of clinical features in early- and late-onset primary degenerative dementia. One entity or two?

The prevalence of a number of clinical features occurring in patients with early- (before age 65) and late-onset primary degenerative dementia of the Alzheimer type (PDDAT) are compared. The data from a total of 65 patients demonstrated a greater prevalence of language disturbance, a disproportionate number of left-handers, and a much shorter relative survival time in the early-onset group. Taken together with other data, these findings indicate a degree of heterogeneity in the clinical features of patients with PDDAT and suggest a possible heightened selective vulnerability of the left hemisphere in early-onset cases. We interpret the data as raising the possibility that the current view of PDDAT as a unitary disorder may not be entirely valid.

The temporal pattern of retrograde amnesia in Korsakoff's disease.

A multiple-choice questionnaire about well-known public events of the past 50 years, grouped with respect to time, was administered to 11 alcoholic patients with Korsakoff's disease and to 50 normal individuals of comparable age and background. Normal persons perform quite well on questions of the recent past and fall off only slightly when tested for more remote memories. In contrast, patients with Korsakoff's disease do very poorly in remembering recent events but improve to normal levels when memories become more remote. This confirms classical clinical observation and raises some important points about the mechanism of memory.

Left-handedness in early and late onset dementia.

Sixty-five men with the diagnosis of dementia of the Alzheimer type were divided into two groups, according to age at onset of dementia before or after 65 years. A handedness questionnaire was then completed for each patient. There was a significantly higher prevalence of left-handedness in the early, as compared with the late, onset group. Taken together with other data, this finding suggests that presenile dementia (Alzheimer's disease) and senile dementia "of the Alzheimer type " may not be biologically identical.

Risk factors for Alzheimer's disease: a case-control study.

A case-control study was conducted to assess personal and family medical history and the appearance of Alzheimer's disease. We compared 98 men with clinically diagnosed Alzheimer's disease and 162 controls, matched by sex, year of birth, and town of residence. Family history of dementia and personal history of depression were more frequent in patients. The number of cigarettes smoked was greater in cases.

Human thalamus: neurochemical mapping of inferior pulvinar complex.

The primate pulvinar connects with the entire array of known visual areas and is postulated to play a role in selective visual attention. Recently, five separate neurochemical subdivisions of a region termed the inferior pulvinar (PI) complex were identified in monkeys. In the present study, similar histochemical procedures were applied to map the extent of the PI complex in humans. Acetylcholinesterase histochemistry and cytochrome oxidase staining demarcated four histochemical zones in human pulvinar, corresponding to the medial, central, lateral and lateral-shell (PI(M), PI(C), PI(L), and PI(L-S)) divisions of the PI complex in monkeys.

Afferent cortical connections and architectonics of the superior temporal sulcus and surrounding cortex in the rhesus monkey.

A cyto- and myeloarchitectonic parcellation of the superior temporal sulcus and surrounding cortex in the rhesus monkey has been correlated with the pattern of afferent cortical connections from ipsilateral temporal, parietal and occipital lobes, studied by both silver impregnation and autoradiographic techniques. The results suggest a definite organization of this region. Subdivisions of the superior temporal gyrus are tied together in a precise sequence of connections beginning in primary auditory cortex. The inferotemporal area, which receives input from the lateral peristriate region, can also be divided into architectonic divisions, each of which is related to the others in a specific pattern of connections. Within the superior temporal sulcus several distinct areas exist. In the caudal reaches is found a region that receives input from both primary visual and visual association cortices. This zone is similar to the Clare-Bishop area of the cat. Other superior temporal sulcus zones receive input primarily from one limited area of association cortex. A strip in the upper bank receives input exclusively from the superior temporal gyrus. An area in the rostral lower bank has afferent connections mainly with the inferotemporal area, and a zone in the depth of the superior temporal sulcus receives fibers from a region within the lower bank of the intraparietal sulcus. Two additional zones, in the upper bank of the superior temporal sulcus, however, have multiple sources of cortical input: the peristriate belt, inferior parietal lobule and caudal superior temporal gyrus.

Converging visual and somatic sensory cortical input to the intraparietal sulcus of the rhesus monkey.

A cyto- and myeloarchitectonic study reveals the presence of a distinct cortical zone ("area POa") in the lower bank of the intraparietal sulcus of the rhesus monkey. Using both autoradiographic and silver impregnation techniques, an analysis of cortical connections shows two overlapping projections to this sulcal zone. These come from (1) the middle portion of the preoccipital gyrus (area OA) and (2) the rostral inferior parietal lobule (area PF).

Conventional MRI volumetric measures of parietal and insular cortex in Alzheimer's disease.

1. Although volumetric Magnetic Resonance Imaging (MRI) studies suggest regional cortical atrophy in Alzheimer's disease (AD), only one prior study documented atrophy of the parietal and insular cortex (Foundas et al, 1993). 2. To further investigate this potential early marker of AD, the authors computed volumetric measures of these regions on conventional axial MRI sections in 25 patients with mild to moderate "probable AD" and 25 age- and sex-matched controls. 3. Regions of interest (ROIs) from T1-axial images (5mm) were scanned into a PCX format (400 dots/inch) and volumes of CSF fluid were calculated using an Autocad program. 4. AD patients showed significant parietal (p < .01) and insular (p < .002) atrophy as compared to controls. 5. These findings suggest that atrophy of the parietal and insular cortex may occur early in AD patients, and that certain quantitative measures on conventional MRI accurately discriminate AD patients from controls.

Diffuse Lewy body disease without amyloid plaques in a patient homozygous for apolipoprotein E allele epsilon 4: a case report.

A middle-aged woman developed extrapyramidal motor symptoms, personality and behavioral changes, and rapidly progressive dementia. Apolipoprotein E genotyping revealed that she was homozygous for the epsilon 4 allele. At autopsy, there were numerous cortical and subcortical Lewy bodies but no neuritic plaques (NPs) or neurofibrillary tangles (NFTs). This case, the first explicitly reported patient homozygous for the epsilon 4 allele having dementia of the Lewy body type (DLBT) without NPs and NFTs, reinforces the distinction between DLBT and dementia of the Alzheimer type. It calls into question the pivotal role of the epsilon 4 allele in the pathogenesis of NPs and NFTs but raises the possibility of its being an independent risk factor for the development of DLBT.